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

Abstract

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

Description

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

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

[0002] The S witch / 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),whereinR1is an optionally substituted bicycle selected from:whereinRais selected from: H, SO2-Ci-4alkyl, SO2-C2-4alkenyl, SO2-C2-4alkynyl, SO2-C1- 4haloalkyl, SO2-CH2CH2OH, SO2-CH2CH2OCH3, SO2-N(CH3)2, SO2-C3-6Cycloalkyl,, (C=O)CH3, and tetrahydropyranyl; Rbis selected from: H, Cl, F, Ci-4alkyl, CH2OH, and CH2NH2; each Rcis independently H, and Ci-4alkyl, or two R8members come together to form a Cs-ecycloalkyl; X is CH or N; Y is CH or N; wherein X and Y are not both N; n is one or two; and — is a single or double bond; oris independently H, halo, OH, or CH2OH; Z is Ci-salkyl, and n is 1 or 2; orR3is H or CH3; andR5ishalo; R° is H, Ci-4alkyl or halo; and Rpis H or Ci-4alkyl; and pharmaceutically acceptable salts and stereoisomers thereof.INCORPORATION BY REFERENCE

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

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. Where reference is made to a URL or other such identifier or address, it is understood that 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 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York.

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

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

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

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

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

[0027] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also 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 “Ci-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 “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”.

[0030] 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, - OCCH3, -OCCH2CH3 and -OCCH2CH2CH3. 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”.

[0031] 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 “haloCi-4alkyl”, “haloCi-ealkyl”, monohaloCi-4alkyl, monohaloCi-ealkyl, polyhaloCi-4alkyl, and polyhaloCi-ealkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi-4alkyl or haloCi-ealkyl may have one, two, three or more halogens. Examples of “haloalkyl” groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CEEF), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluorom ethylethyl (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.

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

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

[0034] The term “aromatic” refers to a planar ring having a delocalized 7t-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, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0035] The term “non-aromatic group” embraces, unless the context indicates otherwise, unsaturated ring systems without aromatic character, partially saturated and fully saturated heterocyclyl ring systems.

[0036] 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.

[0037] The term “fully saturated” refers to rings where there are no multiple bonds between ring atoms. Saturated heterocyclyl groups include piperidine, morpholine, thiomorpholine, piperazine. Partially saturated heterocyclyl groups include pyrazolines, for example 2- pyrazoline and 3-pyrazoline.

[0038] 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.)

[0039] The term “phenyl” represents the following moiety:

[0040] The term “cycloalkyl” 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. Cycloalkyls 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 groups include, but are not limited to, the following moieties:, and the like.

[0041] 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 withan 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:

[0042] 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.

[0043] The heterocyclyl rings also include bridged ring systems such as for example bridged cycloalkanes, such as for example norbornane (l,4endo-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, 3oxa-8-azabicyclo[3.2.1]octane; bridged piperazine rings such as for example 3,6diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4-ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992.

[0044] 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. Insuch polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic ring or by a non-aromatic ring.

[0045] 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. 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. 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.

[0046] 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.

[0047] 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).

[0048] The heterocyclyl and cycloalkyl rings also include bridged ring systems such as for example bridged cycloalkanes, such as for example norbornane (l,4endo-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, 3oxa-8- azabicyclo[3.2.1]octane; bridged piperazine rings such as for example 3,6diazabicyclo[3.1.1]heptane; bridged piperidine rings such as for example 1,4- ethylenepiperidine. For an explanation of the distinction between fused and bridged ring systems, see Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992.

[0049] 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 illustrations below.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure.

[0054] 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

[0055] 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.

[0056] 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.

[0057] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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 diseaseor 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.

[0064] 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.

[0065] 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.

[0066] 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).

[0067] 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

[0068] 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.

[0069] 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 presentdisclosure 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.

[0070] In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0071] 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.keto enol enolate

[0072] 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.

[0073] Where compounds described herein contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to the compounds described herein include all optical isomeric forms thereof (e.g., enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g., racemic mixtures) of two or more optical isomers, unless the context requires otherwise. When a compound has more than one chiral centre, and one chiral centre is indicated as having an absolute stereoconfiguration, the other chiral centre(s) include all optical isomeric forms, either as individual optical isomers, or mixtures (e.g., racemic mixtures) of two or more optical isomers, thereof, unless the context requires otherwise. The optical isomers may be characterized and identified by their optical activity (i.e. as + and - isomers depending on the direction in which they rotate plane polarized light, or d and I isomers) or they may be characterized in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4thEdition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.

[0074] 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 crystallisation, and then dissociating the salts to give the individual enantiomer of the free base.

[0075] 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.

[0076] 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; 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.

[0077] 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.

[0078] The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

[0079] 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.

[0080] 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 adisubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0081] 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(2R.6S) (2S.6R) (2S,6S) (2R.6R)(cis)-2,6-dimethyl-morpholine (trans)-2,6-dimethyl-morpholineN-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l- (methylsulfonyl)indoline-6-carboxamide

[0083] In the present invention, tri substituted piperidine moieties with stereocenters are defined as (3a, 4a, 5a) or (3a, 4b, 5a). For example:

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] Appropriate anions comprise, for example, acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate (e.g. Lascorbate), L-aspartate, benzenesulfonate, benzoate, 4- acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphor-sulphonate, (+)-(15)-camphor-10-sulphonate, calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecyl sulphate, edetate, estolate, esylate, ethane-l,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, hydroxynaphthoate, iodide, isethionate, lactate (e.g. (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methansulfonate, methylbromide, methylnitrate, methyl sulfate, mucate, naphthalene-sulphonate (e.g.naphthalene-2sulphonate), naphthalene- 1,5 -di sulphonate, 1 hydroxy -2 -naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate / diphosphate, propionate, polygalacturonate, Lpyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, subacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g. / ?-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.

[0091] 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 N(CH3)4+, and substituted ammonium ions (e.g., NH3I , NH2R2+, NHR.3+, 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.

[0092] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0093] 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.

[0094] The compounds of the present disclosure include compounds that are isotopically labeled, i.e., with one or more isotopic substitutions. These compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. A reference to a particular element includes within its scope all isotopes of the element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in a diagnostic context. Radiolabeled compounds described herein may comprise a radioactive isotope selected from the group of2H,3H,nC,18F,1221,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of2H,3H,nC and18F. More preferably, the radioactive isotope is2H. In particular, deuterated compounds are intended to be included within the scope of the present invention. In some embodiments, metabolic sites on the compounds described herein are deuterated.

[0095] Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds.

[0096] Embodiments of the 1,6-naphthyridine compounds for use as described herein are compounds of Formula (I):whereinR1is an optionally substituted bicycle selected from: selected from:whereinRais selected from: H, SO2-Ci-4alkyl, SO2-C2-4alkenyl, SO2-C2-4alkynyl, SO2-C1- 4haloalkyl, SO2-CH2CH2OH, SO2-CH2CH2OCH3, SO2-N(CH3)2, SO2-C3-6Cycloalkyl,, (C=O)CH3, and tetrahydropyranyl; Rbis selected from: H, Cl, F, Ci-4alkyl, CH2OH, and CH2NH2; each Rcis independently H, and Ci-4alkyl, or two R8members come together to form a Cs-ecycloalkyl; X is CH or N; Y is CH or N; wherein X and Y are not both N; n is one or two; and — is a single or double bond; oris independently H, halo, OH, or CH2OH; Z is Ci-salkyl, and n is 1 or 2; orR3is H or CH3; andR5isand pharmaceutically acceptable salts and stereoisomers thereof.

[0097] In some embodiments, R1is

[0098] In some embodiments, R3is H or CH3.

[0099] In some embodiments,in some embodiments,

[0103] In some embodiments, the compound of Formula (I) is a compound as shown below in Table 1.

[0104] and pharmaceutically acceptable salts and stereoisomers thereof.

[0105] In some embodiments, the 1,6-naphthyridine compound is selected from the group consisting of: N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;4-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)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine- 6-carboxamide;N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine- 6-carboxamide; l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide;4-chloro-l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)indoline-6-carboxamide; l-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxamide; and l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide; and pharmaceutically acceptable salts and stereoisomers thereof.

[0106] In some embodiments, the 1,6-naphthyridine compound is a compound of Formula(IA):WhereinR3is H or CH3;Rais selected from: H, SO2-Ci-4alkyl, SO2-C2-4alkenyl, SO2-C2-4alkynyl, SO2-Ci-4haloalkyl,(C=O)CH3, tetrahydropyranyl,Rbis selected from: H, Cl, F, Ci-4alkyl, CH2OH, and CH2NH2;Each Rcis independently H, and Ci-4alkyl, or two R8members come together to form a C3- ecycloalkyl; X is CH or N;Y is CH or N; wherein X and Y are not both N; n is one or two; and— is a single or double bond; or a pharmaceutically acceptable salt or stereoisomer thereof.Synthesis of Compounds

[0107] 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.

[0108] The synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary. Techniques and materials recognized in the field are described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein.

[0109] 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.

[0110] 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.

[0111] 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 acidlabile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0112] 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 9fluorenylmethyleneoxycarbonyl (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.

[0113] 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.

[0114] Typically blocking / protecting groups may be selected from:Fmoc

[0115] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure.General synthetic pathwaysSCHEME 1

[0116] According to SCHEME 1, a commercially available or synthetically accessible ester compound of formula (II), where ring B is a suitably substituted bicyclic (hetero)aromatic compound 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).SCHEME 2_ BorylationR5— Hal(IV)

[0117] According to SCHEME 2, a compound of formula (IV), where Hal is Br or Cl and R5is a suitably substituted heteroaryl, can be borylated employing conditions known to one skilled in the art such as Miyaura borylation conditions. For example, a compound of formula (IV), where Hal is Br or Cl, can be treated with a transition metal catalyst such as 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)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).SCHEME 3

[0118] According to SCHEME 3, A compound of formula (VI), where R3is H, can be prepared in a metal mediated coupling reaction of a commercially available or synthetically accessible compound of formula (VII), where Hal is a suitable halogen such as Br (bromine); with a boronic acid or boronic ester such as potassium trifluoro(vinyl)borate; in the presenceof a catalyst such as bis(triphenylphosphine)palladium(II) 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 POCI3, 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 NalCh, in a suitable solvent such as 1,4-di oxane, THF, water, or a mixture thereof, to provide a compound of formula (IX).SCHEME 4(VII) (X) (XI) (XII)

[0119] 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,V-di methyl form am ide (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 (X). Halogenation of a compound of formula (X) can be achieved employing methods previously described, such as using POCI3, to afford a compound of formula (XI). A compound of formula (XI) 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 (XII).SCHEME 5

[0120] According to SCHEME 5, a compound of formula (XII), where P1is Boc, R3is H, and Hal is Cl, can be reacted in a metal mediated cross coupling reaction with a commercially available or synthetically accessible boronic acid of formula R5-B(OH)2 or boronate derivative of formula (Va), where R5is an optionally substituted heteroaryl as described in claim 1, employing methods known to the art. For example, a compound of formula (XII) 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(II) chloride, and the like; in a suitable solvent such as 1,4- dioxane, 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 (XIII), where R3is H and R5is 6-fluoropyridyl. In a similar manner, a compound of formula (XII) where P1is Boc, R3is H, and Hal is Cl, can be reacted in a metal mediated cross coupling reaction with a commercially available or synthetically accessible boronic acid of formula (V) or R5-BOH2, wherein R5is a suitable heteroaryl substituted with a nitrogen linked heterocycloalkyl, to provide a compound of formula (XIV).

[0121] A compound of formula (XIII), where R5is a suitable heteroaryl such as, for example, 2 -pyridyl substituted with a suitable halogen leaving group such as, for example, F (fluorine), can be reacted with an optionally substituted heterocycloalkyl (including but not limited to a 4-8 membered heterocycloalkyl, fused, spiro, and bridged 8-10 membered heterocycloalkyl, each optionally one or two heteroatoms independently selected from N, S, and O) such as cis- 2,6-dimethylmorpholine; 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 (XIV), wherein R5is a suitable heteroaryl substituted with a nitrogen linked heterocycloalkyl.

[0122] Deprotection of a compound of formula (XIV), where P1is Boc, can be achieved according to procedures known to one skilled in the art and employing established methodologies, such as those described in T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 3 ed., John Wiley & Sons, 1999, pgs 518-525. For example, deprotection under acidic conditions such as trifluoroacetic acid (TFAyCHiCh, HCl / Dioxane, and the like, at room temperature for a period of 2 h, to provide a compound of formula (XV).SCHEME 6(XV) (XVI) (XVII) (XV)

[0123] According to SCHEME 6, a compound of formula (XV), wherein R3is H (hydrogen), can be reacted with a suitable ketone such as, for example, benzophenone; in the presence of a suitable catalyst such as, for example, pTsOH; in a suitable solvent such as, for example, toluene, and the like; at a suitable temperature such as, for example, reflux of the solvent; to provide an imine derivative compound of formula (XVI). A compound of formula (XVI) can be reacted with a suitable alkylating agent R3Hal, wherein R3is as defined in the claims, and Hal is a suitable halogen leaving group, such as, for example, iodide; in the presence of a suitable base such as, for example, potassium tert-butoxide, and the like; in a suitable solvent such as, for example, THF, DMF, and the like; at a suitable temperature such as, for example, room temperature; to provide a compound of formula (XVII), where R3is as defined in the claims. Deprotection of the imine compound of formula (XVII) 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 to 2 h, to provide a compound of formula (XV).SCHEME 7

[0124] According to SCHEME 7, a compound of formula (XII), where R3is H, Hal is Cl, and P1is Boc, can be reacted with a suitable sulfinate such as, for example, sodium 1-methyl 3- sulfinopropanoate (CAS [90030-48-1]); in the presence of a suitable catalyst such as, for example, Cui; in a suitable solvent such as, for example, DMSO, and the like; at a suitable temperature such as, for example, 110 °C; to provide a compound of formula (XVIII). A compound of formula (XVIII) 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 (XIV). Deprotection of the Boc protecting group on a compound of formula (XIV) can be achieved employing acidic conditions known to one skilled in the art or as previously described to provide a compound of formula (XV).

[0125] In a similar fashion, a compound of formula (XVIII), where R3is H, Hal is Cl, and P1is Boc, can be reacted with a suitable substituted 2-halo-heteroaryl (R5-Hal), such as, for example, (2R,6S)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine, in the presence of a suitable phosphonium salt such as, for example, di-tert-butyl(methyl)phosphonium tetrafluorob orate (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 (XIII), where R5is 6-((2R,6S) 2,6-dimethylmorpholino)-4-fluoropyridin-2-yl.SCHEME 8

[0126] According to SCHEME 8, a compound of formula (XIII), where R3is H, P1is Boc, and R5is a suitably substituted heteroaryl halide, can be deprotected employing methods known to one skilled in the art or as previously described, to provide a compound of formula (XIX). A compound of formula (XIX) 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 (XIX) 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 (XX).

[0127] In an alternate method, a compound of formula (XX) can be prepared in two steps from a compound of formula (XXI). In a first step, a compound of formula (XXI) can be reacted in an amide bond forming reaction with a carboxylic acid of formula (III), where ring B is a suitably substituted bicyclic (hetero)aryl ring; employing methods known to one skilled in the art or as previously described to provide a compound of formula (XXII). Alternatively, an acid chloride derived from the acid of formula (III) can be reacted with a compound of formula (XXI), 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 (XXII). In a second step, a compound of formula (XXII) 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, Na2COs or NaHCOy 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-di oxane and water, at a suitable temperature such as 85 °C; to provide a compound of formula (XX).SCHEME 9

[0128] According to SCHEME 9, a compound of formula (XXII), where R3is H, and Hal is Cl, and R1is a suitably substituted phenyl as described in claim 1 can be reacted with a suitable sulfinate such as sodium 1 -methyl 3-sulfinopropanoate (CAS [90030-48-1]); in the presence of a suitable catalyst such as Cui, and the like; in a suitable solvent such as DMSO, and the like; at temperatures ranging from 90 to 110 °C; to provide a compound of formula (XXIII).

[0129] A compound of formula (XXIII), can be reacted with a suitably substituted heteroaryl halide of formula R5Hal, wherein Hal is Br or Cl, and R5is heteroaryl as defined in claim 1; in the presence of a suitable phosphonium salt such as, for example, di-tert- butyl(methyl)phosphonium tetrafluorob orate (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

[0130] According to SCHEME 10, a compound of formula (XXIV), R3is H and Hal is Cl, can be reacted with a suitable boronic acid R5-B(OH)2 or a boronate derivative of formula (V), employing coupling methods known to one skilled in the art or as previously described.For example, a compound of formula (XXIV), R3is H and Hal is Cl, can be reacted with R5- B(OH)2, where R5-B(OH)2 is 6-fluoro-pyridine-2-boronic acid; in the presence of a suitable base such as Cs2CO3, K2CO3, K3PO4, K2HPO4, KHCO3, Na2CO3NaHCCh, 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-di oxane, DMF, acetonitrile (ACN), ethanol, water, or a mixture thereof; at a temperature ranging from 80 to 100 °C; to provide a compound of formula (XXV), where R5is 6-fluoro-pyridyl. A compound of formula (XXV) can be reacted with phthalimide; in the presence of a suitable phosphine such as, for example, triphenylphosphine; a suitable azodi carb oxy late such as DIAL), 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 (XXVI).

[0131] In an alternate method, a compound of formula (XXVI) can be prepared in two steps from a compound of formula (XXIV). In a first step, a compound of formula (XXIV), where R3is H and Hal is Cl, can be reacted with phthalimide; in the presence of a suitable phosphine such as, for example, triphenylphosphine, and the like; a suitable azodi carb oxy late 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 (XXVII). In a second step, a compound of formula (XXVII) can be reacted under coupling conditions known to one skilled in the art, or as previously described to provide a compound of formula (XXVI).

[0132] A compound of formula (XXVI)] 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 (XIX).SCHEME 11

[0133] A compound of formula (XXII) 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,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (CAS [72287-26-4]), in a suitable solvent such as, for example, a mixture of water and 1,4- di oxane, at a suitable temperature such as, for example, 100 °C, to provide a compound of Formula (I), wherein R5is defined as a C-linked heteroaryl, aryl, or heterocycloalkyl group.

[0134] According to SCHEME 11, a compound of formula (XXII), can be reacted with a suitable stannane derivative such as 7-(3-fluoro-6-(trimethylstannyl)pyridin-2-yl)-4,7- diazaspiro[2.5]octane; in the presence of a suitable source of Pd such as tetrakis(triphenylphosphine)palladium(0), and the like; in a suitable solvent such as 1,4- di oxane, and the like; at a temperature of 110 °C; to provide a compound of Formula (I), wherein R5is defined as a C-linked heteroaryl.SCHEME 12

[0135] According to SCHEME 12, a compound of formula (XV) 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 (XV), where R3and R5are as described in claim 1, can be reacted with a suitable carboxylic acid, in the presence of a suitable coupling agent such as, for example, HATU (l-[bis(dimethylamino)methylene]-UT- l,2,3-triazolo[4,5-Z>]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).

[0136] Alternatively, a compound of Formula (I) can be prepared by reacting a compound of formula (XV) 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.

[0137] A compound of formula (XX), wherein R5is a suitable heteroaryl, such as, for example, 2-pyridyl, and Hal is a suitable halogen leaving group such as, for example, F (fluorine), can react with a suitable amine, such as, for example, cis-2,6-dimethylmorpholine, 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).

[0138] Wherein when 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.

[0139] 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).

[0140] 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.

[0141] 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-Cn 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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 stereospecifically. 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.

[0146] 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

[0147] 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.

[0148] 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 subjectmay 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 nonhuman transgenic animal such as a transgenic mouse or transgenic pig.

[0149] 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.

[0150] 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.

[0151] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0152] 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.

[0153] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0154] The present invention relates to the compounds of Formula (I) for use in a method of treatment of SMARCA4 deficient cancers, which method comprises administering to a subject in need thereof a compound of Formula (I).

[0155] The present invention relates to the compounds of Formula (I) for use in a method of treatment of SMARCA4 deficient NSCLC, which method comprises administering to a subject in need thereof a compound of Formula (I).

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, or a nose spray. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises 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.

[0161] 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 activeingredient 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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 beadministered 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.

[0167] 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

[0168] The following examples further illustrate the present invention. The following examples are offered for purposes of illustration, and are not intended to limit the scope of the claims provided herein. 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. Commercial sources include, but are not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. Table 2. Abbreviations.protocols as indicated may contain residual solvent or minor impurities.

[0170] 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.

[0171] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.

[0172] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

[0173] 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.

[0174] Example A: Preparation of the Intermediates and the final Compounds, and characterization thereofPreparation of intermediatesIntermediate 1 :

[0175] 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- 1 / 7-1, 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 Intermediate 1 (147 g, yield: 69 %) as a brown solid.Intermediate 2:

[0176] 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 Intermediate 1 (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 Na2SO4, and concentrated to afford Intermediate 2 (58 g, yield: 36 %) as a yellow solid.Intermediate 3: tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate.

[0177] Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DCM (1.74 L), Intermediate 2 (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 (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 Intermediate 3 (60.9 g, yield: 68 %) as a yellow solid.Intermediate 4:

[0178] A suspension of Intermediate 3 (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 a 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 Et2O and filtered. The white solid was washed with a small amount of Et2O to give the title compound (7.47 g, yield: 58 %) as a white solid.Intermediate 5:CIS

[0179] A suspension of Intermediate 4 (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 pressure (microwave) 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 DCMZEt2O 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: EtOHZEtOAc 1 / 3 100:0 -> 20:80) to give Intermediate 5 (5.1 g, quantitative).Intermediate 6: (2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)methanamine.CIS

[0180] HC1 (37 % in H2O, 40 mL, 484.24 mmol, 20 eq.) was added dropwise (1 drop / sec, slightly exothermic) to a yellow suspension of Intermediate 5 (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 the title compound (HC1 salt, 12 g, quantitative) as an orange solid, dried under vacuum at 50 °C.Intermediate 7:CIS

[0181] Intermediate 7 was prepared using of Intermediate 6 and 2,3-dihydro-l / 7-indole-6- carboxylic acid (CAS [732922-86-0]), following Method A and DMF as the solvent.Intermediate 8:

[0182] EtsN (153 pL, l;096 mmol, 2 eq.) was added to a stirred solution of 2,3-dihydro-3,3- dimethyl-lH-indole-6-carboxylic acid, methyl ester (CAS [1824288-68-7], 150 mg, 0.548 mmol) in DCM (10 mL) under nitrogen atmosphere. The reaction mixture was cooled to 0 °C and MsCl (64 pL, 0.822 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between water and DCM. The organic layer was separated, dried (MgSCU), filtered, and evaporated in vacuo. The residue was purified by column chromatography (25 g SiCL, EtOAc / heptane 100 / 00 to 35 / 65) to yield Intermediate 8 (137 mg, yield: 85 %) as a solid.Intermediate 9:

[0183] LiOH (96 mg, 2.294 mmol, 5 eq.) was added to a solution of Intermediate 8(130 mg, 0.459 mmol) in THF (5 mL) and water (2 mL) at room temperature. The reaction mixture was stirred a room temperature overnight. The pH was brought to 3 by the addition of KHSO4 (1 M in water). DCM was added and the layers were separated. The organic layer was dried (MgSCU), filtered, and the solvents evaporated in vacuo to yield Intermediate 9 (115 mg, yield: 88 %) as a solid, used without further purification.Intermediate 10:

[0184] Under nitrogen atmosphere, EtsN (472 pL, 3.389 mmol, 2 eq.) was added to a stirred solution of methyl 2,3-dihydro-4-methyl-U / -indole-6-carboxylate (CAS [928772-66-1], 324 mg, 1.694 mmol) in DCM (5 mL). The reaction mixture was cooled to 0 °C and MsCl (170 pL, 2.203 mmol, 1.3 eq.) was added. The reaction mixture was stirred at room temperature for 15 min. The mixture was partitioned between water and DCM. The aqueous phase was extracted with DCM. The combined organic layer was dried on MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (25 g SiCh, EtOAc / heptane from 100 / 00 to 50 / 50) to afford Intermediate 10 (260 mg, yield: 57 %) as a white solid.Intermediate 11 : 3-methyl-l-(methylsulfonyl)indoline-6-carboxylic acid.

[0185] NaOH (1 M in water, 1.4 mL, 1.419 mmol, 1.5 eq) was added to solution of Intermediate 10 (260 mg, 0.946 mmol) in MeOH (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. More NaOH (1 M in water, 1.9 mL, 1.892 mmol, 2 eq) was added to the reaction and the mixture was stirred further for 24 h. The reaction mixture was diluted with water and HC1 (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 to obtain Intermediate 11.Intermediate 12:

[0186] NaBHaCN (472 mg, 7.633 mmol, 4 eq.) was added at 0 °C to a mixture of methyl 4- chloro-U / -indole-6-carboxylate (CAS [885522-78-1], 400 mg, 1.908 mmol) in AcOH (4.7 mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under vacuo. The residue was dissolved in DCM and washed with aqueous Na2CC>3 1 M. The organic layer was dried on MgSC , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (25 g SiCh; MeOH / DCM 0 / 100 to 20 / 80) to afford Intermediate 12 (85 mg, yield: 21 %) as a white solid. Intermediate 13:

[0187] Under nitrogen atmosphere, EtsN (112 pL, 0.803 mmol, 2 eq.) was added to a stirred solution of Intermediate 12 (85 mg, 0.402 mmol) in DCM (3 mL). The reaction mixture was cooled to 0 °C and MsCl (40 pL, 0.522 mmol, 1.3 eq.) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between water and DCM. The aqueous phase was extracted with DCM. The combined organic layers were dried on MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (25 g SiCh, EtOAc / heptane 100 / 0 to 50 / 50) to afford Intermediate 13 (104 mg, yield: 88 %) as a white solid.Intermediate 14:

[0188] LiOH (44 mg, 1.055 mmol, 3 eq.) was dissolved in water (0.2 mL) and the resulting solution was added to a solution of Intermediate 13 (104 mg, 0.352 mmol) in THF (0.8 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was acidified with aqueous HC1 (1 M) to reach a pH ~3-4. This acidic aqueous layer was extracted with EtOAc. The organic layer was dried on MgSO4, filtered, and concentrated in vacuo to give to afford Intermediate 14 (86 mg, yield: 88 %) as a white solid, used without further purification.Intermediate 15:

[0189] Under nitrogen atmosphere, EtsN (1.15 mL, 8.259 mmol, 2 eq.) was added to a stirred solution of 6-bromo-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine (CAS [74976-34-4], 822 mg, 4.13 mmol) in DCM (10 mL). The reaction mixture was cooled to 0 °C and MsCl (416 pL, 5.369 mmol, 1.3 eq.) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM. The combined organic layers were dried on MgSCU, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (25 g SiCh, MeOH / DCM 100 / 0 to 50 / 50) to afford Intermediate 15 (842 mg, yield: 71 %) as a white solid. Intermediate 16:

[0190] In a pressure reactor, EtsN (4.2 mL, 30.382 mmol, 10 eq.) was added to a solution of Intermediate 15 (842 mg, 3.038 mmol) in MeOH (5 mL) and 1,4-di oxane (5 mL). The mixture was degassed with nitrogen for 20 min. Pd^ppf Ch CEECL (CAS [95464-05-4], 273 mg, 0.304 mmol, 0.1 eq.) was added and the reactor was sealed. The reaction mixture was stirred under 6 atm of CO at 85 °C overnight. After cooling, the mixture was filtered on a pad of celite. The filtrate was washed with aqueous Na2COs (I M) and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried on MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiO2; EtOAc / heptane 0 / 100 to 60 / 40) to afford Intermediate 16 (772 mg, yield: 99 %) as a clear oil.Intermediate 17:

[0191] NaOH (1 M in water, 3.25 mL, 3.247 mmol, 1.1 eq.) was added to solution of Intermediate 16 (772 mg, 2.952 mmol) in MeOH (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and aqueous KHSO4 (1 M) was added, to reach a pH ~2-3. The mixture was concentrated under vacuo and the residue was taken up in DCM / MeOH (9 / 1) (300 mL). This mixture was stirredat room temperature overnight. The solvent was concentrated under vacuo to dryness. The residue was purified by reverse phase chromatography ([25 mM NH4HCO3] / [ACN:MeOH 1 : 1] 95 % / 5 % to 3 % / 37 %) to give Intermediate 17 (1029 mg) as a white solid.Intermediate 18:

[0192] Intermediate 4 (684 mg, 1.93 mmol) and 2,2,6,6-tetramethylmorpholine (CAS [19151- 69-0], 1.16 g, 7.72 mml) and DIPEA (1.27 mL, 7.72 mmol, 4 eq.) in DMSO (10 mL) and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCOs. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g column, gradient of DCM:MeOH 9: 1 in DCM, from 0 % to 35 %) to yield a yellow solid. The solid was triturated in ACN, filtered, washed with Et2O, and dried in vacuo to yield Intermediate 18 (1071 mg, yield: 38 %) as a yellow solid.Intermediate 19:

[0193] HC1 (4 M in 1,4-dioxane, 4.3 mL, 17.127 mmol, 10 eq.) was added to a stirred solution of Intermediate 18 (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 19 (HC1 salt, 448 mg, 86 % pure, quantitative) as an orange solid.Intermediate 20:

[0194] MsCl (38 pL, 0.496 mmol, 2 eq.) was added dropwise to a stirred solution of 1H- pyrrolo[3,2-b]pyridine-6-carboxylic acid, 2,3-dihydro-3,3-dimethyl-, methyl ester (CAS [1824576-89-7], 51 mg, 0.248 mmol) and Et3N (69 pL, 0.496 mmol, 2 eq.) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and was extracted with EtOAc (2 x 10 mL). The organic layer was dried over MgSO4, filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 25 g; EtOAc in heptane from 0 / 100 to 80 / 20) to yield Intermediate 20 (43 mg, yield: 59 %) as a white solid.Intermediate 21 :

[0195] NaOH (18 mg, 0.454 mmol, 3 eq.) was added to a stirred solution of Intermediate 20 (43 mg, 0.151 mmol) in MeOH (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with aqueous HC1 (1 M) to pH = 1 and then extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 21 (33 mg, yield: 77 %) as a yellow solid. Intermediate 22:(3a,4p,5a)

[0196] Intermediate 22 was prepared following the procedures described for the preparation of Intermediate 6 using (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4]) instead of cz -2,6-dimethylmorpholine.Intermediate 23 :(3a,4p,5a)

[0197] A solution of Intermediate 22(540mg, 0.92mmol) in aqueous NaOH (5.5ml, 13.7mmol) was stirred at 72 °C for 16 h. The reaction was allowed to cool to room temperature and partitioned between EtOAc (25 ml) and sat. NaHCO3. The organic layer was separated, dried (MgSCU), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (25 g column, DCM / MeOH (9: 1) in DCM [from 0% to 25%]). The desired fractions were collected and concentrated in vacuo to yield Intermediate 23 (401 mg, yield: 90%) as a yellow solid.Intermediate 24:(3a,4p,5a)

[0198] Trifluoroacetic acid (1.5 mL, 19.6 mmol) was added to a stirred solution of Intermediate 23 (401 mg, 0.83 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to yield Intermediate 24 (508 mg, yield: 99 %) as a yellow solid, used as such without further purification in the next step.Intermediate 25:

[0199] Methanesulfonyl chloride (2.9 mL, 37.7 mmol) was added dropwise to a stirred solution of methyl indoline-6-carboxylate (CAS [341988-36-1], 3.34 g, 18.9 mmol) and EtsN (5.25 mL, 37.7 mmol) in DCM (57 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over MgSCU, filtered, and the solvents evaporated in vacuo to yield Intermediate 25 (4.81 g, yield: 99 %) as a brown solid.Intermediate 26: l-(methylsulfonyl)indoline-6-carboxylic acid.

[0200] Step A: methyl l-(methylsulfonyl)indoline-6-carboxylate. Methanesulfonyl chloride (2.9 mL, 37.7 mmol) was added dropwise to a stirred solution of methyl indoline-6- carboxylate (CAS [341988-36-1], 3.34 g, 18.9 mmol) and EtsN (5.25 mL, 37.7 mmol) in DCM (57 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with water and extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over MgSO4, filtered, and the solvents evaporated in vacuo to yield methyl l-(methylsulfonyl)indoline-6-carboxylate (Intermediate 25) (4.81 g, yield: 99 %) as a brown solid.

[0201] Step B: l-(methylsulfonyl)indoline-6-carboxylic acid. Sodium hydroxide (1.13 g, 28.3 mmol) was added to a stirred solution of Intermediate 25 (4.81 g, 18.9 mmol) in MeOH (40 mL) at room temperature. The reaction mixture was stirred for 65 h at room temperature. The mixture was diluted with water and was neutralized with aqueous HC1 (I M). The mixture was extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over MgSO4, filtered, and evaporated to yield l-(methylsulfonyl)indoline-6-carboxylic acid (Intermediate 26) (3.44 g, yield: 75 %) as a brown solid, used without further purification.Intermediate 27:

[0202] A solution of Intermediate 6 (282 mg, 0.71 mmol), benzophenone (131 mg, 0.71 mmol, 1 eq.), and p-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. The solvent was evaporated to give Intermediate 27 (350 mg, 49 % pure, yield: 47 %) as a brown solid, used directly in the next step.Intermediate 28:RS mixture, CIS

[0203] Potassium tert-butoxide (59 mg, 0.501 mmol, 1.5 eq.) was added in one portion to a solution of Intermediate 27 (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 (31 pL, 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 MgSCU, filtered, and the solvent was evaporated to give Intermediate 28 (354 mg, 63 % pure, assumed quantitative) as a brown solid, used directly in the next step.Intermediate 29:RS mixture, CIS

[0204] HC1 (37 % in water, 0.7 mL, 8.453 mmol, 20 eq.) was added dropwise (1 drop / sec) to a solution of Intermediate 28 (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 timeswith toluene to give Intermediate 29 (HC1 salt, 383 mg, 22 % pure) as a brown solid, dried under vacuum at 50 °C and used without further purification.Intermediate 30:(3a, 40, 5a)

[0205] Benzoyl chloride (CAS [98-88-4], 1.8 mL, 15.507 mmol, 1.55 eq.), EtsN (7 mL, 50.222 mmol, 5 eq.), and DMAP (219 mg, 1.793 mmol, 0.18 eq.) were added to a solution of (3a,40,5a)-3,5-dimethyl-l-(phenylmethyl)-4-piperidinol (CAS [374067-77-3], 2.2 g, 10.031 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCCh. The organic layer was dried with MgSCU, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (80 g, EtOAc / heptane 0 / 100 to 20 / 80) to yield Intermediate 30 (2.88 g, yield: 88 %) as a white solid.Intermediate 31 :(3a, 40, 5a)

[0206] Palladium hydroxide (CAS [12135-22-7], 238 mg, 0.34 mmol, 0.04 eq.) was added to a solution of Intermediate 30 (2.88 g 8.905 mmol, as prepared in the previous step) in MeOH (50mL) under nitrogen atmosphere. The mixture was purged using vacuum and nitrogen.Then, the mixture was purged with hydrogen and stirred at room temperature under hydrogen atmosphere for 18 h. The reaction mixture was filtered through a short pad of celite and the solvent was removed in vacuo to yield Intermediate 31 (1.98 g, yield: 94 %) as a colourless oil.Intermediate 32:(3a, 40, 5a)

[0207] Nitrogen was purged through a solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 1.236 g, 4.384 mmol) in 1,4-dioxane (37 mL). Cs2CO3(3.14 g, 9.644 mmol, 2.2 eq.), Intermediate 31 (1.36 g, 5.041 mmol, 1.15 eq., as prepared in the previous step), DavePhos (CAS [213697-53-1], 173 mg, 0.44 mmol, 0.1 eq.) and Pd2dba3(CAS [51364-51- 3], 200 mg, 0.218 mmol, 0.05 eq.) were then added at room temperature while nitrogen was bubbled through. The vial was sealed and the mixture was stirred at 90 °C for 3 h. Saturated aqueous NaHCO3and EtOAc were added to the reaction mixture and the layers were separated. The aqueous layer was extracted again with EtOAc (3 x). The combined organic layer was dried with MgSO4, filtered, and concentrated under vacuo. The residue was purified by column chromatography on silica gel (25 g, EtOAc / heptane from 0 / 100 to 25 / 75) to yield Intermediate 32 (1.686 g, yield: 84 %) as a yellow solid.Intermediate 33:(3a, 40, 5a)

[0208] Tetramethylammonium fluoride (CAS [373-68-2], 543 mg, 5.83 mmol, 1.5 eq.) was added to a solution of Intermediate 32 (1.686 g, 3.882 mmol, as prepared in the previous step) in DMF (15 mL). The reaction mixture was stirred at 65 °C for 3 h. After cooling, the mixture was diluted with EtOAc (15 mL) and water (15 mL). The layers were separated, and the organic layer was washed with water (20 mL) and brine (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash columnchromatography over silica gel (80 g, EtOAc / heptane from 0 / 100 to 30 / 100) to yield Intermediate 33 (1.265 g, yield: 79 %) as a yellow solid.Intermediate 34:

[0209] Intermediate 3 (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 NH3 (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 34 (801 mg, yield: 53 %) as an orange solid.Intermediate 35:(3a, 40, 5a)

[0210] Intermediate 34 (950 mg, 2.32 mmol, as prepared in the previous step), Intermediate 33 (1006 mg, 3.48 mmol, 1.5 eq. as prepared in the step D), 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- / <? / 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 MgSCU, filtered, and concentrated. The residue was purified by flash column chromatography oversilica gel (25 g column, gradient of EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 35 (428 mg, yield: 39 %) as a yellow solid.Intermediate 36:(3a, 40, 5a)

[0211] TFA (1.505 mL, 19.67 mmol, 30 eq.) was added to a solution of Intermediate 35 (384 mg, 0.656 mmol) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield Intermediate 36 (295 mg, yield: 91 %), used without further purification.Intermediate 37:(3a, 40, 5a)Intermediate 37 was prepared from Intermediate 36 and Intermediate 17 following Method A.Intermediate 38:

[0212] 7-Bromo-l,6-naphthyridin-2(177)-one (CAS [1574395-48-4], 2.3 g, 10.4 mmol), potassium trifluoro(vinyl)borate (CAS [13682-77-4], 1.68 g, 12.5 mmol), bis(triphenylphosphine)palladium(II) chloride (CAS [13965-03-2], 220 mg, 0.31 mmol), and cesium carbonate (10.19 g, 31.3 mmol) were suspended in THF (42 mL) and water (11 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C for 8 h. The reaction mixture was recharged with potassium trifluoro(vinyl)borate (500 mg) and bis(triphenylphosphine)palladium(II) chloride (220 mg) and was stirred at 80 °C for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated and the solvents evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (80 g; AcOEt / heptane from 0 / 100 to 100 / 0) to yield Intermediate 38 (1 g, yield: 55 %) as a white solid.Intermediate 39:

[0213] POCh (1.6 mL, 17.4 mmol) was added to a suspension of Intermediate 38 (1 g, 5.8 mmol) in DCE (30 mL). The reaction mixture was refluxed at 80 °C for 16 h. The mixture was diluted with saturated aqueous Na2COs and extracted with EtOAc (3 x). The organic layer was separated, dried (MgSO4), filtered, and the solvents evaporated in vacuo to yield Intermediate 39 (1 g, yield: 85 %) as an orange solid, used without further purification.Intermediate 40:

[0214] Intermediate 39 (1.04 g, 5.37 mmol) and 2,6-lutidine (CAS [108-48-5], 1.27 mL, 10.9 mmol) were dissolved in dioxane (5 mL) and water (1 ml) and the mixture was cooled to 0 °C. NaIO4 (4.7 g, 21.9 mmol) and OsO4 (35 mg, 0.14 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCOs and extracted with DCM several times. The combined organic layer was dried over MgSCU, filtered, and concentrated to yield Intermediate 40 (820 mg, yield: 47 %) as a black solid, used in the next step without further purification.Intermediate 41 :

[0215] A solution of Intermediate 40 (820 mg, 4.26 mmol) in EtOH (25 mL) was cooled to 0 °C. Sodium borohydride (81 mg, 2.13 mmol) was added and 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 separated, dried over MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (25 g column, gradient of B (DCM / Methanol 9: 1) in A (DCM)), from 0 % to 30 % of B) to yield Intermediate 41 (238 mg, yield: 28 %) as a beige solid.Intermediate 42:

[0216] A solution of Intermediate 41 (238 mg, 1.22 mmol), phthalimide (CAS [85-41-6], 198 mg, 1.35 mmol) and triphenylphosphine (385 mg, 1.47 mmol) in dry THF (10 mL) was bubbled with nitrogen gas. DIAD (CAS [2446-83-5], 0.29 mL, 1.47 mmol) in THF (1 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with EtOAc (3 x). The organic layer was dried, filtered, and evaporated. The residue was triturated with CAN, filtered, and washed twice with Et2O to yield Intermediate 42 (285 mg, yield: 71 %) as a white solid.Intermediate 43 : 2-((2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methyl)isoindoline-l,3- dione.

[0217] Intermediate 42 (285 mg, 0.88 mmol), 4-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyridine (CAS [1009033-83-3], 396 mg, 1.27 mmol) and sodium carbonate (280 mg, 2.64 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) at room temperature in a pressure flask. The mixture was bubbled with nitrogen for 10 min. Then Pd(dppf)C12.CH2C12 (CAS [95464-05-4], 36 mg, 0.04 mmol) was added and the mixture was stirred at 85 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (x 3). The aqueous layer was acidified with aqueous HC1 (1 N) until pH 4-5. A beige solid precipitated and was filtered, washed with DCM and Et2O, and dried to yield Intermediate 43 (270 mg, yield: 63 %) as a brown solid.Intermediate 44: (2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)methanamine.

[0218] Hydrazine hydrate (208 pL, 4.3 mmol) was added to a solution of Intermediate 43 (395 mg, 0.858 mmol) in EtOH (8 mL). The reaction mixture was stirred at 70 °C for 16 h. The mixture was diluted with saturated aqueous NaHCOs and was extracted with DCM (x 3). The organic layer was separated, dried (MgSCU), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash chromatography (12 g SiCL;DCM:MeOH:NH3 (10: 1 :0.25) in DCM, from 0 % to 40 %) to yield Intermediate 44 (135 mg, yield: 50 %) as a brown solid.Intermediate 45: tert-butyl ((2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)carbamate.

[0219] DIPEA (0.176 mL, 1.021 mmol) and l-(pyri din-3 -yl)piperazine (CAS [67980-77-2], 167 mg, 1.02 mmol) were added to Intermediate 3 (tert-butyl ((2-chloro-l,6-naphthyridin-7-yl)methyl)carbamate)(150 mg, 0.511 mmol) in THF (2.6 mL) in a pressure vial. The reaction mixture was stirred at 100 °C for 4 h. Silica was added and the mixture was purified by column chromatography (silica 40 g, using MeOH in DCM (0 to 10 %)) to give Intermediate 45 (177 mg, yield: 82 %).Intermediate 46: (2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methanamine.

[0220] Intermediate 45 (180 mg, 0.444 mmol) was dissolved in DCM (2 mL) and TFA (0.34 mL, 4.4 mmol) was added dropwise. The solution was stirred overnight at room temperature. The reaction mixture was concentrated. The residue was purified by reverse phase column chromatography (Column: OOD-4633-UO-AX Kinetex 5 um EVO cl8 100; 0.1 % TFA in water and ACN, 10 % ACN to 100 %) to yield Intermediate 46 (371 mg, yield: 99 %) as a solid.Intermediate 47: (2-(4-(pyridazin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7-yl)methanamine.

[0221] DIPEA (469 pL, 2.723 mmol, 2.0 eq.) was added to a solution of Intermediate 3 (400 mg, 1.362 mmol) and l-(6-pyridazinyl)piperazine (CAS [51047-56-4], 447 mg, 2.723 mmol, 2.0 eq.) in THF (6.8 mL, 1.362 mmol). The reaction mixture was stirred at 100 °C for 18 h. The solvent was evaporated, and the residue was purified column chromatography (40 g SiCL; MeOH / DCM from 0 / 100 to 10 / 90). The intermediate obtained was dissolved in DCM (1 mL) and treated with TFA (1.0 mL, 13.617 mmol, 10.0 eq.). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to obtain Intermediate 47 (TFA salt, 424 mg, yield: 34 %).Intermediate 48: (3a, 4P,5a)-l-(6-(7-(aminomethyl)-l,6-naphthyri din-2 -yl)-5-methylpyridin- 2-yl)-3 , 5 -dimethylpiperidin-4-ol .(3a, 4p, 5a)

[0222] Step A: tert-butyl ((2-(6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)carbamate. DIPEA (55 mL, 30.182 mmol, 10 eq.) was added to a mixture of Intermediate 4 (1150 mg, 3.018 mmol) and (3a,4p,5a)-3,5-dimethyl-4- piperidinol (CAS [374067-78-4]) (1000 mg, 6.036 mmol, 2 eq.) in DMSO (5 mL). The reaction mixture was stirred at 120 °C for 3 days. The reaction mixture was diluted with EtOAc and brine. The organic layer was separated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (120 g; EtOAc / heptane from 70 / 30 to 100 / 0) to yield the title compound (1.28 g, yield: 91 %) as a yellow solid.

[0223] Step B: tert-butyl ((2-(6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- iodopyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. A solution of tert-butyl ((2-(6- ((3 S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)carbamate (504 mg, 1.087 mmol) in hexafluoroisopropanol (15 mL) was cooled to 0 °C. N-Iodosuccinimide (257 mg, 1.142 mmol, 1.05 eq.) was added portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 h, then at room temperature overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with saturated aqueous Na2S20s followed by brine. The organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (50 g; EtOH / EtOAc 1 / 3 in heptane from 0 % to 80 %), followed by reverse phase HPLC (RP XB ridge Prep C18 OBD- 5 pm, 50 x 250 mm; 0.25 % NH4HCO3 solution in water, ACN) to yield the title compound (283 mg, yield: 44 %) as a yellow solid.

[0224] Step C: tert-butyl ((2-(6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate. Xantphos Pd G3 (CAS [1445085-97-1], 45 mg, 0.043 mmol, 0.1 eq.) was added to a solution of tert-butyl ((2-(6- ((3 S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-iodopyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)carbamate (255 mg, 0.433 mmol), K2CO3 (598 mg, 4.326 mmol, 10 eq.), andtrimethylboroxine (CAS [823-96-1], 611 pL, 4.326 mmol, 10 eq.) in 1,4 dioxane (10 mL) and water (3 mL). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed, and the reaction mixture was stirred at 90 °C for 22 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted a second time 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; EtOHZEtOAc 1 / 3 in heptane from 0 % to 100 %) to yield the tile compound (186 mg, yield: 76 %) as a yellow solid.

[0225] Step D: (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, 2 mL, 8.05 mmol, 25 eq.) was added to a solution of tert-butyl ((2-(6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3- methylpyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (181 mg, 0.322 mmol) in dry 1,4-dioxane (3 mL). The reaction mixture immediately turned from a yellow solution to a dark red sticky solid insoluble in the reaction mixture. The reaction mixture was stirred at room temperature for 4.5 h. The solvent was evaporated to yield the title compound (HC1 salt, 210 mg, yield: quantitative) as a yellow solid, used without further purification.Intermediate 49: 4-(hydroxymethyl)-l-(methylsulfonyl)indoline-6-carboxylic acid.

[0226] Step A: methyl 4-bromo-l-(methylsulfonyl)indoline-6-carboxylate. Methanesulfonyl chloride (CAS [14418-84-9], 3.3 mL, 42.4 mmol, 2 eq.) was added to an ice-cold solution of methyl 4-bromo-2,3-dihydro-lJ / -indole-6-carboxylate (CAS [2067333-71-3], 5.4 g, 21.2 mmol) and EtsN (14.5 mL, 104 mmol, 4.9 eq.) in DCM (100 mL). The mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of Na2COs (1 M in water, 75 mL). The mixture was extracted with DCM (150 mL) and the organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by recrystallization in ACN to give the title compound (5.4 g, yield: 71 %) as a white solid.

[0227] Step B: methyl l-(methylsulfonyl)-4-vinylindoline-6-carboxylate. methyl 4-bromo-l- (methylsulfonyl)indoline-6-carboxylate (5.33 g, 15.9 mmol), potassium trifluoro(vinyl)borate (CAS [13682-77-4], 2.57 g, 19.16 mmol, 1.2 eq.), bis(triphenylphosphine )palladium(II)dichloride (CAS [13965-03-2], 0.33 g, 0.48 mmol, 0.03 eq.), and Cs2CO3(CAS [534-17-8], 10.4 g, 36.2 mmol, 2 eq.) were taken up in THF (100 mL) and water (15 mL), and degassed by bubbling nitrogen in the mixture for 15 min. The reaction vessel was closed tight and the reaction mixture was stirred at 80 °C for 20 h. After cooling, the reaction mixture was diluted with EtOAc (200 mL) and brine (50 mL). The organic layer was separated and the aqueous layer was extracted again with EtOAc (100 mL). The combined organic layer was dried over MgSO4, filtered, and volatiles removed in vacuo. The crude residue was purified by chromatography over silica gel (80 g; EtOAc / heptane from 0 / 100 to 70 / 30) to yield the title compound (3.85 g, yield: 85 %) as a yellow solid.

[0228] Step C: methyl 4-formyl-l-(methylsulfonyl)indoline-6-carboxylate. Water (6.9 mL) and 2,6-lutidine (CAS [108-48-5], 1.67 mL, 14.3 mmol, 2 eq.) were added to a solution of methyl l-(methylsulfonyl)-4-vinylindoline-6-carboxylate (2 g, 7.11 mmol) in 1,4-dioxane (40 mL). NaIO4(CAS [7790-28-5], 6.25 g, 29.2 mmol, 4.1 eq.) and OsO4(CAS [20816-12-0], 45 mg, 0.178 mmol, 0.025 eq.) were added at 0 °C. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with saturated aqueous NaHCCf and extracted with DCM (3 x 100 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. DCM (35 mL) was added and the resulting solid was filtered to give a first crop of Intermediate 106 (946 mg, yield: 44 %). The filtrate was evaporated and the residue was purified by chromatography over silica gel (120 g;EtOAc / heptane from 0 / 100 to 100 / 0) to give a second crop of the title compound (755 mg, yield: 37 %) as a yellow solid.

[0229] Step D: methyl 4-(hydroxymethyl)-l-(methylsulfonyl)indoline-6-carboxylate. Sodium borohydride (CAS [16940-66-2], 151 mg, 4.0 mmol, 1.5 eq.) was added to a solution of methyl 4-formyl-l-(methylsulfonyl)indoline-6-carboxylate (755 mg, 2.66 mmol) in MeOH (20 mL) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was diluted with saturated aqueous NaHCCf 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 SiO2; EtOAc / heptane from 0 / 100 to 100 / 0) to yield the title compound (627 mg, yield: 80 %) as a white solid.

[0230] Step E: 4-(hydroxymethyl)-l-(methylsulfonyl)indoline-6-carboxylic acid. Lithium hydroxide monohydrate (CAS [1310-66-3], 539 mg, 12.8 mmol, 5.8 eq.) was added to a solution of methyl 4-(hydroxymethyl)-l-(methylsulfonyl)indoline-6-carboxylate (627 mg, 2.19 mmol) in THF (24 mL) and water (8 mL) at room temperature. The reaction mixture wasstirred at room temperature for 16 h. The pH was brought to 3 by addition of KHSO4 (1 M in water). DCM was added and the organic layer was separated, dried (MgSCU), filtered, and the solvents evaporated in vacuo to yield Intermediate 49 (623 mg, yield: 99 %) as a sticky yellow solid.Intermediate 50: tert-butyl 7-(6-chloro-3-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate.

[0231] DIPEA (2.0 mL, 12.05 mmol 4.0 eq.) was added to a solution of 2,6-dichloro-3- fluoropyridine (CAS [52208-50-1], 500 mg, 3.012 mmol) and tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate (CAS [674792-08-6], 671 mg, 3.163 mmol 1.05 eq.) in DMSO (5 mL) at room temperature. The reaction mixture was then stirred at 120 °C for 18 h. EtOAc (5.0 mL) was added, and the organic layer was washed with brine (3 x), dried (MgSCU), and concentrated. The residue was purified by column chromatography (40 g SiCL; EtOAc / heptane from 0 / 100 to 100 / 0) to give the title compound (830 mg, yield: 80 %) as an oil, solidifying on standing.Intermediate 51 : (2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine.

[0232] TFA (565 pL, 7.379 mmol, 30 eq.) was added to a solution of Intermediate 64 (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 NaHCOs and extracted with DCM (x 3). The combined organic layer was dried (MgSC ), filtered, and the solventsevaporated in vacuo to yield the title compound (TFA salt, 86 mg, yield: 72 %), used without further purification.Intermediate 52: (2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine.

[0233] 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 suspension of Intermediate 50 (500 mg, 1.463 mmol, 1.5 eq.), hexamethylditin (CAS [661-69-8], 479 mg, 1.448 mmol 1.5 eq.), and tetrakis(triphenylphosphine)palladium(0) CAS [14221-01-3], 676 mg, 0.573 mmol, 0.58 eq.) in 1,4-dioxane (12.5 mL) was degassed by bubbling argon through the mixture for 10 min. The vial was sealed and the reaction mixture was stirred at 110 °C for 3 h. After cooling to room temperature under argon, Intermediate 3 (286 mg, 0.975 mmol) and tetrakis(triphenylphosphine) palladium(O) (225 mg, 0.195 mmol, 0.2 eq.) were added. The reaction mixture was stirred for at 110 °C for 18 h. The solvent was evaporated and the residue was purified by column chromatography (40 g SiCL; EtOAc / heptane from 0 / 100 to 100 / 0) to give the title compound (390 mg, yield: 70 %) as a solid.

[0234] Step B: (2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine. TFA (0.52 mL, 6.907 mmol, 10.0 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. The solvent was evaporated to give Intermediate 52 as an oil, used directly in the next step.Intermediate 53 : (3a,4P,5a)-l-(6-(7-(aminomethyl)-l,6-naphthyridin-2-yl)-3-fluoropyridin-2- y 1 ) -3 , 5 -dimethylpiperidin-4-ol .(3a, 40, 5a)

[0235] Step A: (3R,4r,5S)-l-(6-chloro-3-fluoropyridin-2-yl)-3,5-dimethylpiperidin-4-ol. A solution of 2,6-dichloro-3-fluoropyridine (CAS [52208-50-1], 1.366 g, 8.231 mmol), (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4], 1.5 g, 9.055 mmol), and DIPEA (2.84 mL, 16.463 mmol) in DMSO (2.7 mL) was stirred at 130 °C for 3 h. After cooling, the mixture was diluted with water and extracted three times with EtOAc. The combined organic layer was washed with brine, dried on MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel; EtOAc / hexane) to give the title compound (1.32 g, yield: 62 %).

[0236] Step B: (3R,4r,5S)-l-(3-fluoro-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2-yl)-3 , 5-dimethylpiperidin-4-ol . (3R,4r, 5 S)- 1 -(6-chloro-3 -fluoropyri din-2 -y l)-3 , 5- dimethylpiperidin-4-ol (106 mg, 0.409 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 127 mg, 0.49 mmol), potassium acetate (121 mg, 1.226 mmol), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 30 mg, 0.041 mmol) were placed in a vial and it was evacuated and backfilled with argon (3 x). 1,4- Dioxane (1.3 mL) was added and the reaction mixture was stirred at 90 °C for 2 h. The crude reaction mixture containing the title compound was used directly in the next step.

[0237] Step C: A solution of crude (3R,4r,5S)-l-(3-fhioro-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 Intermediate 3 (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.

[0238] 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 19.Intermediate 54: (cis)-4-(6-bromo-3-fluoropyri din-2 -yl)-2,6-dimethylmorpholine.

[0239] 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), cv.s-2,6- dimethylmorpholine (CAS [6485-55-8], 0.94 mL, 7.627 mmol, 1 eq.) and K^CCh (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.

[0240] 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 1.5 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 NaHCOs. 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.

[0241] 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 tetrafluorob orate (CAS [14635-75-7], 352 mg, 3.014 mmol, 1.1 eq.) in DCM (4 mL) 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 NaHCOs and extracted with EtOAc. The layers were separated and the organic layer wasdried over MgSC , 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.Intermediate 55: tert-butyl 7-(6-bromo-4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carb oxy late.

[0242] Step A: tert-butyl 7-(6-bromo-4-nitropyri din-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, 7.1 mmol, 1.0 eq.) and tert-butyl 5,8-diazaspiro[2.5]octane-8-carboxylate (CAS [674792-08-6], 1.5 g, 7.1 mmol, 1.0 eq.) in 1,4-dioxane (30 mL). Then, CS2CO3 (5 g, 15.35 mmol, 2.0 eq.), DavePhos (CAS [213697-53-1], 303 mg, 0.77 mmol, 0.05 eq.), and Pd2dba3 (CAS [51364-51-3], 330 mg, 0.36 mmol, 0.1 eq.) were added to the stirred solution at room temperature under nitrogen in a closed tube. The mixture was stirred at 90 °C for 3.5 h, then saturated aqueous NaHCCf and EtOAc were added to the reaction mixture. The organic layer was separated, dried with MgSCU, filtered, and concentrated. The residue was purified by silica gel column chromatography (80 g; EtOAc / heptane from 0 / 100 to 10 / 90) to yield the title compound (2.6 g, yield: 80 %) as a yellow solid.

[0243] Step B: tert-butyl 7-(6-bromo-4-fluoropyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate. Tetramethylammonium fluoride anhydrous (CAS [373-68-2], 887 mg, 9.5 mmol, 1.5 eq.) was added to a solution of tert-butyl 7-(6-bromo-4-nitropyridin-2-yl)-4,7- diazaspiro[2.5]octane-4-carboxylate (2.6 g, 6.3 mmol, 1.0 eq.) in DMF (50 mL) at room temperature in a sealed tube. The mixture was stirred for 3 h at 65 °C. After cooling, the reaction mixture was diluted with EtOAc and water. The organic layer was separated, 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 10 / 90) to yield

[0244] Intermediate 55 (2.0 g, yield: 74 %) as an orange oil.Intermediate 56

[0245] Intermediate 34 (0.65 g, 1.59 mmol, 1.0 eq.), Intermediate 55 (0.65 g, 1.68 mmol, 1.06 eq.), and K2CO3 (330 mg, 2.39 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (9 mL) in a sealed tube under nitrogen atmosphere. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 40 mg, 161.26 pmol, 0.1 eq.) and Pd(OAc)2(CAS [3375-31-3], 18 mg, 80.18 pmol, 0.05 eq.) were added and the reaction mixture was stirred at 120 °C for 14 h. After cooling, the mixture was diluted with saturated aqueous NaHCCfi and extracted with EtOAc (x 3). The organic layer was dried over MgSCL, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g SiO2, EtOAc / heptane from 0 / 100 to 100 / 0) to yield Intermediate 56 (470 mg, yield: 52 %) as a yellow oil.Intermediate 57: (2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methanamine.

[0246] HC1 (4 M in 1,4-dioxane, 4.1 mL, 16.4 mmol, 20 eq.) was added to a solution of Intermediate 56 (0.47 g, 0.83 mmol) in DCM (7 mL). The reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated. The crude product was triturated with 1,4-dioxane and collected by filtration to yield Intermediate 57 (390 mg, yield: 96 %) as an orange solid.Intermediate 58:

[0247] A solution of 4-(2-aminoethyl)-benzoic acid methyl ester hydrochloride (CAS [56161- 89-8], 18 g, 83.5 mmol) in chlorosulfonic acid (100 g, 858 mmol) was stirred at 100 °C for 16 h under nitrogen atmosphere. After cooling, a solution of NaOH (90 g, 2.25 mol in 1 L of water) was added dropwise, keeping the temperature below 20 °C. After the addition, the reaction mixture was stirred at 25 °C for 30 min, then treated with additional water (500 mL), and extracted with 2-MeTHF (500 mL x 2). The pH of the aqueous layer was adjusted to 2-3 with HC1 (37 % in water) and extracted with 2-MeTHF (500 mL x 2). The combined organic layer was washed with water (500 mL) and concentrated to dryness to obtain Intermediate 58 (12.9 g, yield: 68 %).Intermediate 59:

[0248] 2,6-Dibromo-4-nitropyridine (CAS [175422-04-5], 5 g, 17.737 mmol) and cis-2,6- dimethylmorpholine (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 MgSCU, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (120 g column, gradient of EtOAc / heptane from 0 / 100 to 40 / 60) to give Intermediate 59 (3.2 g, yield: 56 %) as an orange solid.Intermediate 60:

[0249] Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 eq.) was added to a solution of Intermediate 59 (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 EtOAc. The organic layer was washed with water and brine, dried with MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (80 g column, gradient of EtOAc / heptane from 0 / 100 to 30 / 70) to give Intermediate 60 (1139 mg, yield: 81 %) as an orange solid.Intermediate 61 :

[0250] Intermediate 34 (950 mg, 2.32 mmol), Intermediate 60 (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-tert-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 61 (428 mg, yield: 39 %) as a yellow solid.Intermediate 62:

[0251] Intermediate 61 (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 Et2O to yield Intermediate 62 (HC1 salt, 406 mg, quantitative) as an orange solid.Intermediate 63 :

[0252] NaH (60 % in mineral oil, 2 mg, 0.036 mmol) was added to a solution of Compound 109 (20 mg, 0.035 mmol) in DMF (0.5 mL) at 0 °C. The resulting mixture was stirred for 30 min, then tert-butyl (2-iodoethoxy)dimethylsilane (CAS [101166-65-8], 11 pL, 0.035 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h. Saturated aqueous NH4CI (20 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried (MgSCU), filtered, and evaporated. The residue was purified by flash chromatography (12 g SiCL, EtOAc / heptane, from 0 / 100 to 100 / 0) to yield Intermediate 63 (9 mg, yield: 35 %) as a yellow solid.Intermediate 64:

[0253] Intermediate 64 was prepared in a similar manner as Intermediate 61, starting fromIntermediate 54 instead of Intermediate 60.Intermediate 65: (3-(Hydroxymethyl)-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid)Intermediate 65 may be prepared in 3 steps from methyl 3,4-dihydroxybenzoate (CAS [2150- 43-8]), by reacting it first with [3-bromo-2-(bromomethyl)propoxy]tris(l-methylethyl)silane (CAS [2411459-68-0]) in the presence of potassium carbonate in DMF at 80 °C; then by reacting the formed intermediate with tetrabutylammonium fluoride (CAS [429-41-4]) in THF at room temperature; and finally hydrolysing the ester with LiOH in a mixture of water, MeOH, and THF, at room temperature.Intermediate 66: thiochromane-7-carboxylic acid 1-oxide.

[0254] A solution of 7-bromothiochroman (CAS [855997-36-3], 150 mg, 0.641 mmol) in MeOH (2 mL) was cooled to 0 °C under nitrogen atmosphere. NaIO4 (1.5 mL, 0.5 M in water) was added dropwise. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with saturated aqueouos Na2SOs (2 mL) and H2O (2 mL), and was extracted with DCM (6 mL x 3). The combined organic layer was washed by brine (2 mL), dried with Na2SO4, and concentrated. The residue was purified by columnchromatography on silica gel (EtOAc / petroleum ether from 0 / 100 to 100 / 0) to give Intermediate 66 (160 mg, quantitative) as a white solid.Intermediate 67: 1 -imino- 114-thiochromane-7-carboxylic acid 1 -oxide.

[0255] PhI(OAc)2 (CAS [3240-34-4], 1120 mg, 3.48 mmol) was added to a solution of thiochroman-7-carboxylic acid (CAS [1391274-02-4], 150 mg, 0.769 mmol) and (NH^COs (200 mg, 2.081 mmol) in MeOH (6 mL). The reaction mixture was stirred at room temperature for 12 h. Water (6 mL) was added and the mixture was washed with DCM (6 mL). The pH of the aqueous layer was adjusted to 1~2 with HC1 (1 M in water, 2 mL). The aqueous layer was directly purified by reverse phase HPLC (Welch Xtimate C18 150 * 30 mm * 5 um; A: water (NH4OH+NH4HCO3), B: ACN, from: A (100 %) and B (0 %) to A (70 %) and B (30 %)) to give Intermediate 67 (120 mg, yield: 69 %).Intermediate 68: 4,4-difluorothiochromane-7-carboxylic acid 1,1-dioxide.

[0256] Step A: Methyl 4-oxothiochromane-7-carboxylate (CAS [361371-71-3] 200 mg, 0.9 mmol) was slowly added in portions to bi s(2-m ethoxy ethyl)aminosulfur trifluoride (CAS [202289-38-1], 1.2 g, 5.42 mmol). The mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO3(10 mL) at 0 °C and extracted with DCM (20 mL x 2). The 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 an intermediate sulfide (155 mg, yield: 66 %).

[0257] Step B: Potassium peroxymonosulfate (CAS [70693-62-8], 1450 mg, 2.36 mmol) was added to a solution of this intermediate sulfide (115 mg, 0.47 mmol) in THF / MeOH / H2O (1.8 mL / 3.6 mL / 1.8 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The organic layer was concentrated under reduced pressure to give an intermediate sulfone (90 mg, yield: 64 %).

[0258] Step C: To a solution of this intermediate sulfone (80 mg, 0.29 mmol) in THF (2 mL) was added LiOH (2 N in H2O, 0.4 mL, 0.8 mmol). The solution was stirred for 4 h at room temperature. The mixture was diluted with H2O (10 mL) and acidified with HC1 (2 N in water) to pH=2~3. The mixture was extracted with EtOAc (10 mL x 3) and the organic layer was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Boston Green ODS 150 * 30 mm * 5mm; A: water (0.225 % FA), B: ACN, from: A (68 %) and B (32 %) to A (38 %) and B (62 %)) to give Intermediate 68 (35 mg, yield: 46 %) as a red solid.Intermediate 69: 4-hydroxythiochromane-7-carboxylic acid 1,1-dioxide.NaBFL (90 mg, 2.38 mmol) was added slowly to a solution of 7-bromothiochroman-4-one 1,1-dioxide (CAS [1391147-59-3], 360 mg, 1.31 mmol) in MeOH (10 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. Saturated aqueous NH4CI (3 mL) was added to the mixture dropwise and it was extracted with EtOAc (3 mL x 3). The organic layer was washed with brine (1 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over silica gel (EtOAc / petroleum ether 0 / 100 to 100 / 0) to give an intermediate alcohol (300 mg, 1.08 mmol, 100 % purity, 82.78 % yield). To a solution of this intermediate alcohol (200 mg, 0.72 mmol) in DMSO (2 mL) and water (1.6 mL) was added K2CO3 (150 mg, 1.06 mmol), Pd(OAc)2 (CAS [3375-31-3], 20 mg, 0.09 mmol), and propane-1, 3-diylbis(dicyclohexylphosphonium) tetrafluoroborate(CAS [1002345- 50-7], 23 mg, 0.04 mmol) at room temperature. Then the mixture was degassed with CO 3 times and the mixture was stirred at 80 °C for 12 h under CO atmosphere (50 psi). After cooling, the mixture was filtered and the filtrate was washed with DCM (3 mL). The pH of the aqueous layer was adjusted to 1~2 with HC1 (1 M in water, 2 mL). This aqueous solution was directly purified by reverse phase HPLC (Boston Green ODS 150 x 30 mm x 5Um; A: water (FA), B: ACN, from A (85 %) and B (15 %) to A (55 %) and B (45 %)) to give Intermediate 69 (80 mg, 0.33 mmol, 45 % yield).Intermediate 70: 2-(hydroxymethyl)thiochromane-7-carboxylic acid 1,1-dioxide.

[0259] Step A: EtsN (0.1 mL) was added slowly to a solution of 3 -bromobenzenethiol (CAS [6320-01-0], 3.1 mL, 26.22 mmol) and furan-2, 5-dione (CAS [108-31-6], 2.57 g, 26.21 mmol ) in toluene (50 mL) and the mixture was stirred at 50°C for 1 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (50 mL), and cooled to 0 °C. A1CL (5.3 g, 39.748 mmol) was added to the solution and it was stirred for 30 min. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc / petroleum ether 0 / 100 to 35 / 65) to give an intermediate acid (3.1 g, yield: 40 %).

[0260] Step B: H2SO4 (0.5 mL) was slowly added (over 1 h) to a solution of this intermediate acid (3.1 g, 10.26 mmol) in MeOH (50 mL) at 60 °C. After cooling, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc / petroleum ether from 100 / 0 to 30 / 70) to give an intermediate ester (3 g, yield: 97).

[0261] Step C: SiEtsH (CAS [617-86-7], 3.6 mL, 22.93 mmol) was added to a solution of this intermediate ester (2.9 g, 9.63 mmol) in TFA (30 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After cooling, the mixture was diluted with FLO (50 mL) and extracted with EtOAc (50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc / petroleum ether from 0 / 100 to 40 / 60) to give thiochroman (2.2 g, yield: 78).

[0262] Step D: A solution of oxone (CAS [70693-62-8], 22 mg, 36.11 mmol) in water (10 mL) was added to a stirred solution of this intermediate thiochroman (2.1 g, 7.20 mmol) in MeOH / THF 3 / 1 (40 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solution was concentrated and treated with EtOAc (100 mL) and Na2SOs (aqueous, 50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography oversilica gel (EtOAc / petroleum ether from 0 / 100 to 50 / 50) to give an intermediate sulfone (2 g, yield: 86 %).

[0263] Step E: NaBEU (3.32 g, 87.755 mmol) was added to a solution of this intermediate sulfone (2.8 g, 8.773 mmol) in MeOH (40 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water (50 mL) at room temperature and extracted with EtOAc (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc / petroleum ether from 0 / 100 to 50 / 50) to give an intermediate alcohol (2.2 g, yield: 83 %).

[0264] Step F: K2CO3 (121 mg, 0.88 mmol), Pd(OAc)2(CAS [3375-31-3], 13 mg, 0.06 mmol), and propane- 1, 3 -diylbis (dicyclohexylphosphonium) tetrafluoroborate (CAS [1002345-50-7], 18 mg, 0.03 mmol) were added to a solution of this intermediate alcohol (170 mg, 0.577 mmol) in DMSO / H2O (2 / 1, 9 mL) at room temperature. The mixture was degassed with CO 3 times and the resulting mixture was stirred at 80 °C for 16 h under CO atmosphere (50 psi). After cooling, the reaction mixture was diluted with H2O (50 mL) and the pH of the mixture was adjusted to 3 with HC1 (2 N in water). The reaction mixture was diluted with another 50 mL of H2O and extracted with DCM / iPrOH (2 / 1, 50 mL x 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase column chromatography (H2O / ACN from 10 / 0 to 10 / 1) to give Intermediate 70 (50 mg, yield: 34 %).Intermediate 71 : l-((difluoromethyl)sulfonyl)indoline-6-carboxylic acid.

[0265] Step A: methyl l-((difluoromethyl)sulfonyl)indoline-6-carboxylate. Methyl indoline- 6-carboxylate (CAS [341988-36-1], 500 mg, 2.822 mmol) and K2CO3(1.17 g, 8.465 mmol, 3.0 eq.) were suspended in anhydrous THF (10 mL). Difluoromethanesulfonyl chloride (CAS [1512-30-7], 0.626 mL, 7.054 mmol, 2.6 eq.) was added dropwise at room temperature. After 2.5 h, additional K2CO3(500 mg, 3.6 mmol, 1.3 eq.) and difluoromethanesulfonyl chloride (300 pL, 2.9 mmol, 1.1 eq.) were added and the mixture was stirred overnight. The mixture was filtered through a celite pad, the filtrate was evaporated, and the residue was purified byflash column chromatography (24 g SiCh, EtOAc / heptane from 0 / 100 to 40 / 60) to give the title compound (346 mg, yield: 42 %) as a colourless solid.

[0266] Step B: l-((difluoromethyl)sulfonyl)indoline-6-carboxylic acid. A solution of methyl l-((difluoromethyl)sulfonyl)indoline-6-carboxylate (320 mg, 1.099 mmol) and LiOH (79 mg, 3.3 mmol, 3.0 eq.) in a mixture of THF (2.4 mL), MeOH (2.4 mL), and water (2.4 mL) was stirred at room temperature for 2.5 h. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was washed twice with EtOAc. The aqueous layer was carefully acidified with drops of HC1 (37 % in water) until highly acidic, at which point a solid precipitated. The solid was filtered and washed with water, then dried to give Intermediate 71 (234 mg, yield: 77 %) as a colourless solid.Intermediate 72: 4-chloro-l-((difluoromethyl)sulfonyl)indoline-6-carboxylic acid.

[0267] Step A: methyl 4-chloro-l-((difluoromethyl)sulfonyl)indoline-6-carboxylate. Difluoromethanesulfonyl chloride (CAS [1512-30-7], 0.419 mL, 4.725 mmol, 2.5 eq.) was added dropwise to a suspension of Intermediate 12 (400 mg, 1.89 mmol) and K2CO3 (784 mg, 5.67 mmol, 3.0 eq.) in anhydrous THF (7 mL) at room temperature. After 1 h, an additional portion of K2CO3 (500 mg, 1.9 eq.) and difluoromethanesulfonyl chloride (400 uL, 2.5 eq.) were added and stirring was continued overnight. The mixture was filtered through a celite pad and the filtrate was evaporated. The residue was purified by flash column chromatography (12 g SiCL; EtOAc / heptane 0 / 100 to 30 / 70) to give the title compound (240 mg, yield: 39 %).

[0268] Step B: 4-chloro-l-((difluoromethyl)sulfonyl)indoline-6-carboxylic acid. Intermediate 72 was prepared following the same procedure as Intermediate 71, step B.Intermediate 73 : l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxylic acid.

[0269] Step A: methyl l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6- carboxylate. Methanesulfonyl chloride (CAS [124-63-0], 0.590 mL, 7.62 mmol, 2.02 eq.) was added dropwise to a stirred solution of ethyl 2,3-dihydro-U / -pyrrolo[3,2-b]pyridine-6- carboxylate (CAS [1194732-42-7], 0.725 g, 3.77 mmol, 1.0 eq.) and Et3N (1.1 mL, 7.89 mmol, 2.09 eq.) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was separated, dried over MgSCU, filtered, and the solvents evaporated. The residue was purified by flash column chromatography (silica, 25 g; DCM:MeOH (9: 1) in DCM, from 0 / 100 to 20 / 80) to yield the title compound (588 mg, yield: 57 %) as a yellow solid.

[0270] Step B: l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxylic acid. A solution of NaOH (1 M in water, 4.5 mL, 4.5 mmol, 2.07 eq.) was added to a solution of methyl l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxylate (588 mg, 2.18 mmol, 1.0 eq.) in MeOH (9 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water. KHSO4 (1 M in water, 5 mL, 5.0 mmol, 2.3 eq.) was added dropwise over 10 min with vigorous stirring, reaching a pH of 2-3. AcOEt was added and the mixture was stirred for 2 min. The organic layer was separated, dried with MgSCU, filtered, and concentrated to yield the title compound (460 mg, yield: 86 %) as a yellow solid, used without further purification.Intermediate 74: 4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylic acid.

[0271] Step A: methyl 6-methyl-4-pivalamidopicolinate. Trimethylacetyl chloride (CAS [3282-30-2], 1.8 mL, 14.62 mmol, 1.5 eq.) was added to a stirred solution of methyl 4-amino- 6-methylpyridine-2-carboxylate (CAS [1807222-33-8], 1.6 g, 9.63 mmol, 1.0 eq.) and EtsN (2.7 mL, 19.37 mmol, 2.0 eq.) in dry DCM (21 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with DCM (x 3). The combined organic layer was dried over MgSCU, filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (80 g SiCL; EtOAc / heptane from 100 / 0 to 50 / 50) to yield methyl 6-methyl-4- pivalamidopicolinate (1.65 g, yield: 68 %) as a white solid.

[0272] Step B: Step B: methyl 5-bromo-6-methyl-4-pivalamidopicolinate. N- Bromosuccinimide (CAS [128-08-5], 1.2 g, 6.74 mmol, 1.02 eq.) was added to a stirred solution of methyl 6-methyl-4-pivalamidopicolinate (1.65 g, 6.59 mmol, 1.0 eq.) in ACN (20 mL) at room temperature. The reaction mixture was stirred at 65 °C for 72 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 25 g; EtOAc / heptane from 0 / 100 to 50 / 50) to yield methyl 5-bromo-6- methyl-4-pivalamidopicolinate (1.4 g, yield: 61 %) as a white solid.

[0273] Step C: methyl (E)-5-(2-ethoxyvinyl)-6-methyl-4-pivalamidopicolinate. Palladium(II) acetate (CAS [3375-31-3], 29 mg, 0.13 mmol, 0.03 eq.) and SPhos (CAS [657408-07-6], 132 mg, 0.32 mmol, 0.08 eq.) were added to a mixture of methyl 5-bromo-6-methyl-4- pivalamidopicolinate (1.4 g, 4.25 mmol, 1.0 eq.), (E)-(2-ethoxyvinyl)boronic acid pinacol ester (CAS [1201905-61-4], 1.5 g, 7.57 mmol, 1.78 eq.), and potassium phosphate tribasic (CAS [7778-53-2], 1.8 g, 8.48 mmol, 2.0 eq.) in ACN (21 mL) and water (5 mL) at room temperature while nitrogen was bubbling through the mixture. The mixture was stirred at 90 °C in a sealed tube for 16 h. The mixture was diluted with water and EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (silica, 80 g; DCM:MeOH (9: 1) in DCM from 0 / 100 to 10 / 90) to yield methyl (E)-5-(2-ethoxyvinyl)-6-methyl-4- pivalamidopicolinate (620 mg, yield: 45 %) as a white solid.

[0274] Step D: 4-methyl-lH-pyrrolo[3,2-c]pyridine-6-carboxylic acid, methyl (E)-5-(2- ethoxyvinyl)-6-methyl-4-pivalamidopicolinate (700 mg, 0.13 mmol) was dissolved in HC1 (4 M in water, 14.5 mL, 58.0 mmol) in a sealed tube and the reaction mixture was stirred at 60°C for 2 h. The reaction mixture was concentrated in vacuo to yield 4-methyl-lH-pyrrolo[3,2- c]pyridine-6-carboxylic acid (489 mg, yield: 99 %) as a yellow solid.

[0275] Step E: methyl 4-methyl-lH-pyrrolo[3,2-c]pyridine-6-carboxylate. Sulfuric acid (0.45 mL, 8.44 mmol, 3.0 eq.) was added to a solution of 4-methyl-lH-pyrrolo[3,2-c]pyridine-6- carboxylic acid (489 mg, 2.78 mmol) in MeOH (6 mL). The reaction mixture was stirred at 65 °C for 16 h. After cooling, saturated aqueous Na2COs was added until pH 8, then the mixture was extracted with DCM:MeOH (9: 1) (x 3). The combined organic layer was dried over MgSCU, filtered, and concentrated to give methyl 4-methyl-lH-pyrrolo[3,2-c]pyridine-6- carboxylate (285 mg, yield: 53 %) as a yellow solid.

[0276] Step F: 1 -(tert-butyl) 6-methyl 4-methyl-lH-pyrrolo[3,2-c]pyridine-l,6-dicarboxylate. Di-tert-butyl dicarbonate (CAS [24424-99-5], 660 mg, 3.02 mmol, 2.0 eq.) was added to a stirred solution of methyl 4-methyl-lH-pyrrolo[3,2-c]pyridine-6-carboxylate (285 mg, 1.49 mmol, 1.0 eq.), EtsN (0.44 mL, 3.16 mmol, 2.1 eq.) in dry DCM (7 mL) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water and extracted with DCM (x 3). The combined organic layer was dried over MgSCU, filtered, and the solvent was evaporated. The crude product was purified by flash column chromatography (20 g silica; EtOAc / heptane from 100 / 0 to 45 / 55) to yield 1 -(tert-butyl) 6-methyl 4-methyl-lH-pyrrolo[3,2-c]pyridine-l,6-dicarboxylate (370 mg, yield: 84 %) as a white solid.

[0277] Step G: 1 -(tert-butyl) 6-methyl 4-methyl-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-l,6- di carb oxy late. Palladium hydroxide (CAS [12135-22-7], 60 mg, 0.09 mmol, 0.067 eq.) was added to a stirred solution of 1 -(tert-butyl) 6-methyl 4-methyl-lH-pyrrolo[3,2-c]pyridine-l,6- dicarboxylate (370 mg, 1.27 mmol, 1.0 eq.) in MeOH (8 mL) under nitrogen atmosphere. Then, the mixture was purged with hydrogen and stirred for 16 h at 60 °C under hydrogen atmosphere. The reaction mixture was filtered through a short pad of celite and the solvent of the filtrate was removed to yield 1 -(tert-butyl) 6-methyl 4-methyl-2,3-dihydro-lH- pyrrolo[3,2-c]pyridine-l,6-dicarboxylate (360 mg, yield: 95 %) as a white solid.

[0278] Step H: methyl 4-methyl-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxylate. Trifluoroacetic acid (CAS [76-05-1], 1 mL, 13.07 mmol, 10.0 eq.) was added to a stirred solution of 1 -(tert-butyl) 6-methyl 4-methyl-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-l,6- dicarboxylate (360 mg, 1.23 mmol, 1.0 eq.) in DCM (2 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 saturatedNa2CC>3 aqueous solution was added until pH 8. DCM was added and the aqueous layer was extracted with DCM (x 5). The combined organic layer was dried over MgSCL, filtered, and concentrated to yield methyl 4-methyl-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxylate (205 mg, yield: 85 %) as a yellow solid.

[0279] Step I: methyl 4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylate. Methanesulfonyl chloride (CAS [124-63-0], 0.165 mL, 2.13 mmol, 2.0 eq.) was added dropwise to a stirred solution of methyl 4-methyl-2,3-dihydro-lH-pyrrolo[3,2- c]pyridine-6-carboxylate (0.205 g, 1.07 mmol, 1.0 eq.) and EtsN (0.305 mL, 2.19 mmol, 2.05 eq.) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was separated, dried over MgSCL, filtered, and the solvents evaporated. The crude product was purified by flash column chromatography (silica, 25 g; DCM:MeOH:NH3 (10: 1 :0.25) in DCM, from 0 / 100 to 30 / 70) to yield methyl 4-methyl-l-(methylsulfonyl)-2,3- dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxylate (193 mg, yield: 66 %) as a white solid.

[0280] Step J: 4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylic acid. A solution of NaOH (1 M in water, 1.5 mL, 1.5 mmol, 2.1 eq.) was added to a solution of methyl 4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylate (193 mg, 0.71 mmol, 1.0 eq.) in MeOH (4 mL) at room temperature and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water. KHSO4 (1 M in water, 1.6 mL, 1.6 mmol) was added dropwise with vigorous stirring until the pH reached the value of 2-3. AcOEt was added and the mixture was stirred for 2 min. The layers were separated. The organic layer was dried with MgSCL, filtered, and concentrated to yield 4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylic acid (152 mg, yield: 82 %) as a yellow solid.Intermediate 75: (2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methanamine.

[0281] 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 d (2.67 g, 7.537 mmol)and 4-Boc-4,7-diazaspiro[2.5]octane (CAS [674792-08-6], 4 g, 18.842 mmol, 2.5 eq.) were suspended in DMSO (80 mL) and DIPEA (3.9 mL, 22.61 mmol, 3 eq.) was added. The reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSCU, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (DCM:MeOH 9: 1 in DCM, from 0 % to 20 %) to yield 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 (1.72 g, yield: 42 %).

[0282] 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)-l,6-naphthyridin-2- yl)pyri din-2 -yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (1.54 g, 2.817 mmol) was suspended in MeOH (15 mL) and HC1 (6 M in iPrOH, 15 mL, 90 mmol, 32 eq.) was added. The reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated to yield Intermediate 75 (HC1 salt, 1.49 g, yield: quantitative).Intermediate 76: l-((2-hydroxyethyl)sulfonyl)indoline-6-carboxylic acid and l-((2- methoxyethyl)sulfonyl)indoline-6-carboxylic acid.

[0283] Step A: methyl l-((2-hydroxyethyl)sulfonyl)indoline-6-carboxylate. Methyl indoline- 6-carboxylate (CAS [341988-36-1], 300 mg, 1.693 mmol) was dissolved in DCM (3 mL) and EtsN (0.94 mL, 6.772 mmol, 4 eq.) was added. The reaction mixture was cooled to 0 °C and 2 -hydroxy ethane- 1 -sulfonyl chloride (CAS [78303-70-5], 538 mg, 3.725 mmol, 2.2 eq.) was added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into water and the mixture was extracted with DCM (3 x). The organic layer was dried over MgSCU, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (12 g; EtOAc / heptane from 10 / 90 to 100 / 0) to yield methyl 1- ((2-hydroxyethyl)sulfonyl)indoline-6-carboxylate (125 mg, yield: 26 %) as a white solid.

[0284] Step B: methyl l-(vinylsulfonyl)indoline-6-carboxylate. methyl l-((2- hydroxyethyl)sulfonyl)indoline-6-carboxylate (125 mg, 0.438 mmol) was dissolved in HC1 (4M in 1,4-dioxane, 4 mL, 16 mmol, 36 eq.). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM (3 x). The organic layer was dried over MgSC , filtered, and evaporated to yield the title compound (140 mg, yield: 89 %) as a clear oil.

[0285] Step C: l-((2-hydroxyethyl)sulfonyl)indoline-6-carboxylic acid and l-((2- methoxyethyl)sulfonyl)indoline-6-carboxylic acid, methyl 1 -(vinyl sulfonyl)indoline-6- carboxylate (140 mg, 0.392 mmol) was suspended in THF (1 mL), MeOH (6.5 mL) and water (1.5 mL). LiOH (47 mg, 1.963 mmol, 5 eq.) was added and the reaction mixture was stirred at room temperature for 7 h, then at 60 °C overnight. The reaction mixture was concentrated under reduced pressure and the aqueous suspension was acidified with HC1 (6 M in water). The solid that formed was filtered, and washed with water, to yield the title compounds (140 mg).Intermediate 77: l-(cyclopropylsulfonyl)indoline-6-carboxylic acid.

[0286] Step A: methyl l-(cyclopropylsulfonyl)indoline-6-carboxylate. Methyl indoline-6- carboxylate (CAS [341988-36-1], 500 mg, 2.822 mmol) was dissolved in DCM (5 mL) and EtsN (1.6 mL, 11.287 mmol, 4 eq.). The reaction mixture was cooled to 0 °C and cyclopropane sulfonyl chloride (CAS [139631-62-2], 873 mg, 6.208 mmol, 2.2 eq.) was added. The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into saturated aqueous NH4CI and the aqueous layer was extracted with DCM (3 x). The combined organic layer was dried over MgSCU, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (12 g; EtOAc / heptane from 30 / 70 to 80 / 20) to yield the title compound (678 mg, yield: 85 %).

[0287] Step B: l-(cyclopropylsulfonyl)indoline-6-carboxylic acid, methyl 1- (cyclopropylsulfonyl)indoline-6-carboxylate (678 mg, 2.41 mmol) was dissolved in THF (10 mL), water (10 mL), and MeOH (2 mL). LiOH (577 mg, 24.1 mmol, 10 eq.) was added and the reaction mixture was stirred at room temperature for 20 h. The organic solvents were evaporated and the aqueous layer was acidified with 37 % aqueous HC1. The precipitate was filtered, washed two times with water and two times with Et2O to yield the title compound (620 mg, yield: quantitative) as a white powder.Intermediate 78: l-((difluoromethyl)sulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylic acid.

[0288] Step A: methyl l-((difluoromethyl)sulfonyl)-lH-pyrrolo[3,2-c]pyridine-6-carboxylate. To a suspension of methyl U / -pyrrolo[3,2-b]pyridine-6-carboxylate (CAS [1015609-11-6], 1 g, 5.676 mmol) in anhydrous THF (20 mL) was slowly added sodium hydride (60 % in mineral oil, 500 mg, 12.488 mmol, 2.2 eq.). The reaction mixture was stirred at room temperature for 5 min. Difluoromethane sulfonyl chloride (CAS [1512-30-7], 1.5 mL, 17.028 mmol, 3 eq.) was added dropwise and the reaction mixture was stirred at room temperature for 5 h. Saturated aqueous NH4CI was carefully added to the reaction mixture and it was extracted twice with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography on silica gel (24 g; MeOH in DCM, from 0 % to 8 %) to yield methyl l-((difluoromethyl)sulfonyl)-lH- pyrrolo[3,2-c]pyridine-6-carboxylate (364 mg, yield: 22 %) as a light yellow solid.

[0289] Step B: methyl l-((difluoromethyl)sulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylate. methyl l-((difluoromethyl)sulfonyl)-lH-pyrrolo[3,2-c]pyridine-6-carboxylate (250 mg, 0.861 mmol) and palladium hydroxide on carbon (CAS [12135-22-7], 250 mg, 0.356 mmol, 0.4 eq.) were placed in a microwave vial and MeOH (5 mL) was added. The vial was sealed, evacuated, and refilled with hydrogen ten times. The reaction mixture was stirred vigorously at room temperature overnight under hydrogen atmosphere. The reaction mixture was filtered through a Celite pad, washing with MeOH, and the filtrate was evaporated to yield methyl l-((difluoromethyl)sulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylate (213 mg, yield: 84 %).

[0290] Step C: l-((difluoromethyl)sulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxylic acid. Lithium iodide (CAS [10377-51-2], 400 mg, 2.994 mmol, 5 eq.) was added to a solution of methyl l-((difluoromethyl)sulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine- 6-carboxylate (175 mg, 0.599 mmol) in EtOAc (2.0 mL). The reaction mixture was stirred at 80 °C for 4.5 h. The solvent was evaporated and the residue was taken up in 1,4-di oxane (2 mL) and HC1 (4 M in 1,4-dioxane, 0.5 mL, 1.796 mmol, 3 eq.). The reaction mixture was stirred at room temperature for 10 min and the solvent was evaporated to yield 1-((difluoromethyl)sulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxylic acid (HC1 salt, 188 mg, yield: quantitative).Intermediate 79: tert-butyl ((6-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamoyl)-l-(methylsulfonyl)indolin-4-yl)methyl)carbamate.

[0291] Step A: methyl 4-((l,3-dioxoisoindolin-2-yl)methyl)-l-(methylsulfonyl)indoline-6- carboxylate. Intermediate 49, product from Step D (869 mg, 3.04 mmol), phthalimide (CAS [85-41-6], 1.34 g, 9.14 mmol, 3 eq.), and triphenylphosphine (CAS [603-35-0], 2.4 g, 9.14 mmol, 3 eq.) were dissolved in dry THF (25 mL) under nitrogen atmosphere. A solution of DIAD (CAS [2446-83-5], 1.8 mL, 9.14 mmol, 3 eq.) in dry THF (1 mL) was then added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The solid obtained was recrystallized in acetonitrile and filtered to yield a first crop of the title compound (818 mg, yield: 64 %) as a white solid. The filtrate was evaporated and the residue was purified by flash column chromatography (80 g SiCL; EtOAc / heptane from 0 / 100 to 100 / 0) to give a second crop of the title compound (143 mg, yield: 11 %) as a white solid.

[0292] Step B: methyl 4-(((tert-butoxycarbonyl)amino)methyl)-l-(methylsulfonyl)indoline-6- carboxylate. Hydrazine monohydrate (CAS [7803-57-8], 0.30 mL, 4.0 mmol, 2.2 eq.) was added to a stirred solution of methyl 4-((l,3-dioxoisoindolin-2-yl)methyl)-l- (methylsulfonyl)indoline-6-carboxylate (740 mg, 1.78 mmol) in MeOH (15 mL) at 60 °C. The reaction mixture was then stirred for 24 h at room temperature. The solid was filtered off and washed several times with MeOH. The filtrate was concentrated to dryness. MeOH (15 mL) and DCM (30 mL) were added, followed by di tert-butyl dicarbonate (CAS [24424-99-5], 0.84 mL, 3.58 mmol, 2 eq.), and the reaction mixture was stirred for 1 h at room temperature. Water and DCM were added to the mixture. The organic layer was separated, dried overMgSC , filtered, and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (25 g; EtOAc / heptane from 0 / 100 to 90 / 10) to yield methyl 4- (((tert-butoxycarbonyl)amino)methyl)-l-(methylsulfonyl)indoline-6-carboxylate (521 mg, yield: 75 %) as a white solid.

[0293] Step C: 4-(((tert-butoxycarbonyl)amino)methyl)-l-(methylsulfonyl)indoline-6- carboxylic acid. Lithium hydroxide monohydrate (CAS [1310-66-3], 332 mg, 7.92 mmol, 5.8 eq.) was added to a solution of methyl 4-(((tert-butoxycarbonyl)amino)methyl)-l- (methylsulfonyl)indoline-6-carboxylate (521 mg, 1.35 mmol) in THF (25 mL) and water (5 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). DCM was added and the organic layer was separated, dried (MgSCU), filtered, and the solvents evaporated in vacuo to yield the title compound (505 mg, yield: 99 %) as a white solid, used without further purification.

[0294] Step D: tert-butyl ((6-(((2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamoyl)-l-(methylsulfonyl)indolin-4-yl)methyl)carbamate. HBTU (CAS [94790-37-1], 161 mg, 0.424 mmol. 1.1 eq.) was added to a stirred solution of Intermediate 6 (163 mg, 0.386 mmol), 4-(((tert-butoxycarbonyl)amino)methyl)-l- (methylsulfonyl)indoline-6-carboxylic acid (200 mg, 0.540 mmol, 1.4 eq.), and DIPEA (0.27 mL, 1.54 mmol, 4 eq.) in DMF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed with Na2COs (1 M in water). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL; EtOAc / heptane from 0 to 100 %) to yield the title compound (188 mg, yield: 69 %) as a yellow solid.Intermediate 80: l'-(methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxylic acid.

[0295] Step A: methyl l'-(methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxylate.EtsN (151 pL, 1.08 mmol, 2 eq.) was added to a stirred solution of l',2'-dihydro- spiro[cyclopropane-l,3'-[3J7]indole]-6'-carboxylic acid, methyl ester (CAS [1860865-59-3], 110 mg, 0.54 mmol) in DCM (10 mL) under nitrogen atmosphere. The reaction mixture wascooled to 0 °C and methanesulfonyl chloride (CAS [124-63-0], 63 pL, 0.81 mmol, 1.5 eq.) was added. The reaction mixture was then stirred at room temperature for 2 h. The mixture was partitioned between water and DCM. The organic layer was separated, dried over MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by column chromatography (25 g SiCL; EtOAc / heptane from 0 / 100 to 65 / 35) to yield methyl 1'- (methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxylate (91 mg, yield: 59 %) as a solid.

[0296] Step B: l'-(methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxylic acid. Lithium hydroxide monohydrate (CAS [1310-66-3], 90 mg, 2.15 mmol, 5 eq.) was added to a solution of methyl l'-(methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxylate (121 mg, 0.43 mmol) in THF (5 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 48 h. The pH was brought to 3 by addition of KHSO4 (1 M in water). DCM was added and the organic layer was separated, dried over MgSCU, filtered, and the solvents evaporated in vacuo to yield l'-(methylsulfonyl)spiro[cyclopropane- l,3'-indoline]-6'-carboxylic acid (100 mg, yield: 85 %) as a solid, used without further purification.Intermediate 81 : (R)-(2-(6-(3-methoxypyrrolidin-l-yl)pyrazin-2-yl)-l,6-naphthyridin-7- yl)methanamine.

[0297] Step A: (R)-2-chloro-6-(3-methoxypyrrolidin-l-yl)pyrazine. (R)-3- Methoxypyrrolidine (CAS [120099-60-7], 0.65 g, 6.42 mmol, 1.2 eq.) was added to a stirred solution of 2,6-dichloropyrazine (CAS [4774-14-5], 0.798 g, 5.35 mmol) and DIPEA (1.86 mL, 10.7 mmol, 2 eq.) in DMSO (3 mL) at room temperature. The reaction mixture was stirred at 120 °C for 2 h. After cooling, the mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL;EtOAc / heptane from 0 / 100 to 60 / 40) to afford (R)-2-chloro-6-(3-methoxypyrrolidin-l- yl)pyrazine (0.538 g, yield: 47 %) as an oil.

[0298] Step B: tert-butyl (R)-((2-(6-(3-methoxypyrrolidin-l-yl)pyrazin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamate. Anhydrous AcOK (CAS [127-08-2], 230 mg, 2.34 mmol 2.5 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 261 mg, 1.03 mmol, 1.1 eq.), tricyclohexylphosphine (CAS [2622-14-2], 10 mg, 0.037 mmol, 0.04 eq.), and Pd(OAc)2 (CAS [3375-31-3], 4 mg, 0.019 mmol. 0.02 eq.) were added to a solution of (R)-2-chloro-6- (3-methoxypyrrolidin-l-yl)pyrazine (200 mg, 0.936 mmol) in 1,4-dioxane (4 mL) under nitrogen atmosphere. The reaction mixture was stirred at 110 °C for 30 min. The reaction mixture was allowed to cool to room temperature under nitrogen. K2CO3 (258 mg, 1.87 mmol, 2 eq.), CuCl (CAS [7758-89-6], 93 mg, 0.936 mmol, 1 eq.), and Intermediate 3 (274 mg, 0.936 mmol, 1 eq.) were added. The reaction mixture was then stirred at 110 °C for 16 h. After cooling, the mixture was diluted with water and EtOAc. The organic layer was separated, dried over MgSCU, filtered, and solvents evaporated in vacuo. The residue was purified by flash column chromatography (25 g SiCL; EtOAc / heptane from 0 / 100 to 100 / 0) to yield the title compound (265 mg, yield: 58 %) as a yellow solid.

[0299] Step C: (R)-(2-(6-(3-methoxypyrrolidin-l-yl)pyrazin-2-yl)-l,6-naphthyridin-7- yl)methanamine. A solution of tert-butyl (R)-((2-(6-(3-methoxypyrrolidin-l-yl)pyrazin-2-yl)- l,6-naphthyridin-7-yl)methyl)carbamate (0.265 g, 0.607 mmol) in HC1 in (4 N in 1,4-dioxane, 1.5 mL, 6.0 mmol, 10 eq.) and 1,4-dioxane (7 mL) was stirred at room temperature for 3 h. The solvent was evaporated to yield (R)-(2-(6-(3-methoxypyrrolidin-l-yl)pyrazin-2-yl)-l,6- naphthyridin-7-yl)methanamine (HC1 salt, 285 mg, yield: 92 %).Intermediate 82: (*S)-4-cyano-4-methylisochromane-6-carboxylic acid and Intermediate 83: (*R)-4-cyano-4-methylisochromane-6-carboxylic acid.

[0300] Step A: 6-bromo-4-methylisochroman-4-ol. Methylmagnesium bromide (CAS [75-16- 1], 2.4 M in Et2O, 9.8 mL, 23.76 mmol) was added dropwise to a suspension of 6-bromo-lJT- 2-benzopyran-4(3J7)-one (CAS [676134-68-2], 1.786 g, 7.87 mmol) and anhydrous cerium(III) chloride (CAS [7790-86-5], 0.984 g, 4 mmol) in dry THF (65 mL) at 0 °C undernitrogen atmosphere. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. The reaction was quenched carefully with water (30 mL), then EtOAc (50 mL) was added. The mixture was filtered through a pad of Celite that was further rinsed with EtOAc (3 x 20 mL). The organic layer was separated and the aqueous layer was extracted once more with EtOAc (30 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (80 g; EtOAc / heptane from 0 / 100 to 35 / 65) to give 6- bromo-4-methylisochroman-4-ol (1.54 g, yield: 80 %) as an oil.

[0301] Step B: 6-bromo-4-methylisochromane-4-carbonitrile. Indium(III) bromide (CAS [13465-09-3], 508 mg, 1.43 mmol) was added to a solution of 6-bromo-4-methylisochroman- 4-ol (1.54 g, 6.33 mmol) and trimethyl silyl cyanide (CAS [7677-24-9], 1.6 mL, 12.8 mmol) in DCM (35 mL) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 15 min, then at room temperature for 1.5 h. The reaction mixture was poured into water (25 mL) and the mixture was extracted with DCM (2 x 25 mL). The combined organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25 g; EtOAc / heptane from 0 / 100 to 25 / 75) to give 6-bromo-4- methylisochromane-4-carbonitrile (794 mg, yield: 50 %) as a thick oil.

[0302] Step C: 4-cyano-4-methylisochromane-6-carboxylic acid. A pressure reactor was charged with 6-bromo-4-methylisochromane-4-carbonitrile (1.50 g, 5.95 mmol), Pd(dppf)Cl2.CH2Cl2(CAS [95464-05-4], 270 mg, 0.331 mmol), and K2CO3(1.3 g, 9.40 mmol) in a mixture of DMSO (25 mL) and water (5 mL). The mixture was degassed and purged with carbon monoxide (3 times). Finally, the mixture was pressurized with carbon monoxide (10 bar) and stirred at 100 °C for 16 h. After cooling, the mixture was diluted with water (150 mL) and Na2CO3(1 M in water, 10 mL). The aqueous solution was washed with EtOAc (2 x 100 mL) and the washes were discarded. The aqueous solution was then acidified with HC1 (1 M in water) to pH 2-3 and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (2 x 25 mL) dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography over silica gel (80 g; MeOH in DCM from 0 to 10 %) to afford 4-cyano-4-methylisochromane-6-carboxylic acid (960 mg, yield: 74 %) as a white solid.

[0303] Step D: (*S)-4-cyano-4-methylisochromane-6-carboxylic acid and Intermediate 83: (*R)-4-cyano-4-methylisochromane-6-carboxylic acid. 4-cyano-4-methylisochromane-6- carboxylic acid (970 mg) was purified by preparative SFC (Lux Amylose-1, 5 pm 250 x 30mm; 83 % CO2 - 17 % MeOH + 0.1 % DEA). The desired fractions were collected and concentrated in vacuo. The residues were partitioned between water (25mL) and EtOAc (50 mL). The pH of the aqueous layer was brought to 1 with HC1 (1 M in water). The organic layers were separated and aqueous layers were extracted twice more with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give Intermediate 82 (198 mg, yield: 15 %) and Intermediate 83 (167 mg, yield: 12 %), both as white solids.Intermediate 83: (*R)-4-fluoro-4-methylisochromane-6-carboxylic acid and Intermediate 84: (*S)-4-fluoro-4-methylisochromane-6-carboxylic acid.

[0304] The title compounds were prepared in a manner analogous to Intermediate 81 and Intermediate 82, using 4-fluoro-3,4-dihydro-4-m ethyl- IT / -2-benzopyran-6-carboxylic acid (CAS [2677883-83-7]) in Step D.Intermediate 85: (2-(3-(azetidin-l-yl)-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7- yl)methanamine.

[0305] Step A: tert-butyl ((2-(3-bromo-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. 3-Bromo-4-fluoro-17 / -pyrazole (CAS [1621526-49-5], 500 mg, 3.03 mmol, 5 eq.) was added to a stirred solution of Intermediate 3 (178 mg, 0.606 mmol) and DIPEA (1 mL, 6.06 mmol, 10 eq.) in DMSO (2 mL) at room temperature. The reaction mixture was stirred at 120 °C for 2 h. After cooling, the mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSCU, filtered, and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (12 g SiCE; EtOAc / heptane from 0 / 100 to 100 / 0) to yield tert-butyl ((2-(3-bromo-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (218 mg, yield: 84 %) as a brown solid.

[0306] Step B: tert-butyl ((2-(3-(azetidin-l-yl)-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. tert-butyl ((2-(3-bromo-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7- yl)methyl)carbamate (186 mg. 0.440 mmol), azetidine (CAS [503-29-7], 59 pL, 0.881 mmol, 2 eq.), and CS2CO3 (CAS [534-17-8], 362 mg, 1.11 mmol, 2.5 eq.) were dissolved in 1,4- di oxane (4 mL). The mixture was bubbled with nitrogen for 10 min. Then, XantPhos (CAS [161265-03-8], 51 mg, 0.088 mmol, 0.2 eq.) and Pd(OAc)2(CAS [3375-31-3], 10 mg, 0.044 mmol, 0.1 eq.) were added and the mixture was stirred at 120 °C for 16 h under nitrogen atmosphere. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSCU, 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 100 / 0), followed by reverse phase column chromatography (Phenomenex Gemini C18 30 x 100 mm, 5 pm; from 49 % [25mM NH4HCO3] - 51 % [ACN:MeOH (1 :1)] to 6 % [25mM NH4HCO3] - 94 % [ACN:MeOH (1 : 1)]) to yield tert-butyl ((2-(3-(azetidin-l-yl)-4-fluoro-lH- pyrazol-l-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (87 mg, yield: 49 %) as a white solid.

[0307] Step C: (2-(3-(azetidin-l-yl)-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7- yl)methanamine. TFA (CAS [76-05-1], 0.4 mL, 4.36 mmol, 20 eq.) was added to a stirred solution of tert-butyl ((2-(3-(azetidin-l-yl)-4-fluoro-lH-pyrazol-l-yl)-l,6-naphthyridin-7- yl)methyl)carbamate (0.087 g, 0.218 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 to yield Intermediate 85 (TFA salt, 125 mg, yield: 98 %) as an orange oil.Intermediate 86: 4-fluoro-l-(methylsulfonyl)indoline-6-carboxylic acid.

[0308] Step A: methyl 4-fluoroindoline-6-carboxylate. Triethylsilane (CAS [617-86-7], 1.75 mL 11 mmol, 3 eq.) was added dropwise at room temperature to a solution of methyl 4- fluoro-U / -indole-6-carboxylate (CAS [885518-27-4], 705 mg, 0.26 mmol) in TFA (10 mL). The reaction mixture was stirred at 60 °C for 1 h. The resulting mixture was evaporated in vacuo. The residue was taken up in Na2CO3 (1 M in water) and the mixture was extractedwith DCM. The organic layer was dried over MgSCU, filtered, and concentrated under reduced pressure to yield methyl 4-fluoroindoline-6-carboxylate (625 mg, yield: 71 %) as a sticky brown solid.

[0309] Step B: methyl 4-fluoro-l-(methylsulfonyl)indoline-6-carboxylate. Methanesulfonyl chloride (CAS [14418-84-9], 0.54 mL, 6.97 mmol, 2 eq.) was added to an ice-cold solution of methyl 4-fluoroindoline-6-carboxylate (0.681 g, 3.49 mmol) and EtsN (2.3 mL, 17.1 mmol, 4.8 eq.) in DCM (15 mL). The mixture was stirred at room temperature for 2 h. The reaction was quenched by addition of Na2COs (1 M in water). The mixture was extracted with DCM. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (25 g SiCL; EtOAc / heptane from 0 / 100 to 100 / 0) to give methyl 4-fluoro-l-(methylsulfonyl)indoline-6-carboxylate (472 mg, yield: 49 %) as a white solid.

[0310] Step C: 4-fluoro-l-(methylsulfonyl)indoline-6-carboxylic acid. Lithium hydroxide monohydrate (CAS [1310-66-3], 423 mg, 10.1 mmol, 5.8 eq.) was added to a solution of methyl 4-fluoro-l-(methylsulfonyl)indoline-6-carboxylate (472 mg, 0.358 mmol) in THF (24 mL) and water (6 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). DCM was added and the organic layer was separated, dried on MgSCU, filtered, and the solvents evaporated in vacuo to yield 4-fluoro-l-(methylsulfonyl)indoline-6-carboxylic acid (420 mg, yield: 94 %) as a white solid.Intermediate 87: 4-hydroxythiochromane-7-carboxylic acid 1,1 -di oxide.

[0311] Step A: 7-bromo-4-hydroxythiochromane 1,1-dioxide. NaBHi (90 mg, 2.379 mmol) was added slowly to a solution of 7-bromo-2,3-dihydro-4Z / -l-benzothiopyran-4-one, 1,1- dioxide (CAS [1391147-59-3], 360 mg, 1.309 mmol) in MeOH (10 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. Saturated aqueous NH4CI (3 mL) was added to the mixture dropwise and it was extracted with EtOAc (3 mL x 3). The organic layer was washed with brine (1 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over silica gel (EtOAc / petroleum ether from 0 / 100to 100 / 0) to give 7-bromo-4-hydroxythiochromane 1,1-dioxide (300 mg, yield: 83 %) as a white solid.

[0312] Step B: 4-hydroxythiochromane-7-carboxylic acid 1,1-dioxide. K2CO3 (80 mg, 0.579 mmol), Pd(OAc)2 (CAS [3375-31-3], 10 mg, 0.045 mmol), and propane-1, 3- diylbis(dicyclohexylphosphonium) tetrafluoroborate (CAS [1002345-50-7], 11 mg, 0.018 mmol) were added to a solution of 7-bromo-4-hydroxythiochromane 1,1-dioxide (100 mg, 0.343 mmol) in DMSO / H2O (2 / 1, 3 mL) at room temperature. The mixture was degassed with CO 3 times and the mixture was stirred at 80 °C for 12 h under CO atmosphere (50 psi). After cooling, the mixture was filtered, and the filtrate was extracted with DCM (3 mL). The aqueous layer was acidified to pH 1~2 with HC1(2 mL, 1 M in water) and it was directly purified by reverse phase HPLC (Welch Xtimate C18 150 * 30 mm * 5 um; water (NH3H2O + NHIHCO3) / ACN from 100 / 0 to 70 / 30) to give 4-hydroxythiochromane-7-carboxylic acid 1,1- dioxide (75 mg, yield: 90 %) as a white solid.Intermediate 88: 2-(hydroxymethyl)thiochromane-7-carboxylic acid 1,1-dioxide.

[0313] Step A: 7-bromo-4-oxothiochromane-2-carboxylic acid. EtsN (0.5 mL, 3.587 mmol) was added slowly to a solution of 3 -bromobenzenethiol (CAS [6320-01-0], 17.5 g, 92.557 mmol) and furan-2, 5-dione (CAS [108-31-6], 9.5 g, 96.883 mmol) in toluene (170 mL) and the mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (170 mL), and the solution was cooled to 0 °C. AlCh (19.5 g, 146.242 mmol) was added, and the mixture was stirred at 0 °C for 1 h, then at room temperature overnight. The reaction mixture was diluted with water (50mL) and extracted with DCM (70 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 7-bromo-4-oxothiochromane-2-carboxylic acid (9.5 g, 56 % pure, yield: 20 %) as a yellow oil, used without further purification.

[0314] Step B: methyl 7-bromo-4-oxothiochromane-2-carboxylate. H2SO4 (0.5 mL) was added slowly to a solution of 7-bromo-4-oxothiochromane-2-carboxylic acid (3.1 g, 10.257 mmol) in MeOH (50 mL) and the mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (50 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (petroleum ether / EtOAc from 1 / 0 to 2 / 1 ) to give methyl 7-bromo-4-oxothiochromane-2-carboxylate (3 g, yield: 97 %) as a white solid.

[0315] Step C: methyl 7-bromothiochromane-2-carboxylate. Et3SiH (CAS [617-86-7], 3.6 mL, 22.929 mmol) was added to a solution of methyl 7-bromo-4-oxothiochromane-2- carboxylate (2.9 g, 9.630 mmol) in TFA (30 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc from 1 / 0 to 2 / 1) to give methyl 7-bromothiochromane-2-carboxylate (2.2 g, yield: 73 %) as a white solid.

[0316] Step D: methyl 7-bromothiochromane-2-carboxylate 1,1-dioxide. A solution of oxone (22 mg, 36.111 mmol) in water (10 mL) was added to a stirred solution of methyl 7- bromothiochromane-2-carboxylate (2.1 g, 7.204 mmol) in MeOH / THF (3 / 1, 40 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solution was concentrated, and the residue was taken up in EtOAc and aqueous Na2SOs (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc from 1 / 0 to 1 / 1) to give methyl 7-bromothiochromane-2-carboxylate 1,1-dioxide (2 g, yield: 86 %) as a white solid.

[0317] Step E: 7-bromo-2-(hydroxymethyl)thiochromane 1,1-dioxide. NaBEL (86 mg, 2.335 mmol) was added to a solution of methyl 7-bromothiochromane-2-carboxylate 1,1-dioxide (500 mg, 1.549 mmol) in MeOH (5 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. Water (15 mL) was slowly added to the reaction mixture at room temperature, and it was extracted with EtOAc (10 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM / MeOH from 1 / 0 to 10 / 1) to give 7-bromo-2-(hydroxymethyl)thiochromane 1,1-dioxide (410 mg, yield: 91 %) as a white solid.

[0318] Step F: 2-(hydroxymethyl)thiochromane-7-carboxylic acid 1,1-dioxide. K2CO3 (121 mg, 0.876 mmol), Pd(OAc)2 (CAS [3375-31-3], 13 mg, 0.058 mmol), and propane- 1, 3 -diylbis (dicyclohexylphosphonium) tetrafluoroborate (CAS [1002345-50-7], 18 mg, 0.026 mmol) were added to a solution of 7-bromo-2-(hydroxymethyl)thiochromane 1,1-dioxide (170 mg,0.577 mmol) in DMSO / H2O (2 / 1, 9 mL) at room temperature. The mixture was degassed with CO 3 times and was stirred at 80 °C for 12 h under CO atmosphere (50 psi). After cooling, the mixture was acidified to pH 3 with HC1(1 M in water). The reaction mixture was diluted with water (50 mL) and extracted with DCM / iPrOH (2 / 1, 50 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (H2O / ACN from 1 / 0 to 10 / 1) to give 2- (hydroxymethyl)thiochromane-7-carboxylic acid 1,1-dioxide (50 mg, yield: 34 %) as a yellow solid.Intermediate 89: N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din- 7-yl)methyl)-2,3-dihydrobenzo[b][l,4]oxathiine-6-carboxamide.

[0319] 2,3-Dihydro-l,4-benzoxathiin-6-carboxylic acid (CAS [14789-69-6], 20 mg, 0.073 mmol) and HATU (CAS [148893-10-1], 41 mg, 0.11 mmol) were dissolved in DMF (0.7 mL), and DIPEA (0.05 mL, 0.29 mmol) was added. The reaction mixture was stirred for 2-3 min before Intermediate 6 (37 mg, 0.08 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and directly purified by reverse phase HPLC (30 x 100 C18 Gemini; ACN:H2O (10 mM NH4OH) from 48 to 68 %) to give the title compound (30 mg, yield: 79 %).Intermediate 90: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-lH-indole-6-carboxamide.

[0320] Indole-6-carboxylic acid (CAS [1670-82-2], 200 mg, 1.24 mmol), Intermediate 6 (626 mg, 1.37 mmol), and HATU (CAS [148893-10-1], 708 mg, 1.86 mmol) were dissolved in DMF (6 mL). DIPEA (0.86 mL, 4.96 mmol) was added and the reaction mixture was stirredat room temperature for 3 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the organic layer was washed twice with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (24 g silica; EtOAc / heptane from 0 / 100 to 100 / 0) to give the title compound (347 mg, yield: 51 %).Intermediate 91 : (2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methanamine.

[0321] Step A: (2-chloropyrimidin-4-yl)zinc(II). 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 Et2O, 3 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture, containing (2- chloropyrimidin-4-yl)zinc(II), was used as such for the next step.

[0322] Step B: tert-butyl ((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)carbamate. (2-chloropyrimidin-4-yl)zinc(II) (0.18 M in THF / Et2O, 14.18 mL, 2.55 mmol, 3 eq.) was added to a solution of Intermediate 3 (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 tert-butyl ((2-(2-chloropyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)carbamate (213 mg, yield: 65 %) as a solid.

[0323] Step C: (2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methanamine. HC1 (4 M in 1,4-di oxane, 5 mL, 20 mmol) was added to a solution of tert-butyl ((2-(2-chloropyrimidin-4- yl)-l,6-naphthyridin-7-yl)methyl)carbamate (500 mg, 1.35 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 2 h. The solvent was evaporated in vacuo to yield (2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methanamine (HC1 salt, 465 mg, yield: 90 %) as a white solid, used without further purification.Intermediate 92: (2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyri din-7- yl)methanamine.

[0324] 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, 5.65 mmol, 4.2 eq.) was added to a solution of Intermediate 91, product from Step B (500 mg, 1.35 mmol) and DIPEA (0.9 mL, 5.45 mmol, 4 eq.) in DMSO (7.5 mL). The mixture was stirred at 120 °C for 16 h. After cooling, the mixture was diluted with water and extracted with EtOAc (2 x 20 mL).The combined organic layer was dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiCL 25 g; EtOAc in heptane from 0 % to 50 %) to yield tert-butyl ((2-(2- ((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)carbamate (440 mg, yield: 71 %) as a pale brown solid.

[0325] Step B: (2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methanamine. HC1 (4 M in 1,4-dioxane, 3.7 mL, 14.8 mmol, 15.1 eq.) was added to a solution of Intermediate 158 (440 mg, 0.98 mmol) in DCM (7.4 mL). The mixture was stirred at room temperature for 20 h, then concentrated to dryness to yield the title compound (410 mg, yield: 94 %) as a beige solid.Intermediate 93 : N-((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-2,3-dihydro- 5H-benzo[e] [ 1 ,4]oxathiepine-8-carboxamide 1 , 1 -dioxide.

[0326] Step A: methyl 4-bromo-2-mercaptobenzoate. A mixture of methyl 4-bromo-2- fluorobenzoate (CAS [179232-29-2], 250 g, 1072.79 mmol) and sodium sulfide (83.72 g, 1072.79 mmol, 1.0 eq.) in DMF (2.5 L) was stirred overnight at room temperature undernitrogen atmosphere. The reaction mixture was diluted with ice / water (3 L). The resulting mixture was extracted with EtOAc (3 x 3 L). The combined organic layer was washed with brine (2 x 2 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with EtOAc / petroleum ether 20 / 1) to afford methyl 4-bromo-2 -mercaptobenzoate (210 g, yield: 79 %) as a white solid.

[0327] Step B: (4-bromo-2-mercaptophenyl)methanol. LiAlEU (32.25 g, 849.82 mmol, 1.0 eq.) was added in portions to a solution of methyl 4-bromo-2 -mercaptobenzoate (210 g, 849.82 mmol) in THF (2.1 L) under nitrogen atmosphere at -10 °C. The solution was stirred for 2 h at 0 °C. The reaction was quenched with H2O at 0 °C. The mixture was acidified to pH=3 with HC1 (1 N in water). The resulting mixture was extracted with EtOAc (2 x 3 L). The combined organic layer was washed with brine (2 x 3 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether 1 / 10) to afford (4-bromo-2- mercaptophenyl)methanol (130 g, yield: 70 %) as a white solid.

[0328] Step C: (4-bromo-2-(vinylthio)phenyl)methanol. A solution of (4-bromo-2- mercaptophenyl)methanol (130 g, 593.33 mmol), K2CO3 (247.80 g, 1780.00 mmol, 3.0 eq.), and 1,2-dibromoethane (334.40 g, 1780.00 mmol, 3.0 eq.) in DMF (1.3 L) was stirred for 48 h at room temperature. The reaction was quenched with ice / water (3 L) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 3 L). The combined organic layer was washed with brine (2 x 3 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether 1 / 10) to afford (4-bromo-2-(vinylthio)phenyl)methanol (90 g, yield: 62 %) as a yellow oil.

[0329] Step D: (4-bromo-2-(vinylsulfonyl)phenyl)m ethanol. A solution of (4-bromo-2- (vinylthio)phenyl)methanol (90 g, 367.15 mmol) and Oxone (CAS [70693-62-8], 92.61 g, 550.72 mmol, 1.5 eq.) in MeOH (0.9 L) and water (0.9 L) was stirred for 48 h at room temperature. The reaction was quenched with ice / water (3 L) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 3 L). The combined organic layer was washed with brine (2 x 3 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether 1 / 5) to afford (4- bromo-2-(vinylsulfonyl)phenyl)methanol (90 g, yield: 88 %) as a white solid.

[0330] Step E: 8-bromo-2,3-dihydro-5H-benzo[e][l,4]oxathiepine 1,1-dioxide. NaH (60 % in mineral oil, 15.59 g, 1.2 eq.) was added in portions to a solution of (4-bromo-2- (vinylsulfonyl)phenyl)methanol (90 g, 324.75 mmol) in DMF (900 mL) under nitrogen atmosphere at 0°C. The solution was stirred for 1 h at room temperature. The reaction mixture was diluted with ice / water (200 mL). The resulting mixture was extracted with EtOAc (2 x 1 L). The combined organic layer was washed with brine (2 x 1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether 1 / 5) to afford 8-bromo-2,3-dihydro-5H- benzo[e][l,4]oxathiepine 1,1-dioxide (71 g, yield: 79 %) as a white solid.

[0331] Step F: 2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxylic acid 1,1-dioxide. A mixture of 8-bromo-2,3-dihydro-5H-benzo[e][l,4]oxathiepine 1,1-dioxide (71 g, 256.19 mmol, 1.0 eq.), K2CO3 (53.11 g, 384.29 mmol, 1.5 eq.), Pd(OAc)2(CAS [3375-31-3], 5.75 g, 25.62 mmol, 0.1 eq.), l,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (CAS [1002345-50-7], 31.4 g, 0.2 eq.) in DMSO (800 mL) and water (80 mL) was stirred overnight at 100 °C under CO atmosphere. After cooling, the mixture was diluted with ice / water (3 L). The resulting mixture was extracted with EtOAc (3 x 3 L). The combined organic layer was washed with brine (2 x 2 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether 3 / 2) to afford 2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxylic acid 1,1-dioxide (40 g, yield: 64 %) as a white solid.

[0332] Step G: N-((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-2,3-dihydro- 5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide. Propylphosphonic anhydride solution (50 % in EtOAc, CAS [68957-94-8], 291 pL, 0.49 mmol) was added to a mixture of Intermediate 91 (112 mg, 0.32 mmol), 2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxylic acid 1,1-dioxide (100 mg, 0.39 mmol), and DIPEA (216 pL, 1.3 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2 12 g; MeOEFDCM (1 :9) in DCM, from 0 % to 100 %) to yield N-((2-(2-chloropyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-2,3-dihydro- 5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide (148 mg, yield: 90 %) as a colourless oil.Intermediate 94: 4-(l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid.

[0333] Step A: methyl 4-(l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylate. Sodium borohydride (373 mg, 9.86 mmol, 2 eq.) was added to a solution of methyl 4-acetyl-5, 6,7,8- tetrahydro-2-quinolinecarboxylate (CAS [459216-41-2], 1.15 g, 4.93 mmol) in MeOH (25 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was stirred for 1 h at room temperature. The reaction was quenched by addition of saturated aqueous NH4CI and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic layer was dried over MgSO4, filtered, and volatiles removed in vacuum. The crude product was purified by flash column chromatography (80 g SiO2; EtOAc in heptane from 0 % to 50 %) to yield methyl 4- (l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylate (614 mg, yield: 52 %) as a colourless foam.

[0334] Step B: 4-(l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid. A solution of NaOH (1 M in water, 5.2 mL, 5.2 mmol, 2 eq.) was added to a solution of methyl 4-(l- hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylate (614 mg, 2.61 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 18 h. The pH was brought to 4 with HC1 (1 M in water). The solvents were evaporated to dryness. A mixture of DCM:MeOH (9: 1) (50 mL) was added and the suspension was filtered. The filtrate was concentrated to dryness to yield 4-(l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxylic acid (583 mg, yield: 99 %) as a colourless foam.Intermediate 95: 3-hydroxy-2,3-dihydrobenzo[b]thiophene-6-carboxylic acid 1,1-dioxide.

[0335] NaOH (1 M in water, 4.2 mL, 4.2 mmol, 2 eq.) was added to a stirred solution of 2,3- dihydro-3-hydroxy-benzo[b]thiophene-6-carboxylic acid, 1,1-dioxide, methyl ester (CAS [192809-97-5], 510 mg, 2.1 mmol) in MeOH (10 mL) at room temperature and the mixture was stirred for 3 h. The mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified to pH=l-2 with HC1 (1 M in water) and extracted with EtOAc (2 x 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield 3-hydroxy-2,3-dihydrobenzo[b]thiophene-6-carboxylic acid 1,1-dioxide (340 mg, yield: 68 %) as an orange solid.Intermediate 96: N-((2-(2-((2R,6S)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6- naphthyridin-7-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][l,4]thiazine-7-carboxamide.

[0336] Propylphosphonic anhydride solution (50 % in EtOAc, CAS [68957-94-8], 432 pL, 0.73 mmol, 2 eq.) was added to a mixture of 3,4-dihydro-3-oxo-2J / -l,4-benzothiazine-7- carboxylic acid (CAS [1094107-96-6], 100 mg, 0.48 mmol, 1.3 eq.), Intermediate 92 (152 mg, 0.36 mmol), and DIPEA (248 pL, 1.5 mmol, 4.2 eq.) in DMF (3.5 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (40 g SiO2; DCM:MeOH (9: 1) in DCM from 0 % to 100 %) to yield the title compound as a yellow solid (64 mg, yield: 32 %).Intermediate 97: (2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine.

[0337] 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 aqueousNaHCOs was added and the mixture was extracted with EtOAc. The organic layer was dried with MgSCU, 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 tert-butyl 7-(6-chloro-4,5-dimethylpyridin-2-yl)-4,7-diazaspiro[2.5]octane-4- carboxylate (40 mg, yield: 6 %) as a colourless oil.

[0338] 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 34 (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 34 (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 NaHCOs 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 12 g; EtOAc / heptane from 0 / 100 to 40 / 60) to yield the title compound (60 mg, yield: 26 %) as a yellow solid.

[0339] Step C: (2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methanamine. TFA (0.59 mL. 7.7 mmol, 40 eq.) was added to a stirred solution of 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 (110 mg, 0.191 mmol) in DCM (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then 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, the solid washed with DCM:MeOH 9: 1, and discarded. The filtrate was concentrated under reduced pressure to yield the title compound (70 mg, yield 96 %) as yellow solid.COMPOUNDSCompound 1 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.CISMethod A

[0340] Intermediate 26 (36.4 mg, 0.151 mmol, 1.1 eq.) and DIPEA (71.7 pL, 0.412 mmol, 3 eq.) were added to a solution of Intermediate 6 (48 mg, 0.137 mmol) in DCM (4 mL). After 1 min, HATU (60 mg, 0.158 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 NaHCOs and extracted with EtOAc. The organic layer was dried (MgSCU), 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 Compound 1 (22 mg, yield: 28 %) as a yellow solid.Compound 2: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(isopropylsulfonyl)indoline-6-carboxamide.CIS

[0341] Intermediate 6 (HC1 salt, 75 mg, 0.178 mmol, 1.2 eq.) was added to a stirred solution of 2,3-dihydro-l-[(l methylethyl)sulfonyl]-lH-indole-6-carboxylic acid (CAS [1911780-08- 9], 40 mg, 0.149 mmol), HATU (85 mg, .0223 mmol, 1.5 eq.), and DIPEA (78 pL, 0.446 mmol, 3 eq.) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSOY filtered, and the solvent was evaporated. The residue was purified by flash column chromatography (silica 12g; MeOH in DCM from 0 / 100 to 3 / 97), followed by reverse phase chromatography (Phenom enex Gemini C18 30 x 100 mm5 pm Column; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1 : 1)] to 17 % [25 mM NH4HCO3] - 83 % [ACN:MeOH (1:1)]) to yield Compound 2 (67 mg, yield: 74 %) as a yellow solid.Compound 3 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(N,N-dimethylsulfamoyl)indoline-6-carboxamide.CIS

[0342] Compound 3 was prepared from l-[(dimethylamino)sulfonyl]-2,3-dihydro-lH-indole- 6-carboxylic acid, CAS [1915294-56-2] and Intermediate 6 using Method A (with DCM as the solvent).Compound 4: l-(but-2-yn-l-ylsulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)indoline-6-carboxamide.

[0343] But-2 -yne-1 -sulfonyl chloride (CAS [1342209-39-5], 40 mg, 0.264 mmol, 2 eq.) was added dropwise to a stirred solution of Intermediate 7 (65 mg, 0.132 mmol) and EtsN (37 pL, 0.264 mmol, 2 eq.) in DCM (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with water and was extracted with EtOAc (2 x 100 mL). The combined organic layer was dried (MgSCU), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (silica 24 g; MeOH in DCM from 0 / 100 to 10 / 90) to yield Compound 4 (54 mg, yield: 66 %) as a white solid.Compound 5: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(ethylsulfonyl)indoline-6-carboxamide.CIS

[0344] Compound 5 was prepared as described for Compound 4, using Intermediate 7 and ethanesulfonyl chloride (CAS [594-44-5]) instead of but-2-yne-l -sulfonyl chloride.Compound 6: l-(allylsulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide.CIS

[0345] Compound 6 was prepared as described for Compound 4, using Intermediate 7 and prop-2-ene-l -sulfonyl chloride (CAS [14418-84-9]) instead of but-2-yne-l -sulfonyl chloride.Compound 7: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,3-dimethyl-l-(methylsulfonyl)indoline-6-carboxamide.CIS

[0346] HBTU (203 mg, 0.534 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 9 (111 mg, 0.392 mmol), Intermediate 6 (150 mg, 0.356 mmol, 1 eq.), and DIPEA (311 pL, 1.78 mmol, 5 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 Na2COs (1 M in water) and extracted with EtOAc. The organic layer was dried on MgSCU, filtered, and evaporated. The residue was purified by reverse phase chromatography (72 % H2O - 28 % ACN -MeOH to 36% H2O - 64 % ACN - MeOH - [0.1 % HCOOH]) to yield Compound 7 (110 mg, yield: 51 %) as a solid.Compound 8: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-l-(methylsulfonyl)indoline-6-carboxamide.CIS

[0347] Compound 8 was prepared from Intermediate 6 and Intermediate 11 following Method A (using DMF as the solvent).Compound 9: 4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.CIS

[0348] Intermediate 14 (86 mg, 0.312 mmol, 1.2 eq.), Intermediate 6 (HC1 salt, 110 mg, 0.26 mmol), and DIPEA (177 pL, 1.04 mmol, 4 eq.) were dissolved in DMF (3 mL). After 15 min, HBTU (118 mg, 0.312 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with aqueous Na2COs (I M) and extracted with DCM. The organic layer was washed with brine, dried on MgSCU, filtered, 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 9 (82 mg, yield: 51 %) as a light green solid.Compound 10: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide.CIS

[0349] Compound 10 was prepared in a similar manner as Compound 9 using Intermediate 17 and Intermediate 6.Compound 11 : 4-methyl-l-(methylsulfonyl)-N-((2-(6-(2,2,6,6- tetramethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)indoline-6-carboxamide.

[0350] Compound 11 was prepared according to Method A, starting from Intermediate 19 and Intermediate 11.Compound 12: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,3-dimethyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6- carb oxami de.CIS

[0351] Intermediate 6 (51.7 mg, 0.122 mmol) was added to a stirred solution of Intermediate 21 (33 mg, 0.122 mmol), HATU (70 mg, 0.184 mmol 1.5 eq.), and DIPEA (64 pL, 0.367 mmol, 3 eq.) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 72 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried (MgSCU), filtered, and the solvent was evaporated. The residue was purified by flash column chromatography (silica 12 g; MeOH in DCM from 0 / 100 to 3 / 97), followed by reverse phase chromatography (Phenom enex Gemini Cl 8 30 x100 mm 5 pm Column; from 59 % [25 mM NH4HCO3] - 41 % [ACN eOH (1 : 1)] to 17 % [25 mM NH4HCO3] - 83 % [ACN:MeOH (1 : 1)]) to yield Compound 12 (76 mg, yield: 97 %).Compound 13: N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.(3a, 4P, 5a)Method B

[0352] 1-Propanephosphonic anhydride (50 % in EtOAc, 0.22 mL, 0.37 mmol, 1.7 eq.) was added to a solution of Intermediate 22 (80 mg, 0.176 mmol), Intermediate 26 (64 mg, 0.264 mmol, 1.5 eq.), and EtsN (0.18 mL, 1.32 mmol, 6 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and water, filtered, and purified by preparative HPLC (Stationary phase: RP XB ridge Prep C18 OBD - 5 pm, 50 x 250 mm, Mobile phase: 0.25 % NH4HCO3 solution in water, ACN) to yield Compound 13 (65 mg, yield: 62 %).Compound 14: l-(N,N-dimethylsulfamoyl)-N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5- dimethylpiperidin-l-yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)indoline-6-carboxamide.(3a, 4P, 5a)

[0353] Compound 14 was prepared from l-[(dimethylamino)sulfonyl]-2,3-dihydro-UT- indole-6-carboxylic acid, CAS [1915294-56-2] and Intermediate 22 using Method B.Compound 15: N-((2-(4-fluoro-6-((3a,40,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.(3a, 40, 5a)

[0354] Intermediate 24 (41 mg, 0.17 mmol) and DIPEA (0.158 mL, 0.91 mmol) were added to a solution of Intermediate 26 (75 mg, 0.15 mmol) in DMF (1 mL). The reaction mixture was stirred for 1 min and treated with HATU ([CAS 148893-10-1], 72 mg, 0.19 mmol). After 2 h, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (x 3). The combined organic layer was dried with MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL, DCM:MeOH (9:1) in DCM 0 / 100 to 20 / 80) to yield Compound 15 (52 mg, yield: 69 %) as a yellow solid.Compound 16: N-((2-(6-((3a,40,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carb oxami de.(3a, 40, 5a)

[0355] Compound 16 was prepared from Intermediate 22 and Intermediate 17 following Method A (using DMF as the solvent).Compound 17: N-((*R)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)ethyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0356] 1-Propanephosphonic anhydride (50 % in EtOAc, CAS [68957-94-8], 379 pL, 0.63 mmol, 1.3 eq.) was added to a suspension of Intermediate 29 (178 mg, 0.49 mmol) and Intermediate 26 (130 mg, 0.539 mmol, 1.1 eq.) in dry DCM (5 mL) at room temperature, under nitrogen atmosphere. EtsN (340 pL, 2.4 mmol, 5 eq.) was then added dropwise. 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 a mixture of isomers (150 mg, yield: 52 %). This mixture was further purified by preparative SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, iPrOH + 0.4 % iPrNEE) to obtain Compound 17 (*R, pure stereoisomer but absolute stereochemistry undetermined) and Compound 18 (*S, pure stereoisomer but absolute stereochemistry undetermined), both as yellow solids.Compound 18: N-((*S)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)ethyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0357] Isolated from the reaction from Compound 17.Compound 19: l-acetyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide.CIS

[0358] Acetic anhydride (29 pL, 0.303 mmol, 1 eq.) was added to a solution of Intermediate 7 (150 mg, 0.303 mmol) and EtsN (85 pL, 0.607 mmol, 2 eq.) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water (x 3). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 25 g; MeOH / DCM 0 / 100 to 4 / 96) to yield title compound (92 mg, yield: 55 %) as a yellow solid.Compound 20: N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin- 2-yl)- 1 , 6-naphthyri din-7 -yl)methyl)- 1 -(methyl sulfonyl)-2, 3 -dihydro- 1 H-pyrrolo[3 ,2- c]pyridine-6-carboxamide.(3a, 40, 5a)

[0359] A solution of Intermediate 37 (97 mg, 0.137 mmol) in aqueous NaOH (546. mL,1.36 mmol, 2.5 M, 10 eq.) was stirred at 65 °C for 72 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with DCM (x 3). The combined organic layer was dried (MgSC ), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica, DCM / MeOH (9 / 1) in DCM, from 0 % to 30 %) to yield Compound 20 (45 mg, yield: 84 %).Compound 21 : l-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)methyl)indoline-6-carboxamide.

[0360] Intermediate 26 (64 mg, 0.26 mmol) and DIPEA (104 pL, 0.6 mmol) were added to a solution of Intermediate 44in (75 mg, 0.24 mmol) in DMF (3 mL). The reaction mixture was stirred and was treated after 1 min with HATU (CAS [94790-37-1], 114 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCOs and was extracted with DCM (3 x). The combined organic layer was dried with MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, DCM:MeOH (9: 1) in DCM, 0 / 100 to 40 / 60) to yield Compound 21 (72 mg, yield: 55 %) as a white solid.Compound 22: l-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)indoline-6-carboxamide.

[0361] Intermediate 26 (60 mg, 0.25 mmol) was dissolved in DMF (2.6 mL). DIPEA (254 pL, 1.458 mmol) and HBTU (CAS [94790-37-1], 103 mg, 0.272 mmol) were added and the reaction mixture was stirred for 10 min at room temperature. Intermediate 46 (185 mg, 0.208 mmol) was then added. The total volume of the mixture was brought to 3 mL with DMF and the reaction mixture was stirred for 50 min at room temperature. The crude reaction mixture was directly purified by reverse phase purification (Column: OOD-4633-UO-AX Kinetex 5 um EVO cl8 100; 0.1 % TFA in water and ACN, 10 % ACN slow ramp to 50 % then a fast ramp to 100 % to the end) to yield Compound 22 (55 mg, yield: 49 %) as a solid.Compound 23 : l-(methylsulfonyl)-N-((2-(4-(pyridazin-3-yl)piperazin-l-yl)-l,6-naphthyridin- 7-yl)methyl)indoline-6-carboxamide.

[0362] DIPEA (390 pL, 2.24 mmol, 10 eq.) and HBTU (CAS [94790-37-1], 102 mg, 0.269 mmol, 1.2 eq.) were added to a solution of l-(methylsulfonyl)indoline-6-carboxylic acid (CAS [1566993-05-2], 65 mg, 0.269 mmol, 1.2 eq.) in DMF (1.2 mL). The reaction mixture was stirred for 10 min at room temperature before Intermediate 47 (200 mg, 0.224 mmol) was added all at once. The reaction mixture was stirred for 50 min at room temperature. The solvent was evaporated, and the residue was purified by reverse phase column chromatography (Kinetex 5 um EVO cl8 100; 0.1 % TFA in water and ACN, from 10 % ACN to 100 %) to give Compound 23 (65 mg, yield: 53 %) as a white solid.Compound 24: 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-l-(methylsulfonyl)indoline-6-carboxamide.(3a, 4p, 5a)

[0363] Intermediate 11 (42 mg, 0.17 mmol, 1.3 eq.) and DIPEA (129 pL, 0.74 mmol, 6.0 eq.) were added to a solution of Intermediate 24 (75 mg, 0.12 mmol, 1.0 eq.) in DMF (3 mL). The mixture was stirred for 2 min and HATU (CAS [148893-10-1], 58 mg, 0.15 mmol, 1.25 eq.) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and the solvents were evaporated. The crude product was purified by flash column chromatography (12 g SiO2, DCM:MeOH (9: 1) in DCM, from 0 % to 20 %) to yield Compound 24 (30 mg, yield: 39 %) as a white solid.Compound 25: N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0364] 1-Propanephosphonic anhydride (50 % in EtOAc, 58 pL, 0.097 mmol, 1.3 eq.) was added to a suspension of Intermediate 48 (48 mg, 70 % pure, 0.075 mmol) and Intermediate 26 (20 mg, 0.082 mmol, 1.1 eq.) in dry DCM (3 mL) at room temperature. EtsN (52 pL, 0.373 mmol, 5 eq.) was added dropwise to the orange suspension. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN), followed by preparative SFC (Torus Diol 30 x 150 mm; CO2, MeOH + 20 mM NH4OH) to yield Compound 25 (11 mg, yield: 24 %) as a yellow solid.Compound 26: N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0365] HBTU (CAS [94790-37-1], 119 mg, 0.313 mmol, 1.1 eq.) was added to a stirred solution of Intermediate 6 (120 mg, 0.284 mmol), Intermediate 49 (108 mg, 0.398 mmol, 1.4 eq.), and DIPEA (0.20 mL, 1.13 mmol, 4 eq.) in DMF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed with Na2COs (1 M in water). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCh; EtOAc / heptane from 0 to 100 %) to yield Compound 26 (55 mg, yield: 32 %) as a yellow solid.Compound 27 : N-((2-(5 -fluoro-6-(4, 7 -diazaspiro[2.5 ] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0366] Compound 27 was prepared following the same procedure as Compound 23, using Intermediate 52 instead of Intermediate 47.Compound 28: N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0367] The title compound was prepared in a manner analogous to Compound 2, using Intermediate 51 ((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)methanamine) and Intermediate 26 (1 -(methyl sulfonyl)indoline-6- carboxylic acid).Compound 29: N-((2-(5-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin- 2-yl)-l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0368] The title compound was prepared in a manner analogous to Compound 2, using Intermediate 53 (3a, 40, 5a)-l -(6-(7-(aminomethyl)-l, 6-naphthyri din-2 -yl)-3-fluoropyri din-2 - yl)-3,5-dimethylpiperidin-4-ol) and Intermediate 26 (l-(methylsulfonyl)indoline-6-carboxylic acid).Compound 30: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-((tetrahydro-2H-pyran-4-yl)sulfonyl)indoline-6-carboxamide.

[0369] HATU (CAS [148893-10-1], 87 mg, 0.23 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (64.6 mg, 0.15 mmol, 1 eq.), Intermediate 132 (50 mg, 0.16 mmol, 1.05 eq.), and DIPEA (0.2 mL, 1.2 mmol, 4 eq.) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with Na2COs (I M in water) and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL, MeOH in DCM from 0 to 5 %) to yield Compound 30 (79 mg, yield: 79 %) as a yellow solid.Compound 31 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-r-(methylsulfonyl)spiro[cyclopentane-l,3'-indoline]-6'-carboxamide.

[0370] HATU (CAS [148893-10-1], 145 mg, 0.38 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (130 mg, 0.31 mmol, 1.2 eq.), Intermediate 134 (75 mg, 0.25 mmol, 1 eq.), and DIPEA (0.13 mL, 0.76 mmol, 3 eq.) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with Na2COs (1 M in water) and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (12 g SiCh, MeOH in DCM from 0 to 3 %) to yield Compound 31 (35 mg, yield: 22 %) as a yellow solid.Compound 32: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l'-(methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxamide.

[0371] HBTU (CAS [94790-37-1], 188 mg, 0.495 mmol. 1.5 eq.) was added to a stirred solution of Intermediate 6 (139 mg, 0.330 mmol), Intermediate 80 (97 mg, 0.363 mmol, 1.1 eq.), and DIPEA (0.288 mL, 1.65 mmol, 5 eq.) in DMF (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with Na2COs (1 M in water). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The product was crystallized in ACN to give Compound 32 (130 mg, yield: 65 %) as a solid.Compound 33 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-7-(methylsulfonyl)-2,3-dihydro-lH-indene-5-carboxamide.

[0372] Compound 33 was prepared using the same procedure as Compound 25, using Intermediate 6 instead of Intermediate 26, and Intermediate 92 instead of Intermediate 48.Compound 34: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-4-(l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.

[0373] Intermediate 6 (200 mg, 0.47 mmol) was added to a stirred solution of Intermediate 94 (126 mg, 0.56 mmol, 1.2 eq.), HATU (CAS [148893-10-1], 270 mg, 0.71 mmol, 1.5 eq.), and DIPEA (0.25 mL, 1.42 mmol, 3 eq.) in DCM (5 mL) at room temperature. The mixture was stirred at room temperature for 4 h, then diluted with saturated aqueous NaHCOs and EtOAc. The layers were separated, and the organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiCE 25 g; EtOAc in DCM from 0 % to 100 %), followed by reverse phase column chromatography (Phenomenex Gemini C18 100 x 30 mm 5 pm; gradient from 49 % [0.1 % HCOOH] - 51 % [ACN:MeOH (1 : 1)] to 6 % [0.1 % HCOOH] - 94 % [ACN:MeOH (1 : 1)]), and finally trituration in Et2O to yield Compound 34 as a yellow solid (4 mg, yield: 2 %).Compound 35: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-((*S)-l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide and Compound 36: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-((*R)-l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.(*R) CIS Compound 36

[0374] Compound 34 was separated into its stereoisomers by preparative SFC (Lux Amylose- 1, 250 x 30mm 5 pm; isocratic 55 % [EtOH + 0.1 % DEA] - 45 % [CO2]) to yield Compound35 (137 mg, yield: 27 %) and Compound 36 (84 mg, yield: 16 %), both as yellow solids.

[0375] The compounds in Table 4 were prepared from Intermediate 22 and the acid listed in the table, using Method B. Table 4.Compound 43 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepine-7-carboxamide.

[0376] Step A: tert-butyl 7-(((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)carbamoyl)-l,2,4,5-tetrahydro-3H-benzo[d]azepine-3-carboxylate.1-Propanephosphonic anhydride (50 % in EtOAc, 153 pL, 0.257 mmol, 1.3 eq.) was added to a suspension of Intermediate 6 (138 mg, 50 % pure, 0.197 mmol) and 3-(tert- butoxycarbonyl)-2,3,4,5-tetrahydro-U / -benzo[d]azepine-7-carboxylic acid (CAS [149353-73- 1], 63 mg, 0.217 mmol, 1.1 eq.) in dry DCM (5 mL) at room temperature. Et3N (137 pL, 0.987 mmol, 5 eq.) was 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 flash column chromatography on silica gel (25 g; EtOH / EtOAc 1 / 3 in heptane from 0 % to 80 %) to yield the title compound (103 mg, yield: 84 %) as a yellow solid.

[0377] Step B: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2,3,4,5-tetrahydro-lH-benzo[d]azepine-7-carboxamide. HC1 (4 M in 1,4-dioxane, 2 mL, 8.029 mmol, 50 eq.) was added to a solution of tert-butyl 7-(((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)carbamoyl)-l, 2,4,5- tetrahydro-3H-benzo[d]azepine-3-carboxylate (100 mg, 0.161 mmol) in dry 1,4-dioxane (1 mL). The mixture was stirred at room temperature for 1.5 h. The solvent was evaporated and the residue was dissolved in NH3 / MeOH 7 N (5 mL), forming a yellow solution. This solution was evaporated and the residue was purified by flash column chromatography on silica gel (25 g; 7 N NH3in MeOH / DCM 1 / 9 in DCM, from 0 % to 100 %) to yield Compound 43 (72 mg, yield: 86 %) as a yellow solid.Compound 44: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-(vinylsulfonyl)indoline-6-carboxamide.

[0378] 2-Chloroethanesulfonyl chloride (CAS [1622-32-8], 0.035 mL, 0.34 mmol, 1.1 eq.) was added to a stirred solution of Compound 111 (150 mg, 0.3 mmol) and Et3N (0.13 mL, 0.91 mmol, 3 eq.) in DCM (2 mL) at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with water (x 3). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL; MeOH in DCM from 0 to 2 to yield Compound 44 (68 mg, yield: 38 %) as a yellow solid.Compound 45: 4-(aminomethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)- l -(methyl sulfonyl )indoline-6-carboxamide.

[0379] A solution of Intermediate 79 (178 mg, 0.254 mmol) in HC1 (4 N in 1,4-dioxane, 1.6 mL, 6.34 mmol, 25 eq.) and 1,4-dioxane (1.5 mL) was stirred at room temperature for 6 h. Na2CC>3 (1 M in water) was added and the mixture was extracted twice with DCM. The combined organic layer was dried over MgSC , filtered, and concentrated. The crude product was purified by flash column chromatography (25 g SiCL; DCM / MeOH / NFL (9.0 / 0.9 / 0.1) in DCM from 0 to 100 %) to yield Compound 45 (99 mg, yield: 64 %) as a yellow solid.Compound 46 : N-((2-(4-fluoro-6-(4, 7 -diazaspiro[2.5 ] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carb oxami de.

[0380] DIPEA (104 pL, 0.6 mmol, 2.5 eq.) and HATU (CAS [148893-10-1], 109 mg, 0.28 mmol, 1.2 eq.) were added to a solution of Intermediate 17 (49 mg, 0.20 mmol, 0.85 eq.) in DMF (3 mL). The reaction mixture was stirred and after 1 min, it was treated with Intermediate 73 (HC1 salt, 100 mg, 0.24 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCOs and was extracted with DCM (x 3). The combined organic layer was dried with MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiCL, DCM / MeOH (9: 1) in DCM, from 0 / 100 to 20 / 80) to yield Compound 46 (25 mg, yield: 17 %) as a yellow solid.Compound 47: 4-fluoro-N-((2-(4-fluoro-6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.(3a, 40, 5a)

[0381] HATU (CAS [148893-10-1], 0.152 g, 0.40 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 24 (0.121 g 0.266 mmol), Intermediate 86 (76 mg, 0.293 mmol, 1.1 eq.), and DIPEA (0.182 mL, 1.04 mmol, 3.9 eq.) in DMF (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiCL; 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, 5 pm; from 72 % [0.1 % HCOOH] - 28 % ACN to 36 % [0.1 % HCOOH] - 64 % ACN) to give Compound 47 (17 mg, yield: 10 %) as a yellow solid.Compound 48: N-((2-(4-fluoro-6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l -(methyl sulfonyl)-2, 3-dihy dro-lH- py rrol o [3 , 2-b ] py ri dine-6-carb oxami de .(3a, 40, 5a)

[0382] Intermediate 73 (77 mg, 0.32 mmol, 1.2 eq.) and DIPEA (0.37 mL, 2.12 mmol, 8.0 eq.) were added to a solution of HATU (CAS [148893-10-1], 131 mg, 0.35 mmol, 1.3 eq.) in DMF (5 mL). The reaction mixture was stirred and, after 1 min, Intermediate 24 (HC1 salt, 120 mg, 0.26 mmol, 1.0 eq.) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with saturated aqueous NaHCOs and extracted with DCM (x 3). The organic layer was separated, dried (MgSCU), filtered, and the solvents evaporated to yield anorange solid. The solid was triturated in ACN, filtered, and washed with Et2O to yield Compound 48 (111 mg, yield: 68 %) as a yellow solid.Compound 49: N-((2-(6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6- carb oxami de.(3a, 40, 5a)

[0383] DIPEA (173 pL, 0.99 mmol) and HATU (CAS [148893-10-1], 163 mg, 0.43 mmol) were added to a solution of Intermediate 73 (96 mg, 0.4 mmol) in DMF (5 mL). The reaction mixture was stirred and, after 1 min, was treated with Intermediate 22 (120 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCOs and was extracted with DCM (x 3). The combined organic layer was dried with MgSCU, 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 30 / 70), followed by trituration with ACN and washing with Et2O to yield Compound 49 (150 mg; yield: 77 %) as a yellow solid.Compound 50: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-4-(methylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxamide.

[0384] Compound 50 was prepared according to Method A, using Intermediate 6 and 3,4- dihydro-4-(methylsulfonyl)-2J / -l,4-benzoxazine-6-carboxylic acid (CAS [1368755-98-9]).Compound 51 : N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0385] Compound 51 was prepared following Method B, using Intermediate 75 instead of Intermediate 22.Compound 52: N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(cyclopropylsulfonyl)indoline-6-carboxamide.

[0386] Compound 52 was prepared following Method B from Intermediate 75 instead of Intermediate 22, and Intermediate 77 instead of Intermediate 26.Compound 53: N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide.

[0387] Compound 53 was prepared following Method B, from Intermediate 75 instead of Intermediate 22, and Intermediate 17 instead of Intermediate 26.Compound 54: N-((2-(4-fluoro-6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)indoline-6-carboxamide.(3a, 40, 5a)

[0388] DIPEA (100 pL, 0.57 mmol, 5.0 eq.) and HATU (CAS [148893-10-1], 44 mg, 0.12 mmol, 1.0 eq.) were added to a solution of 2,3 -dihydro- lZZ-indole-6-carboxylic acid (CAS [732922-86-0], 19 mg, 0.12 mmol, 1.0 eq.) in DMF (3 mL). The reaction mixture was stirred and, after 1 min, was treated with Intermediate 24 (70 mg, 0.12 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCOs and was extracted with DCM (x 3). The combined organic layer was dried with MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (12 g SiCh; DCM:MeOH (9: 1) in DCM, from 0 / 100 to 35 / 65) to yield Compound 54 (30 mg; yield: 48 %) as a brown solid.Compound 55 : N-((2-(4-fluoro-6-(4, 7 -diazaspiro[2.5 ] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)thiochromane-7-carboxamide 1,1 -di oxide.

[0389] Compound 55 was prepared according to Method A (in DMF), using Intermediate 57 instead of Intermediate 6, and 3,4-dihydro-27 / - l -benzothiopyran-7-carboxylic acid, 1,1- dioxide (CAS [1785527-60-7]) instead of Intermediate 26.Compound 56: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-l-((2 -methoxy ethyl)sulfonyl)indoline-6-carboxamide.

[0390] Compound 56 was prepared in a similar manner as Compound 57 using 2, 3 -dihydro- 1- [(2-methoxyethyl)sulfonyl]-U / -indole-6-carboxylic acid (CAS [1923487-10-8]) instead of Intermediate 76.Compound 57: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-((2 -hydroxy ethyl)sulfonyl)indoline-6-carboxamide.

[0391] 1-Propanephosphonic anhydride (50 % in EtOAc, 68 pL, 0.114 mmol, 1.2 eq.) was added to a solution of Intermediate 76 (38 mg, 0.098 mmol), Intermediate 6 (40 mg, 0.095 mmol), and EtsN (0.095 mL, 0.682 mmol, 7.2 eq.) in DCM (5 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (4 g; DCM:MeOH 9:1 in DCM, from 0 % to 100 %) to yield Compound 57 (30 mg, yield: 52 %) as a yellow solid.Compound 58: N-((2-(6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-1.6-naphthyri din-7-yl)methyl)-l -((2 -methoxy ethyl)sulfonyl)indoline-6-carboxamide and Compound 59: N-((2-(6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-1.6-naphthyridin-7-yl)methyl)-l-((2-hydroxyethyl)sulfonyl)indoline-6-carboxamide.(3a, 40, 5a) Compound 59

[0392] Compound 59 and Compound 58 were isolated from a similar procedure as Compound 57, using Intermediate 22 instead of Intermediate 6.Compound 60: N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-((2 -hydroxy ethyl)sulfonyl)indoline-6-carboxamide.

[0393] Compound 60 was prepared in a similar manner as Compound 57 using Intermediate 75 instead of Intermediate 6.Compound 61 : N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l -((2 -m ethoxy ethyl)sulfonyl)indoline-6-carboxamide. HC1 salt.

[0394] Compound 61 was prepared in a similar manner as Compound 57 using 2, 3 -dihydro- 1- [(2-methoxyethyl)sulfonyl]-lH-indole-6-carboxylic acid (CAS [1923487-10-8]) instead of Intermediate 76, and Intermediate 75 instead of Intermediate 6. Compound 61 was isolated as a HC1 salt after suspension in HC1 (4 M in 1,4- dioxane) and evaporation of the solvent.Compound 63 : N-((2-(4-fluoro-6-(4, 7 -diazaspiro[2.5 ] octan-7 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2- c]pyridine-6-carboxamide.

[0395] Intermediate 74 (65 mg, 0.25 mmol, 1.0 eq.) and DIPEA (0.310 mL, 1.78 mmol, 7.0 eq.) were added to a solution of HATU (CAS [148893-10-1], 120 mg, 0.32 mmol, 1.24 eq.) in DMF (6 mL). The reaction mixture was stirred and, after of 1 min, was treated with Intermediate 73 (HC1 salt, 170 mg, 0.36 mmol, 1.4 eq.). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with DCM. The organic layer was separated, dried (MgSCU), filtered, and thesolvents were evaporated. The residue was purified by flash chromatography (25 g SiO2, DCM / MeOH / NH3(10 / 1 / 0.25) in DCM, from 0 % to 20 %) to yield Compound 63 (30 mg, yield: 19 %) as a yellow solid.Compound 64: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carb oxami de.

[0396] Intermediate 6 (100 mg, 0.24 mmol) was added to a stirred solution of Intermediate 74 (66 mg, 0.26 mmol, 1.1 eq.), HATU (CAS [148893-10-1], 137 mg, 0.36 mmol, 1.5 eq.), and DIPEA (0.35 mL; 2.00 mmol, 8.4 eq.) in DMF (5mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with brine, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (SiCE 24 g; MeOH in DCM from 0 % to 10 %), followed by reverse phase column chromatography (Phenomenex Gemini C18 100 x 30 mm, 5 pm; gradient from 59 % [0.1 % HCOOH] - 41 % [ACN:MeOH (1 : 1)] to 17 % [0.1 % HCOOH] - 83 % [ACN:MeOH (1 : 1)) to yield Compound 64 (22 mg, yield: 15 %) as a yellow solid.Compound 66: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dihydropyrido[2,l-c][l,2,4]thiadiazine-9-carboxamide 2,2-dioxide.

[0397] A solution of Intermediate 6 (50 mg, 0.143 mmol), 3,4-dihydropyrido[2,l- c][l,2,4]thiadiazine-9-carboxylic acid 2,2-dioxide (CAS [565165-53-9], 50 mg, 0.219 mmol, 1.5 eq.), TBTU (CAS [125700-67-6], 70 mg, 0.218 mmol, 1.5 eq.), and DIPEA (74 pL, 0.429mmol, 3 eq.) in DMF (1 mL) was stirred at room temperature for 48 h. Water was added and a solid formed. The precipitate was filtered and collected, washed with water and TBME then dried to yield Compound 66 (54 mg, yield: 66 %) as a light yellow powder.Compound 67: N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0398] HATU (CAS [148893-10-1], 107 mg, 0.28 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 26 (45 mg, 0.19 mmol), Intermediate 97 (70 mg, 0.19 mmol), and DIPEA (0.130 mL, 0.75 mmol, 4 eq.) in DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 16 h, diluted with H2O, and extracted with DCM. The organic layer was washed with brine, dried over MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (SiCL 12 g; (DCM / MeOH 9 / 1) in DCM from 0 % to 15 %), followed by reverse phase column chromatography (Phenomenex Gemini C18 100 x 30 mm 5 pm; gradient from 90 % [0.1 % HCOOH] - 10 % [ACN:MeOH (1 : 1)] to 54 % [0.1 % HCOOH] - 46 % [ACN:MeOH (1 : 1)]) to yield Compound 67 (12 mg, yield: 10 %) as a yellow solid.Compound 71 : N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carb oxami de.

[0399] HATU (CAS [148893-10-1], 113 mg, 0.3 mmol, 1.5 eq.) was added to a mixture of Intermediate 97 (73 mg, 0.2 mmol), Intermediate 17 (53 mg, 0.22 mmol), and DIPEA (0.14 mL, 0.8 mmol, 4 eq.) in DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with H2O and extracted with DCM. The organic layer was washed with brine, dried over MgSCU, filtered, and the solvents evaporatedin vacuo. The crude product was purified by flash column chromatography (SiCh 12 g; gradient of (DCM / MeOH 9 / 1) in DCM from 0 % to 15 %), followed by reverse phase column chromatography (Phenomenex Gemini C18 100 x 30 mm 5 pm; gradient from 70 % [25 mM NH4HCO3] - 30 % [ACN:MeOH (1 :1)] to 27 % [25 mM NH4HCO3] - 73 % [ACN:MeOH (1 : 1)]), to yield Compound 71 as brown solid (17 mg, yield: 14 %).Compound 72: 4-chloro-N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide.

[0400] HATU (CAS [148893-10-1], 94 mg, 0.25 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 14 (46 mg, 0.16 mmol), Intermediate 97 (62 mg, 0.16 mmol), and DIPEA (0.116 mL, 0.66 mmol, 4 eq.) in DCM (2 mL) at room temperature. The mixture was stirred at room temperature for 16 h, diluted with H2O, and extracted with DCM. The organic layer was washed with brine, dried over MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (SiCh 12 g; gradient of (DCM / MeOH 9 / 1) in DCM from 0 % to 15 %) to yield Compound 72 (40 mg, yield: 36 %) as a yellow solid.Compound 74: (*S)-4-cyano-N-((2-(6-((R)-3-methoxypyrrolidin-l-yl)pyrazin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide.(*S, R)

[0401] Compound 74 was prepared following the same procedure as Compound 22, using Intermediate 81 instead of Intermediate 46, and Intermediate 82 instead of Intermediate 26.Compound 75 : (*R)-4-cy ano-N -((2-(6-((R)-3 -methoxypyrrolidin- 1 -yl)pyrazin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide.(*R, R)

[0402] Compound 75 was prepared following the same procedure as Compound 74, using Intermediate 83 instead of Intermediate 82.Compound 77: (*S)-4-cyano-N-((2-(4-fluoro-3-((3-hydroxypropyl)amino)-lH-pyrazol-l-yl)- l,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide.

[0403] Compound 77 was prepared following the same procedure as Compound 74, using Intermediate 85 instead of Intermediate 81.Compound 78: (*R)-4-cyano-N-((2-(4-fluoro-3-((3-hydroxypropyl)amino)-lH-pyrazol-l-yl)- l,6-naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide.

[0404] Compound 78 was prepared following the same procedure as Compound 74, using Intermediate 85 instead of Intermediate 81, and Intermediate 83 instead of Intermediate 82.Compound 91 : (*S)-4-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide.(*S), (CIS)

[0405] A solution of Intermediate 6 (25 mg, 0.059 mmol), Intermediate 82 (21 mg, 0.097 mmol, 1.6 eq.), TBTU (CAS [125700-67-6], 27 mg, 0.0841 mmol, 1.4 eq.), and DIPEA (31 pL, 0.18 mmol, 3 eq.) in DMF (1 mL) was stirred at 35 °C for 2 h. The reaction mixture was diluted with DCM, washed with water, aqueous sodium bicarbonate, and brine. The organic layer was dried over MgSCU, filtered, and evaporated. The residue was purified twice by flash column chromatography on silica gel (4 g; MeOH in DCM from 0 % to 10 %) to yield Compound 91 (17 mg, yield: 51 %) as a yellow solid.Compound 92: (*R)-4-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide.(*R), (CIS)

[0406] Compound 92 was prepared in a similar manner as Compound 91 using Intermediate83 instead of Intermediate 82Compound 97: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-3-hydroxy-2,3-dihydrobenzo[b]thiophene-6-carboxamide 1,1-dioxide.

[0407] HATU (CAS [148893-10-1], 125 mg, 0.33 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 95 (50 mg, 0.22 mmol), DIPEA (0.152 mL, 0.87 mmol, 4 eq.), andIntermediate 6 (100 mg, 0.22 mmol) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with Na2COs (1 M in water) and extracted with EtOAc (2 x 25 mL). The organic layers were combined, dried over MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (SiCL 12 g; MeOH in DCM from 0 % to 10 %) to yield Compound 97 (71 mg, yield: 57 %) as a yellow solid.Compound 99: (*R)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin- 7-yl)methyl)-3-hydroxy-2,3-dihydrobenzo[b]thiophene-6-carboxamide 1, 1-dioxide and Compound 100: (*S)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-3-hydroxy-2,3-dihydrobenzo[b]thiophene-6-carboxamide 1, 1-dioxide.(*S) CIS Compound 100

[0408] Compound 97 was separated into its stereoisomers by preparative SFC (Cellulose 4, 250 x 30 mm, 5 pm; isocratic 17 % [EtOH + 0.1 % DEA] - 83 % [CO2]) to yield Compound 99 and Compound 100, both as yellow solids.Compound 101 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-hydroxythiochromane-7-carboxamide 1, 1-dioxide.

[0409] DIPEA (50 mg, 0.387 mmol) and HATU (70 mg, 0.184 mmol) were added to a solution of Intermediate 87 (35 mg, 0.144 mmol) in DMF (2 mL) and the mixture was stirredat room temperature for Imin. Intermediate 6 (50 mg, 0.120 mmol) was added to the mixture and it was stirred at room temperature for 2 h. Water (2 mL) was added to the mixture and it was extracted with DCM (3 mL x 3). The organic layer was washed with brine (1 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SIO2; MeOH / DCM 0 / 100 to 10 / 90), followed by reverse phase HPLC (Boston Prime C18 150 * 30 mm * 5 um; water(NH3H2O + NH4HCO3) / ACN from 60 / 40 to 30 / 70) to give Compound 101 (36 mg, yield: 52 %) as a yellow powdery.Compound 102: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-2-(hydroxymethyl)thiochromane-7-carboxamide 1,1 -di oxide.

[0410] DIPEA (0.16 mL, 0.829 mmol) and HATU (CAS [148893-10-1], 82 mg, 0.215 mmol) were added to a solution of Intermediate 88 (50 mg, 0.195 mmol) in DCM (2 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 10 min. Intermediate 6 (76 mg, 0.196 mmol) was added and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Welch Xtimate C18 150 * 30 mm * 5 urn; water (NH3H2O + NH4HCO3) / ACN; from 68 / 32 to 38 / 62) to give Compound 102 (5 mg, yield: 4 %) as a yellow solid.Compound 103 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2,3-dihydrobenzo[b][l,4]oxathiine-6-carboxamide 4,4-dioxide.

[0411] Intermediate 6 (100 mg, 0.24 mmol) was added to a stirred solution of 2,3-dihydro- l,4-benzoxathiin-6-carboxylic acid, 4,4-dioxide (CAS [2090970-88-8], 70 mg, 0.25 mmol, 1.03 eq.), HATU (CAS [148893-10-1], 136 mg, 0.36 mmol, 1.51 eq.), and DIPEA (0.355 mL,2.03 mmol, 8.58 eq.) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCOs and extracted with EtOAc. The organic layer was separated, dried over MgSCU, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiCh 12 g; gradient of MeOH in DCM from 0 % to 10 %) to yield Compound 103 (7 mg, yield: 6 %) as a yellow solid.Compound 104: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7- yl)methyl)thiochromane-7-carboxamide 1, 1 -di oxide.

[0412] Compound 104 was prepared according to Method A (in DMF), starting fromIntermediate 6 and 3,4-dihydro-2J / -l-benzothiopyran-7-carboxylic acid, 1,1-dioxide (CAS[1785527-60-7]).Compound 106: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-3,4-dihydro-2H-benzo[e][l,2]thiazine-7-carboxamide 1,1-dioxide.

[0413] Compound 106 was prepared according to Method A (in DMF), starting fromIntermediate 62 instead of Intermediate 6, and Intermediate 58 instead of Intermediate 26.Compound 107: N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyri din-7- yl)methyl)-4-oxo-2,3 ,4, 5-tetrahydrobenzo[b] [ 1 ,4]thiazepine-8-carboxamide 1 , 1 -dioxide.(CIS)

[0414] Propylphosphonic anhydride solution (50 % in EtOAc, CAS [68957-94-8], 85 pL, 0.14 mmol, 1.25 eq.) was added to a mixture of Intermediate 92 (48 mg, 0.11 mmol), 2, 3,4,5- tetrahydro-4-oxo-l,5-benzothiazepine-8-carboxylic acid, 1,1-dioxide (CAS [1781955-01-8], 35 mg, 0.14 mmol, 1.2 eq.), and DIPEA (76 pL, 0.45 mmol, 4 eq.) in DMF (5 mL) at room temperature. The mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCOs. The organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by reverse phase column chromatography (Phenom enex Gemini C18 100 x 30 mm, 5 pm; gradient from 81 % [25 mM NH4HCO3] - 19 % ACN to 45 % [25 mM NH4HCO3] - 55 % ACN) to yield Compound 107 (8 mg, yield: 11 %) as a yellow solid.Compound 108: N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-3-hydroxy-4H-benzo[b][l,4]thiazine-7-carboxamide 1,1 -di oxide.

[0415] Ruthenium (III) chloride hydrate (CAS [14898-67-0], 1 mg, 0.038 mmol, 0.06 eq.) was added to a stirred solution of Intermediate 96 (30 mg, 0.06 mmol) and sodium periodate (CAS [7790-28-5], 44 mg, 0.21 mmol. 3.7 eq.) in DCM (1 mL), ACN (1 mL), and water (2 mL). The mixture was stirred at room temperature for 1 h. Water and EtOAc were added, the layers were separated, and the aqueous layer was extracted several times with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Phenom enex Gemini C18 100 x 30 mm; 5 pm; gradient 81 % [25 mM NH4HCO3] - 19 % ACN to 45 % [25 mM NH4HCO3] - 55 % ACN) to yield Compound 108 (17 mg, yield: 27 %) as a yellow solid.Compound 109: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7- yl)methyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2]thiazine-7-carboxamide 1 , 1 -dioxide.

[0416] Compound 109 was prepared according to Method A (in DMF), starting fromIntermediate 58 instead of Intermediate 26.Compound 111 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)indoline-6-carboxamide.

[0417] HATU (CAS [148893-10-1], 766 mg, 2 mmol, 1.5 eq.) was added to a stirred solution of Intermediate 6 (567 mg, 1.3 mmol, 1 eq.), 2,3-dihydro-17 / -indole-6-carboxylic acid (CAS [732922-86-0], 230 mg, 1.4 mmol, 1.05 eq.), and DIPEA (0.9 mL, 5.4 mmol, 4 eq.) in DMF (10 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with Na2COs (1 M in water) and extracted with EtOAc (2 x 15 mL). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (25 g SiCL, MeOH in DCM from 0 to 5 %), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x 100mm 5 pm; from 72 % [25 mM NH4HCO3] - 28 % ACN to 36 % [25 mM NH4HCO3] - 64 % ACN) to yield Compound 111 (65 mg, yield: 9 %) as a green powder.Compound 112: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-imino-3,4-dihydro-2H-414-benzo[b][l,4]oxathiine-6-carboxamide 4-oxide.(CIS)

[0418] Intermediate 89 (30 mg, 0.057 mmol) was suspended in MeOH (0.6 mL). diacetoxyiodo)benzene (CAS [3240-34-4], 46 mg, 0.14 mmol) and ammonium carbamate (CAS [1111-78-0], 9 mg, 0.11 mmol) were added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and directly purified by reverse phase HPLC (30 x 100 C18 Gemini; from 27 to 47 % ACN / ELO (10 mM NH4OH)) to give Compound 112 (9 mg, yield: 27 %).Compound 113: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2-(2-hydroxyethyl)-3,4-dihydro-2H-benzo[e][l,2]thiazine-7-carboxamide 1,1- dioxide.

[0419] TFA (0.3 mL, 4.01 mmol) was added to a solution of Intermediate 63 (220 mg, 0.307 mmol) in THF. The resulting mixture was stirred at room temperature for 12 h. The solvent was evaporated and the residue was taken up in saturated aqueous NaHCOs (20 mL). The mixture was extracted with DCM and then with EtOAc. The combined organic layer was filtered and concentrated. The residue was purified by column chromatography on silica gel (DCM / MeOH from 100 / 0 to 80 / 20) to give Compound 113 (98 mg, yield: 53 %) as a solid.Compound 114: l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4-methylindoline-6- carb oxami de.

[0420] Compound 110 (60 mg, 0.093 mmol), Ruphos Pd G3 (CAS [1445085-77-7], 8 mg, 0.0093 mmol, 0.1 eq.), and K2CO3 (39 mg, 0.28 mmol, 3.0 eq.) were added to a vial under nitrogen atmosphere. Then dioxane (0.8 mL) and trimethylboroxine (CAS [823-96-1], 79 pL,0.28 mmol, 3.0 eq.) were added and the reaction mixture was stirred at 90 °C for 2 h. After cooling, the mixture was filtered through a Celite® pad, the filtrate was evaporated, and the residue was purified by flash column chromatography (12 g SiCh; MeOH / DCM 0 / 100 to 6 / 94), followed by reverse phase HPLC (EVO C18 5 uM, 100:30 mM; 50 to 100 % ACN in H2O w / 10 mM NH4OH) to give Compound 114 (24 mg, yield: 41 %) as a yellow solid.Compound 115: N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)-lH-indole-6-carboxamide.

[0421] Intermediate 90 (25 mg, 0.046 mmol) was dissolved in Me-THF (0.5 mL). KOtBu (CAS [865-47-4], 13 mg, 0.11 mmol) and MsCl (CAS [124-63-0], 18 pL, 0.23 mmol) were added, and the reaction mixture was stirred overnight at room temperature, then at 50 °C for 1 h. The reaction mixture was diluted with water and extracted with 10 % TFE in DCM (3 x). The organic layer was dried with Na2SO4, filtered, and concentrated. The residue was purified by reverse phase column chromatography.Compound 121 : N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-((*R)-S-methylsulfonimidoyl)indoline-6-carboxamide and Compound 122: N- ((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l-((*S)-S- methylsulfonimidoyl)indoline-6-carboxamide.(*S), (CIS) Compound 122

[0422] l-[Imino(methyl)oxo-X6-sulfanyl]-2,3-dihydro-U / -indole-6-carboxylic acid (CAS [2001362-83-8], 100 mg, 0.416 mmol), Intermediate 6 (210 mg, 0.458 mmol), and HATU (CAS [148893-10-1], 194 mg, 0.499 mmol) were suspended in DMF (4 mL). The vial was evacuated and refilled with nitrogen 3 times. DIPEA (0.364 mL, 2.081 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted with additional EtOAc. The combined organic layer was washed twice with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by reverse phase column chromatography, followed by SFC to give Compound 121 (51 mg, yield: 22 %) and Compound 122 (50 mg, yield: 21 %).Compound 123 : N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7- yl)methyl)-2,3 -dihydro-5H-benzo[e] [ 1 ,4]oxathiepine-8-carboxamide 1 , 1 -dioxide.

[0423] Cis-2,6-dimethylmorpholine (CAS [6485-55-8], 77 pL, 0.62 mmol) was added to a solution of Intermediate 93 (148 mg, 0.29 mmol) and DIPEA (147 pL, 0.89 mmol) in DMSO (2 mL) in a sealed tube. The mixture was stirred at 120 °C for 16 h. After cooling, the mixture was diluted with water and extracted with EtOAc (x 2). The organic layer was separated, dried (MgSCU), filtered, and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 25 g; DCM:MeOH (9:l,v / v) in DCM from 0 / 100 to 100 / 0), followed by reverse phase column chromatography (Phenomenex Gemini Cl 8 100A 100 mm long x 30 mm I.D.; 5 pm; from 59 % [25 mM NH4HCO3] - 41 % [ACN:MeOH (1 : 1)] to 17 % [25 mM NEUIICOs] - 83 % [ACN:MeOH (1 :1)]), and finally trituration in Et2O and filtration to give Compound 123 (42 mg, yield: 24 % ) as a yellow solid.Compound 124: l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-2, 3-dihy dro-lH- pyrrolo[3,2-c]pyridine-6-carboxamide.

[0424] DIPEA (0.731 mL, 4.176 mmol, 7 eq.) was added to a solution of Intermediate 6 (HC1 salt, 650 mg, 1.312 mmol, 2.2 eq.), Intermediate 78 (166 mg, 0.597 mmol), and HATU (490 mg, 1.264 mmol, 2.1 eq.) in anhydrous DMF (6 mL). The reaction mixture was stirred at room temperature for 4 h. The crude reaction mixture was directly purified by reverse phase column chromatography (Waters XSelect CSH Cl 8, 5 um, 19 x 150 mm; 25-60 % ACN with 0.16 % TFA / H2O) to yield Compound 124 (122 mg, yield: 33 %) as a light yellow solid.

[0425] The compounds in Table 5 were prepared from Intermediate 6 and the corresponding acid, following procedures similar to Method A: Table 5.Example B: Analytical characterization methods of Intermediates and Compounds LCMS General procedure

[0426] 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.

[0427] Hereinafter, “MSD” means Mass Selective Detector, “DAD” Diode Array Detector.LC-MS

[0428] 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).

[0429] 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 skilledperson 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.

[0430] 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.

[0431] 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. Table 6: LCMS Method Codes (Flow expressed in mL / min; column temperature (T) in °C;Run time in minutes).Table 7. LCMS results (RT means retention time)NMRSome 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. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer at ambient temperature (298.6 K), using internal deuterium lock and equipped with reverse double-resonance (1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz.

[0432] ’H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CDCL was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane.

[0433] 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, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets. It will be understood that for compounds comprising an exchangeable proton, saidproton 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.Table 8: ’H NMR results.Melting points: Melting Points

[0434] For melting points, values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method. Melting points weredetermined 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 9: Melting Point Results.High Resolution Mass Spectrometry

[0435] Method Code: 1; Agilent 1260 Infinity DAD, column: YMC-pack ODS-AQ C18 (50 x4.6 mm, 3 pm), mobile phase: A: 0.1 % HCOOH in H2O B: CH3CN, gradient: From 95 % A to 5 % A in 4.8 min, held for 1.0 min, to 95 % A in 0.2 min., Flow / Col T : 2.6 / 35, Run time:6.8.Table 10: HRMS results.SFC methods

[0436] 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. “iPrNEh” means isopropylamine, “iPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes, “DEA” means diethylamine.* Jasco 4000 SFC System DAD LC / MS Advion expression L cms

[0437] 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. No. means number.Table 12: Analytical SFC data ; SFC results.Optical Rotation (OR)

[0438] Optical rotations were measured at 20°C or 23°C on a Perkin Elmer 341 digital polarimeter at = 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).Table 13: Optical rotation Results.Example C: Pharmacological Assays

[0439] 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

[0440] 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.

[0441] 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 MgCL (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).

[0442] 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 MgCb 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:

[0443] 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.

[0444] 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).

[0445] 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:

[0446] 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 MgCb (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).

[0447] 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 MgCb 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.

[0448] Results (indicated as IC50, in pM) obtained from testing the compounds of the present disclosure in the present assays are indicated in the Table 14 below.Table 14: SMARCA2 or 4 / SMARCC1 / SMARCC2 / SMARCB1 ADP-Glo Assay ResultsNT : Not testedExample D: Prophetic formulations

[0449] “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. TabletsActive ingredient 5 to 50 mgDi-calcium phosphate 20 mgLactose 30 mgTalcum 10 mgMagnesium stearate 5 mgPotato starch ad 200 mg2. SuspensionAn aqueous suspension is prepared for oral administration so that each milliliter contains 1 to5 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. InjectableA 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. OintmentActive ingredient 5 to 1000 mgStearyl alcohol 3 gLanoline 5 gWhite petroleum 15 gWater ad 100 g

[0450] 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

CLAIMS1. A compound of Formula (I), whereinR1is an optionally substituted bicycle selected from:whereinRais selected from: H, SO2-Ci-4alkyl, SO2-C2-4alkenyl, SO2-C2-4alkynyl, SO2-C1- 4haloalkyl, SO2-CH2CH2OH, SO2-CH2CH2OCH3, SO2-N(CH3)2, SO2-C3-6Cycloalkyl,, (C=O)CH3, and tetrahydropyranyl; Rbis selected from: H, Cl, F, Ci-4alkyl, CH2OH, and CH2NH2; each Rcis independently H, and Ci-4alkyl, or two R8members come together to form a Cs-ecycloalkyl; X is CH or N; Y is CH or N; wherein X and Y are not both N; n is one or two; and — is a single or double bond; orwherein each Rfis independently H, halo, OH, or CH2OH; Z is Ci-salkyl, and n is 1 or 2; orR3is H or CH3; and R5isand pharmaceutically acceptable salts and stereoisomers thereof.

2. A compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR1is3. A compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3is H or CH3.

4. A compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof,6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof,7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the Formula (IA),Rais selected from: H, SO2-Ci-4alkyl, SO2-C2-4alkenyl, SO2-C2-4alkynyl, SO2-Ci-4haloalkyl,(C=O)CH3, tetrahydropyranyl, Rbis selected from: H, Cl, F, Ci-4alkyl, CH2OH, and CH2NH2;Each Rcis independently H, and Ci-4alkyl, or two R8members come together to form a C3. ecycloalkyl;X is CH or N;Y is CH or N; wherein X and Y are not both N; n is one or two; and— is a single or double bond;or a pharmaceutically acceptable salt or stereoisomer thereof.

8. A compound of claim 1 selected from the group consisting of:N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l - (methylsulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l - (isopropylsulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l-(N,N- dimethylsulfamoyl)indoline-6-carboxamide; l-(but-2-yn-l-ylsulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l - (ethylsulfonyl)indoline-6-carboxamide; l-(allylsulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-3, 3- dimethyl-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- methyl-l-(methylsulfonyl)indoline-6-carboxamide;4-chloro-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l- (methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;4-methyl-l-(methylsulfonyl)-N-((2-(6-(2,2,6,6-tetramethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-3, 3- dimethyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxamide;N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide; l-(N,N-dimethylsulfamoyl)-N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l- yl)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;N-((*R)-1 -(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)ethyl)-l- (methylsulfonyl)indoline-6-carboxamide;N-((*S)-l-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)ethyl)-l- (methylsulfonyl)indoline-6-carboxamide; l-acetyl-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine- 6-carboxamide; l-(methylsulfonyl)-N-((2-(3-(pyridin-4-yl)phenyl)-l, 6-naphthyri din-7-yl)methyl)indoline-6- carboxamide; l-(methylsulfonyl)-N-((2-(4-(pyridin-3-yl)piperazin-l-yl)-l,6-naphthyridin-7- yl)methyl)indoline-6-carboxamide;1 -(methyl sulfonyl)-N-((2-(4-(pyridazin-3 -yl)piperazin- 1 -yl)- 1 , 6-naphthyri din-7 - yl)methyl)indoline-6-carboxamide;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-l-(methylsulfonyl)indoline-6-carboxamide ;N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide ;N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)-3-methylpyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(5-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-5-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(5-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l - ((tetrahydro-2H-pyran-4-yl)sulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l'- (methylsulfonyl)spiro[cyclopentane-l,3'-indoline]-6'-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l'- (methylsulfonyl)spiro[cyclopropane-l,3'-indoline]-6'-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-7- (methylsulfonyl)-2,3-dihydro-lH-indene-5-carboxamide;N-((2-(6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-(l- hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-((*S)- l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4-((*R)- l-hydroxyethyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)pyrazolo[l,5-a]pyridine-6-carboxamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2,3-dihydrobenzofuran-6-carboxamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-2,3-dihydrobenzofuran-5-carboxamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)benzo[d] [ 1 ,3 ]dioxole-5-carboxamide;N-((2-(6-((3a,4p,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-2, 3,4,5- tetrahydro-lH-benzo[d]azepine-7-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l - (vinylsulfonyl)indoline-6-carboxamide;4-(aminomethyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;4-fluoro-N-((2-(4-fluoro-6-((3a, 4p, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- 1, 6-naphthyri din-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3 a, 4p, 5 a)-4-hy droxy-3 , 5 -dimethylpiperidin- 1 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxamide;N-((2-(6-((3a, 4P, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6- carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- (methylsulfonyl)-3,4-dihydro-2H-benzo[b][l,4]oxazine-6-carboxamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l- (methylsulfonyl)indoline-6-carboxamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l- (cyclopropylsulfonyl)indoline-6-carboxamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l- (methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;N-((2-(4-fluoro-6-((3 a, 4p, 5 a)-4-hy droxy-3 , 5 -dimethylpiperidin- 1 -yl)pyridin-2-yl)- 1,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)thiochromane-7-carboxamide 1, 1 -di oxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l-((2- methoxyethyl)sulfonyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l-((2- hydroxyethyl)sulfonyl)indoline-6-carboxamide;N-((2-(6-((3a, 4P, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-l -((2 -methoxy ethyl)sulfonyl)indoline-6-carboxamide;N-((2-(6-((3a, 4P, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)methyl)-l-((2 -hydroxy ethyl)sulfonyl)indoline-6-carboxamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l-((2- hydroxyethyl)sulfonyl)indoline-6-carboxamide;N-((2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-l-((2- methoxyethyl)sulfonyl)indoline-6-carboxamide ;N-((2-(4-fluoro-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)- 4-methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4- methyl-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)methyl)-3,4- dihydropyrido[2, 1 -c] [ 1 ,2,4]thiadiazine-9-carboxamide 2,2-dioxide;N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide;4-chloro-N-((2-(3,4-dimethyl-6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;(* S)-4-cyano-N-((2-(6-((R)-3 -methoxypyrrolidin- 1 -yl)pyrazin-2-yl)- 1 , 6-naphthyri din-7- yl)methyl)-4-methylisochromane-6-carboxamide;(*R)-4-cyano-N-((2-(6-((R)-3-methoxypyrrolidin-l-yl)pyrazin-2-yl)-l,6-naphthyri din-7- yl)methyl)-4-methylisochromane-6-carboxamide;(*S)-4-cyano-N-((2-(4-fluoro-3-((3-hydroxypropyl)amino)-lH-pyrazol-l-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide;(*R)-4-cy ano-N -((2-(4-fluoro-3 -((3 -hy droxypropyl)amino)- 1 H-pyrazol- 1 -yl)- 1 , 6- naphthyridin-7-yl)methyl)-4-methylisochromane-6-carboxamide;(*S)-4-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)-4-methylisochromane-6-carboxamide;(*R)-4-cyano-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-4-methylisochromane-6-carboxamide;(*R)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)thiochromane-7-carboxamide 1 -oxide;(*S)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)methyl)thiochromane-7-carboxamide 1 -oxide;(*R)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l - imino- 114-thiochromane-7-carboxamide 1 -oxide;(*S)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-l - imino- 114-thiochromane-7-carboxamide 1 -oxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-3- hydroxy -2, 3-dihydrobenzo[b]thiophene-6-carboxamide 1,1-dioxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4, 4- difluorothiochromane-7-carboxamide 1, 1 -di oxide;(*R)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-3- hydroxy -2, 3-dihydrobenzo[b]thiophene-6-carboxamide 1,1-dioxide;(*S)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-3- hydroxy -2, 3-dihydrobenzo[b]thiophene-6-carboxamide 1,1-dioxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4- hydroxythiochromane-7-carboxamide 1, 1 -di oxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-2- (hydroxymethyl)thiochromane-7-carboxamide 1 , 1 -dioxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-2, 3- dihydrobenzo[b][l,4]oxathiine-6-carboxamide 4,4-dioxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)thiochromane-7-carboxamide 1, 1 -di oxide; l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l, 6-naphthyri din-7- yl)methyl)-3,4-dihydro-2H-benzo[e][l,2]thiazine-7-carboxamide 1,1-dioxide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l, 6-naphthyri din-7-yl)methyl)-4- oxo-2, 3 ,4, 5-tetrahydrobenzo[b] [ 1 ,4]thiazepine-8-carboxamide 1 , 1 -dioxide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l, 6-naphthyri din-7-yl)methyl)-3- hydroxy-4H-benzo[b][l,4]thiazine-7-carboxamide 1,1-dioxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-3, 4- dihydro-2H-benzo[e] [ 1 ,2]thiazine-7-carboxamide 1 , 1 -dioxide;4-chloro-l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- 1, 6-naphthyri din-7-yl)methyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)indoline- 6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-4-imino- 3,4-dihydro-2H-414-benzo[b][l,4]oxathiine-6-carboxamide 4-oxide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)methyl)-2-(2- hydroxy ethyl)-3 ,4-dihydro-2H-benzo[e] [ 1 ,2]thiazine-7-carboxamide 1 , 1 -dioxide;l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-4-methylindoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-l - (methylsulfonyl)-lH-indole-6-carboxamide;(*R)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-4- methylthiochromane-7-carboxamide 1, 1 -di oxide(*S)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-4- methylthiochromane-7-carboxamide 1, 1 -di oxide;(*S)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-2- (hydroxymethyl)thiochromane-7-carboxamide 1 , 1 -dioxide;(*R)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)methyl)-2- (hydroxymethyl)thiochromane-7-carboxamide 1 , 1 -dioxide; l-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-l-((*R)- S-methylsulfonimidoyl)indoline-6-carboxamide;N-((2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)methyl)-l-((*S)- S-methylsulfonimidoyl)indoline-6-carboxamide;N-((2-(2-((cis)-2,6-dimethylmorpholino)pyrimidin-4-yl)-l,6-naphthyridin-7-yl)methyl)-2,3- dihydro-5H-benzo[e] [ 1 ,4]oxathiepine-8-carboxamide 1 , 1 -dioxide; and l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide; and pharmaceutically acceptable salts and stereoisomers thereof.

9. A compound of claim 1 selected from the group consisting of:N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6- carboxamide;4-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)-l-(methylsulfonyl)indoline-6-carboxamide;N-((2-(4-fluoro-6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6- carboxamide;N-((2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6- carboxamide; l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)indoline-6-carboxamide;4-chloro-l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)methyl)indoline-6-carboxamide; l-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-6-carboxamide; and l-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)methyl)-2,3-dihydro-lH-pyrrolo[3,2-c]pyridine-6-carboxamide; and pharmaceutically acceptable salts, and stereoisomers thereof.

10. 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.

11. A compound according to any one of claims 1 to 9 for use in therapy.

12. A compound according to any one of claims 1 to 9 for use in the treatment of a SMARCA4 deficient cancer.

13. The compound for the use of claim 12, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).

14. A compound according to any one of claims 1 to 9 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

15. The compound for the use of claim 14, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

16. Use of a compound as defined in any one of claims 1 to 9 for the manufacture of a medicament for the treatment of cancer or NSCLC.

17. 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 9.

18. 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 9.

19. The method of claim 18, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

20. 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 9.

21. The method of claim 20, wherein the disease or condition is selected from a cancer or NSCLC.

22. The method of any one of claims 18 to 21, wherein the subject is a mammal.

Images