WO2025008059A1

WO2025008059A1 - 1,6-naphthridine compounds as smarca2 inhibitors useful for the treatment of smarca4 deficient cancers

Info

Publication number: WO2025008059A1
Application number: PCT/EP2023/068561
Authority: WO
Inventors: Ian Stansfield; Kristi Anne Leonard; Michael Peter Winters
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2023-07-05
Filing date: 2023-07-05
Publication date: 2025-01-09
Anticipated expiration: 2026-01-05

Abstract

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

Description

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

FIELD OF THE INVENTION

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

BACKGROUND OF THE INVENTION

[0002] The 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 and isoquinoline chemical entities having SMARCA2 modulating properties, and pharmaceutical compositions comprising these chemical entities, to the use of said chemical entities as inhibitors of the SMARCA2 protein, and to methods of treatment or use in the treatment of SMARCA4 deficient cancers, as described in the claims.

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

[0011] Embodiments of this invention are uses and methods of treatment using compounds of Formula (I),

wherein

R¹ is selected from the group consisting of:

R^c is halo, Ci-4alkyl, or OCi-4alkyl;

R^f is halo, Ci-4alkyl, or O-Ci-4alkyl;

R¹ is SO2-Ci-4haloalkyl, NH-SO2-Ci-4haloalkyl, N(CH3)-SO2-Ci-4haloalkyl, or SO₂-

N(CH₃)₂,

(iii) 5 or 6-membered heteroaryl selected from:

Rⁿ is SO2CH3, CH₂C(OH)(CH₃)2, CH2CH2SO2CH3;

R^p is SO2CH3 or CH2CH2CN; or

R^q is H or CH₃;

(iv) Cs-ecycloalkyl or bridged-Cs-vcycloalkyl each substituted with SO2Ci-4alkyl, SO2-C3-6cycloalkyl. CO2CH3, or NH-SO2Ci-4haloalkyl; or,

(v) carbon linked pyrrolidine, piperidine, or azepane: each independently substituted with one or two substituents selected from: halo, Ci-4alkyl, Ci-4haloalkyl, CH2OH, OH, OCi-₄alkyl, SO₂Ci-₄alkyl, SO₂Ci-₄haloalkyl, SO2CH2CH2OH, and C(=O)Ci-₄haloalkyl; or 5-azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane, and 3- azabicyclo[3.1.0]hexane each independently substituted with SO2Ci-4haloalkyl;

and X is CH or N; 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 INVENTION

Definitions

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

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

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

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

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

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

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

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

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

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

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

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

[0025] As used herein, “C_x-y” (where x and y are integers) refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). Thus, a Ci-ealkyl group contains from 1 to 6 carbon atoms, a Cs-ecycloalkyl group contains from 3 to 6 carbon atoms, and so on. [0026] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo. [0027] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Cnealkyl” or similar designations. [0028] By way of example, the term “Ci-4alkyl”, or “Cnealkyl” as used herein as a group or part of a group refers to a linear or branched saturated hydrocarbon group containing from 1 to 4 or 1 to 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, and the like.

[0029] The term “haloalkyl” refers to an alkyl group as defined herein wherein one or more than one hydrogen atom is replaced with one or more halogens. The term “haloalkyl” includes “haloCi-4alkyl”, “haloCnealkyl”, monohaloCi-4alkyl, monohaloCnealkyl, polyhaloCi-4alkyl, and polyhaloCnealkyl. There may be one, two, three or more hydrogen atoms replaced with a halogen, so the haloCi-4alkyl or haloCnealkyl 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), tetrafluorotrifluoromethylethyl (CF(CF₃)₂), and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.

[0030] The term “cyanoCi-4alkyl” or “cyanoCnealkyl” as used herein refers to a Ci-4alkyl or Cnealkyl group as defined herein which is substituted with one or two cyano groups, in particular with one cyano group.

[0031] “Amino” refers to a -NH2 group.

[0032] The terms “carboxy” or “carboxyl” refer to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,

[0033] 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).

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.)

[0038] The term “phenyl” represents the following moiety:

[0039] The term “cycloalkyl” refers to a monocyclic or polycyclic (bridged or fused) nonaromatic 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.

[0040] The term “heterocyclyl” or “heterocycloalkyl”, is as defined herein, contains at least one heteroatom typically selected from nitrogen, oxygen or sulphur, in particular containing up to 5, up to 4, up to 3, up to 2, or a single heteroatom. Where reference is made herein to a heterocyclyl or heterocycloalkyl ring system, the heterocyclyl or heterocycloalkyl ring can, unless the context indicates otherwise, be optionally substituted (i.e. unsubstituted or substituted) by one or more substituents as discussed herein. The radicals may be fused with an aryl or heteroaryl. It is understood that a heterocyclyl or heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. Illustrative examples of heterocycloalkyl groups, also referred to as non-aromatic heterocycles, include:

[0041] 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.

[0042] The term “heteroaryl” is used herein to denote a heterocyclyl ring system having aromatic character. The term “heteroaryl” embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the ring system may be attached to the remainder of the compound by an aromatic ring or by a non-aromatic ring. [0043] 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. Non-limiting examples of illustrative of heteroaryls are:

[0044] 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.

[0045] 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). [0046] 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, 4^th Edition, Wiley Interscience, pages 131-133, 1992.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [0053] 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.

[0054] 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. [0055] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.

[0062] 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.

[0063] 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.

[0064] 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).

[0065] 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

[0066] 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.

[0067] In certain embodiments, the compounds presented herein possess one or more stereocenters and each center independently exists in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. Stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In some embodiments, a compound of the present disclosure is used as a single enantiomer. In some embodiments, a compound of the present disclosure is used as a racemic mixture. In some embodiments, a compound of the present disclosure possesses hindered rotation about a single bond resulting in atropisomers.

[0068] In some situations, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0069] 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

[0070] 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.

[0071] Where compounds described herein contain one or more chiral centers and can exist in the form of two or more optical isomers, references to the compounds described herein include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) of two or more optical isomers, unless the context requires otherwise. When a compound has more than one chiral center, and one chiral center is indicated as having an absolute stereoconfiguration, the other chiral center(s) include all optical isomeric forms, either as individual optical isomers, or mixtures (e.g. racemic mixtures) of two or more optical isomers, thereof, unless the context requires otherwise. The optical isomers may be characterized and identified by their optical activity (i.e. as + and - isomers depending on the direction in which they rotate plane polarized light, or d and I isomers) or they may be characterized in terms of their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold and Prelog, see Advanced Organic Chemistry by Jerry March, 4^th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew. Chem. Int. Ed. Engl., 5, 385-415. For instance, resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. [0072] Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. As an alternative to chiral chromatography, optical isomers can be separated by forming diastereoisomeric salts with chiral acids such as (+)-tartaric acid, (-)- pyroglutamic acid, (-)-di-toluoyl-L-tartaric acid, (+)mandelic acid, (-)-malic acid, and (-)- camphorsulphonic, separating the diastereoisomers by preferential crystallization, and then dissociating the salts to give the individual enantiomer of the free base.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter are used interchangeably.

[0077] 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.

[0078] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible. [0079] 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-morpholine

[0080] For example,

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- 1 ,6-naphthyridin-7-yl)- jV-(4-methyl-3 - (methylsulfonyl)phenyl)acetamide

[0081] In the present invention, tri substituted piperidine moi eties with stereocenters are defined as (3a, 4a, 5a) or (3a, 4b, 5a). For example:

(3a,4a,5a)-3,5-dimethyl-4-piperidinol (3a,4p,5a)-3,5-dimethyl-4-piperidinol

(3a,4a,5a)-3,5-dimethyl-4-piperidinol (3a,4b,5a)-3,5-dimethyl-4-piperidinol

(3p,4p,5p)-3,5-dimethyl-4-piperidinol (3p,4a,5p)-3,5-dimethyl-4-piperidinol

(3b,4b,5b)-3,5-dimethyl-4-piperidinol (3b,4a,5b)-3,5-dimethyl-4-piperidinol

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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. [0087] 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.

[0088] 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, camphorsulphonate, (+)-(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.

[0089] 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., NH3RT, 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. [0090] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0091] 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.

[0092] The compounds of the present disclosure include compounds that are isotopically labeled, i.e., with one or more isotopic substitutions. These compounds are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. A reference to a particular element includes within its scope all isotopes of the element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in a diagnostic context. Radiolabeled compounds described herein may comprise a radioactive isotope selected from the group of ²H, ³H, ⁿC, ¹⁸F, ¹²²I, ¹²³1, ¹²⁵I, ¹³¹1, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactive isotope is selected from the group of ²H, ³H, ⁿC and ¹⁸F. More preferably, the radioactive isotope is ²H. In particular, deuterated compounds are intended to be included within the scope of the present invention. In some embodiments, metabolic sites on the compounds described herein are deuterated.

[0093] Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds. [0094] Embodiments of the 1,6-naphthyridine and isoquinoline compounds for use as described herein are compounds of Formula (I):

wherein

R¹ is selected from the group consisting of:

R^c is halo, Ci-4alkyl, or OCi-4alkyl;

R^f is halo, Ci-4alkyl, or O-Ci-4alkyl;

(ii) C_2.3alkyl substituted

R¹ is SO₂-Ci-4haloalkyl, NH-SO₂-Ci-4haloalkyl, N(CH₃)-SO₂-Ci-4haloalkyl, or SO₂-

N(CH₃)₂,

(iii) 5 or 6-membered heteroaryl selected from:

Rⁿ is SO2CH3, CH₂C(OH)(CH₃)₂, CH₂CH₂SO₂CH₃;

R^p is SO₂CH₃ or CH₂CH₂CN; or

R^q is H or CH₃;

(iv) C₃-6cycloalkyl or bridged-Cs-vcycloalkyl each substituted with SO₂Ci-4alkyl, SO₂-C₃-6cycloalkyl. CO₂CH₃, or NH-SO₂Ci-4haloalkyl; or,

(v) carbon linked pyrrolidine, piperidine, or azepane: each independently substituted with one or two substituents selected from: halo, Ci-4alkyl, Ci-4haloalkyl, CH₂OH, OH, OCi-₄alkyl, SO₂Ci-₄alkyl, SO₂Ci-₄haloalkyl, SO₂CH₂CH₂OH, and C(=O)Ci-₄haloalkyl; or 5-azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane, and 3- azabicyclo[3.1.0]hexane each independently substituted with SO₂Ci-4haloalkyl;

R⁵ is an optionally substituted 6-membered ring selected from:

[0095] In some embodiments of Formula

[0096] In some embodiments of Formula (I), Xis CH. In some embodiments, X is N.

[0097] In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R¹ is

In some embodiments, R⁵ is an optionally substituted 6-membered ring selected from:

[0098] In some embodiments, the compound of Formula (I) is a compound as shown below in

Table 1.

0099] and pharmaceutically acceptable salts and stereoisomers thereof.

[0100] In some embodiments, the 1,6-naphthyridine or isoquinoline compound is selected from the group consisting of:

[0101 ] N-(3 -((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0102] N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

[0103] N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0104] N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

[0105] N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0106] N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

[0107] N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

[0108] N-((R)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0109] N-((R)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0110] N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide;

[0111] N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0112] N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; [0113] N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0114] N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0115] N-(2-((l,l-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

[0116] N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; and

[0117] N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; and pharmaceutically acceptable salts and stereoisomers thereof.

[0118] In some embodiments, the isoquinoline compound is a compound of Formula (IA):

[0119] In some embodiments, the 1,6-naphthyridine compound is a compound of Formula (IB):

wherein, R¹ is (i)

pharmaceutically acceptable salt or stereoisomer thereof.

[0120] An additional embodiment of the invention is a method of treating cancer or nonsmall-cell lung carcinoma (NSCLC) in a subject comprising administering an effective amount of a pharmaceutical composition, or use of a pharmaceutical composition for treating cancer or non-small-cell lung carcinoma (NSCLC), or a pharmaceutical composition for such use, comprising: at least one compound selected from compounds of Formula (I); and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of compounds of Formula (I); and (B) at least one pharmaceutically acceptable excipient. [0121] In some embodiments, such pharmaceutical compositions comprise a therapeutically effective amount of at least one compound in Table 1, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, or a pharmaceutically acceptable prodrug of at least one compound of Table 1, or at least one pharmaceutically active metabolite of Table 1; and at least one pharmaceutically acceptable excipient.

[0122] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of Formula (IA), or a pharmaceutically acceptable salt, N-oxide or solvate, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of Formula (IA); and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound of Formula (IB), or a pharmaceutically acceptable salt, N- oxide or solvate, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite of Formula (IB); and at least one pharmaceutically acceptable excipient.

Synthesis of Compounds

[0123] 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.

[0124] The synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the field are described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4^th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3^rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. [0125] 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, Fischer Scientific (Fischer Chemicals), and AcrosOrganics.

[0126] 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. [0127] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyl dimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t- butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0128] 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.

[0129] 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.

[0130] Typically blocking/protecting groups may be selected from:

Fmoc

[0131] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure.

General synthetic pathways [0132] Compounds of Formula (I), wherein R⁵ is aryl or heteroaryl and all other substituents are defined as in the general scope, are prepared according to SCHEME 1.

SCHEME 1

[0133] According to SCHEME 1, a compound of formula (II), wherein X is CH or N, and R⁵ bears a suitable halide (Hal), such as, for example, fluoride, is reacted with a commercially available or synthetically accessible nucleophilic heterocycle such as, for example, cis-2,6- dimethylmorpholine, in the presence of a suitable base such as, for example, DIPEA, and the like; in a suitable solvent such as, for example, DMSO, and the like; at a suitable temperature such as, for example, 120 °C; to provide a compound of Formula (I).

[0134] In an alternate method, a compound of formula (II), wherein X is CH or N, and R⁵ bears a suitable halide, such as, for example, Cl, Br or I, is reacted with a suitable commercially available or synthetically accessible nucleophilic heterocycle such as, for example, cis-2,6-dimethylmorpholine, under standard transition metal catalyzed amination conditions, to provide a compound of Formula (I).

[0135] A compound of Formula (III), where X is CH or N, is reacted with a suitable commercially available or synthetically accessible amine of formula R¹NH2, in the presence of a suitable coupling agent such as, for example, HATU, HBTU, or 1-propanephosphonic anhydride, in the presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, room temperature, to provide a compound of Formula (I). In an alternate method, formation of the corresponding acyl halide of formula (III) is achieved employing a suitable activating agent such as, for example, thionyl chloride, subsequent reaction of the acyl halide intermediate with a commercially available or synthetically accessible suitable amine of formula R¹ NH2, in the presence of a suitable base such as, for example, EtsN or DIPEA in a suitable solvent such as, for example, DCM at a suitable temperature such as, for example, room temperature provides a compound of Formula (I).

[0136] Intermediates of formula (II), wherein R⁵ is a suitably substituted aryl or heteroaryl group, such as, for example, pyridyl, Hal is a suitable halide such as, for example, fluoride, and all other substituents are defined as in the general scope, are prepared according to SCHEME 2. Intermediates of formula (III), wherein R⁵ is a suitably substituted aryl or heteroaryl group, such as, for example, pyridyl, and all other substituents are defined as in the general scope, are prepared according to SCHEME 2.

SCHEME 2

[0137] A compound of formula (VII), where X is CH or N, such as, for example, 7-chloro- l,6-naphthyridin-2(lH)-one (CAS [1345091-18-0]) is commercially available or synthetically accessible by one skilled in the art, following procedures described herein or in literature. A compound of formula (VII), wherein Hal is a suitable halide such as, for example, chloride, is reacted with a suitable 2-halogenozinc acetic ester, such as, for example, 2-tert-butoxy-2- oxoethylzinc bromide (CAS [51656-70-3]), in the presence of a suitable catalyst such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5]), in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 60 °C, to provide a compound of formula (VI).

[0138] A compound of formula (V) is prepared in two steps, by reacting first a compound of formula (VI) with a suitable activating agent such as, for example, PyBroP (CAS [132705-51- 2]), in the presence of a suitable base such as, for example, DBU, in a suitable solvent such as, for example, 1,4-di oxane, at a suitable temperature such as, for example, room temperature; and in a second step, reacting the formed intermediate with a suitable aryl- or heteroaryl- boronic acid or boronate such as, for example, 6-fluoropyridine-2-boronic acid pinacol ester, in the presence of a suitable base such as, for example, Na2COs, in the presence of a suitable catalyst such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5]), in a suitable solvent such as, for example, 1,4-di oxane, at a suitable temperature such as, for example, 100 °C. Alternatively, a compound of formula (V) is prepared by treating a compound of formula (VI) with a suitable activating agent such as, for example, phosphorus oxychloride then reacting it with a suitable aryl- or heteroaryl- boronic acid or boronate such as, for example, 6-fluoropyridine-2 -boronic acid pinacol ester, in the presence of a suitable base such as, for example, Na2COs, in the presence of a suitable catalyst such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5]), in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, 100 °C.

[0139] A compound of formula (V), where Hal is a suitable halide such as, for example, chloride, is reacted with a suitable deprotecting agent such as, for example, when R is a tertbutyl group, TFA, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature to provide a compound of formula (IV). A compound of formula (IV) is reacted with a suitable commercially available or synthetically accessible amine R¹NH2; in the presence of a suitable coupling agent such as, for example, HATU, HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, for example, DIPEA; in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, room temperature provides a compound of formula (II). [0140] A compound of formula (VIII) is prepared in two steps; first, a compound of formula (VI) is reacted with a suitable activating agent such as, for example, PyBroP (CAS [132705- 51-2]), in the presence of a suitable base such as, for example, DBU, in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, at room temperature. In a second step, the resulting intermediate is coupled with a suitably substituted aryl or heteroaryl boronic acid or boronate ester such as, for example, [3-(pyridin-4- yl)phenyl]boronic acid (CAS [337536-25-1]), in the presence of a suitable base such as, for example, Na2COs, in the presence of a suitable catalyst such as, for example, X-Phos-Pd G2 (CAS [1310584-14-5]), in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, 100 °C.

[0141] In an alternate method, a compound of formula (VIII), wherein R⁵ is defined as a substituted heteroaryl, is prepared by reaction of a compound of formula (V) wherein Hal is a suitable halide, such as, for example, fluoride, with a suitable nucleophile R^5aH such as, for example, an amine R^9aR^9bNH, 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, 110 °C.

[0142] In an alternate method, a compound of formula (VIII), is prepared by reaction of a compound of formula (V), wherein R⁵ bears a suitable halide Hal, such as, for example, Cl, Br, or I, with a suitable nucleophile such as, for example, cis-2,6-dimethylmorpholine, under standard transition metal catalyzed amination conditions. [0143] A compound formula (III) is prepared by reaction a compound of formula (VIII), where R is Ci-4alkyl, with a suitable hydrolyzing reagent such as, TFA, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature. In an alternate method, saponification of the ester compound of formula (VIII) to the acid compound of formula (III) is achieved employing conditions known to one skilled in the art, for example, using a suitable base such as NaOH, LiOH, and the like, in a suitable solvent such as water/THF/MeOH, at a temperature of about 60 °C, for a period of about 2 h.

[0144] Compounds of Formula (I), wherein R⁵ is defined as an optionally substituted 6- membered ring, and all other substituents are as defined in the general scope, are prepared according to SCHEME 3.

SCHEME 3

[0145] According to SCHEME 3, a compound of formula (VI), where R is Ci-4alkyl, is reacted with a suitable hydrolyzing reagent such as, TFA, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature, to provide a compound of formula (XV). In an alternate method, saponification of the ester compound of formula (VI) to the acid compound of formula (XV) is achieved employing conditions known to one skilled in the art, for example, using a suitable base such as NaOH, LiOH, and the like, in a suitable solvent such as water/THF/MeOH, at a temperature of about 60 °C, for a period of about 2 h. A compound formula (XV) is reacted with a commercially available or synthetically accessible suitable amine R¹NH2, such as, for example, 3-methylsulfonyl-4- methylaniline, in the presence of a suitable coupling agent, such as, for example, HATU, in the presence of a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, ACN, at a suitable temperature such as, for example, room temperature to provide a compound of formula (XIV). [0146] A compound of formula (XIV) is reacted with a suitable amine or heteroaryl of formula R⁵H, in the presence of a suitable activating agent such as, for example, BOP (CAS [56602-33-6]), in the presence of a suitable base such as, for example, DBU, in a suitable solvent such as, for example, ACN, at a suitable temperature such as, for example, 80 °C.

[0147] Alternatively, compounds of Formula (I), wherein all substituents are as defined in the general scope, can be prepared according to SCHEME 4.

SCHEME 4

[0148] According to SCHEME 4, a compound of formula (XVI) is prepared by reacting a compound of formula (XIV) with a suitable chlorinating agent such as, for example, phosphorus oxychloride, at a suitable temperature such as, for example, 80 °C. A compound of formula (XVI) wherein Hal is a suitable halide such as, for example, chloride, is reacted with a suitable boronate or boronic acid R⁵B(OR)2, under standard transition metal-catalyzed coupling conditions known to one skilled in the art, to provide a compound of Formula (I).

[0149] The skilled person will realize that another sequence of the chemical reactions shown in the SCHEMES, may also result in the desired compound of Formula (I).

[0150] 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.

[0151] 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 or Ci-6alkyl-O-C(=O)-, can be converted into carboxyl 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.

[0152] 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. [0153] 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.

[0154] 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.

[0155] 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.

[0156] 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

[0157] 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.

[0158] The subject being treated is a mammal. The subject may be a human. The subject may be a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. The subject may be a companion animal such as a dog or cat. The subject may be a livestock animal such as a cow, pig, horse, sheep, or goat. The subject may be a zoo animal. The subject may be a research animal such as a rodent, dog, or non-human primate. The subject may be a nonhuman transgenic animal such as a transgenic mouse or transgenic pig.

[0159] 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.

[0160] 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.

[0161] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0162] 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.

[0163] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18^th ed., Mack Publishing Company, 1990, see especially Part 8 : Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, or a nose spray. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment.

[0169] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] The one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved. It will be appreciated that the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated, and the particular host being treated. The optimum method and order of administration and the dosage amounts, and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.

[0175] 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

[0176] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0177] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained.

Example A: Preparation of the Intermediates and the final Compounds, and characterization thereof [0178] Several methods for preparing the Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods. Table 2: Abbreviations

[0179] As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities.

[0180] 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.

[0181] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context. Preparation of intermediates:

[0182] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no molar amounts are mentioned for such intermediate in the next reaction step or alternatively estimated molar amounts or theoretical molar amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below.

Intermediate 1 : tert-butyl 2-(2-oxo-l,2-dihydro-l,6-naphthyridin-7-yl)acetate.

[0183] To a suspension of 7-chloro-l,6-naphthyridin-2(177)-one (CAS [1345091-18-0], 1792 mg, 9.92 mmol) in anhydrous THF (75 mL) at room temperature under nitrogen atmosphere was added XPhos Pd G2 (CAS [1310584-14-5], 787 mg, 1 mmol) followed by 2-tert-butoxy- 2-oxoethylzinc bromide (100 mL of a 0.5 M solution in THF, 50 mmol). This solution was heated to 60 °C for 2 h then was cooled to room temperature. Water and aqueous saturated NH4CI were added, the aqueous layer was extracted with EtOAc/Et2O (1/1), the organics combined, washed with brine, dried over MgSCU, and concentrated in vacuo. Purification by column chromatography on silica gel (80 g) eluting with 0 to 100 % (10 % MeOH/EtOAc)/heptane provided Intermediate 1 (2.85 g, yield: 90 %) as a yellow solid.

Intermediate 2: tert-butyl 2-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)acetate.

[0184] To a stirred solution of Intermediate 1 (576 mg, 2.21 mmol) in 1,4-dioxane (20 mL) at room temperature under nitrogen atmosphere was added PyBrop (CAS [132705-51-2], 1.24 g, 2.66 mmol) followed by DBU (0.66 mL, 4.43 mmol). After 30 min, 6-fluoropyridine-2- boronic acid pinacol ester (CAS [842136-58-7], 987 mg, 4.43 mmol), Catacxium Pd G4 (CAS [2230788-67-5], 164 mg, 0.22 mmol), and aqueous sodium carbonate (2 N, 3.32 mL, 6.64 mmol) were added and the solution quickly brought to 100 °C. After 16 h at 100 °C, water was added, the aqueous layer extracted with DCM, dried over MgSCU, and concentrated in vacuo. Purification by column chromatography on silica gel (40 g) eluting with 0 to 100 % EtOAc/heptane provided Intermediate 2 (452 mg, yield: 60 %).

Intermediate 3: tert-butyl 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)acetate.

[0185] To a solution of Intermediate 2 (85 mg, 0.25 mmol) in DMSO (3.8 mL) was added cis- 2,6-dimethylmorpholine (0.061 mL, 0.48 mmol) and DIPEA (0.16 mL, 0.95 mmol). The solution was heated to 100 °C for 2 h, then 110 °C for 16 h. CA-2,6-dimethylmorpholine (0.031 mL, 0.24 mmol) and DIPEA (0.04 mL, 0.24 mmol) were added, and the mixture was heated at 110 °C for 24 h. Water and brine were added, the aqueous layer was extracted with EtOAc/Et2O (1/1), and the organics washed with water and brine. The combined organic layer was dried over MgSCU and concentrated in vacuo. Purification by column chromatography on silica gel (12 g) eluting with 0 to 100 % EtOAc/heptane provided Intermediate 3 (104 mg, yield: 99 %).

Intermediate 4: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyridin-7- yl)acetic acid.

[0186] To a solution of Intermediate 3 (1.27 g, 2.92 mmol) in DCM (15 mL) was added HC1 (4 M in 1,4-dioxane, 7.5 mL, 30 mmol). The solution was stirred at room temperature overnight, then diluted with Et2O (20 mL), and filtered to collect the solid. The filter cake was washed with Et2O and dried under suction to give Intermediate 4 (1.21 g, yield: 99 %) as a yellow solid.

Intermediate 5:tert-butyl 2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)acetate.

[0187] To a solution of Intermediate 1 (74 mg, 0.28 mmol) in 1,4-dioxane (3 mL) at room temperature under nitrogen atmosphere was added PyBrop (CAS [132705-51-2], 159 mg, 0.34 mmol) followed by DBU (0.084 mL, 0.57 mmol). After 30 min, -[3-(4- pyridinyl)phenyl]boronic acid (CAS [337536-25-1], 85 mg, 0.43 mmol), X-Phos Pd G2 (CAS [1310584-14-5], 22 mg, 0.028 mmol) and aqueous sodium carbonate (2 N, 0.43 mL, 0.85 mmol) were added and the solution quickly brought to 100 °C. After 16 h at 100 °C, the reaction was cooled to room temperature, water was added, and the aqueous layer was extracted with DCM. The organic layer was dried over MgSCU and concentrated in vacuo. Purification by column chromatography on silica gel (24 g) eluting with 0 to 100 % EtOAc/heptane provided the title compound (55 mg, yield: 49 %). Intermediate 6: 2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)acetic acid.

[0188] To a solution of Intermediate 5 (55 mg, 0.14 mmol) in DCM (2 mL) was added TFA (0.5 mL). After 16 h at room temperature, the solution was concentrated in vacuo. The title compound was used without further purification.

Intermediate 7 : (E)-5-bromo-2-(hydroxyimino)-2, 3 -dihydro- IH-inden-l -one.

[0189] Into a 500 mL 3-necked flask was added 5-bromo-2,3-dihydroinden-l-one (20 g, 94.8 mmol, 1.00 eq.), EtOH (200 mL) and HC1 (16 mL). Then, t-BuNO₂ (10.5 g, 101.4 mmol, 1.07 eq.) was added. The resulting mixture was stirred for 2 h at room temperature. The precipitated solids were collected by filtration and washed with Et₂O (2x10 mL) to afford Intermediate 7 (20.4 g, yield: 90 %) as a white solid.

Intermediate 8: 6-bromo-l,3-dichloroisoquinoline.

[0190] Into a 2000-mL 4-necked round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was placed Intermediate 7 (20.4 g, 85.0 mmol, 1 eq.), POCL (200 mL), and PCI5 (22.4 g, 107.6 mmol, 1.3 eq.). To the mixture was added HC1 (gas). The mixture was stirred for 1 h at room temperature and then stirred for 6 h at 60 °C. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of water/ice (200 mL). The resulting solution was extracted with EtOAc (3 x 500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from EtOAc/petroleum ether 1/10 to afford Intermediate 8 (20 g, yield: 85 %) as a yellow solid. Intermediate 9: 6-bromo-3-chloroisoquinoline.

[0191] Into a 500-mL 3-necked round-bottom flask, were placed Intermediate 8 (20 g, 72.2 mmol, 1 eq.), AcOH (200 mL), P (5.6 g, 2.5 eq.), and HI (21 mL, 1.60 eq., 45 % in water). The resulting solution was stirred overnight at 120 °C. After cooling, the mixture was concentrated under vacuum and the resulting solution was diluted with H2O (500 mL). The pH of the solution was adjusted to 10 with saturated aqueous sodium carbonate. The resulting solution was extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (2 x 300 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography with EtOAc/petroleum ether (1/30) to afford Intermediate 9 (19.8 g, yield: 96 %) as a yellow solid.

Intermediate 10: 3-chloro-6-(6-fluoropyridin-2-yl)isoquinoline.

[0192] Procedure A:

[0193] Into a 2 L 3-necked flask were added 6-fluoropyridin-2-ylboronic acid (CAS [916176- 61-9], 20.9 g, 148.0 mmol, 1.30 eq.), Pd(dppf)Cl₂ (CAS [72287-26-4], 8.3 g, 11.4 mmol, 0.10 eq.), Intermediate 9 (27.6 g, 113.8 mmol, 1.00 eq.), K2CO3 (47.2 g, 341.4 mmol, 3.00 eq.), 1,4-di oxane (828 mL), and H₂O (276 mL). The system was evacuated and refilled with nitrogen three times. The reaction mixture was heated to 80 °C for 40 min. The mixture was cooled to room temperature, diluted with EtOAc (1 L), and washed with brine (2 x 300 mL). The organic layer was dried over Na₂SO4, filtered, and concentrated. The crude solid was triturated with ACN (60 mL) and filtered to afford Intermediate 10 (23.6 g, yield: 80 %) as a dark gray solid.

[0194] Procedure B:

[0195] 6-Bromo-3 -chloroisoquinoline (CAS [552331-06-3], 1.009 g, 4.161 mmol), 6- fluoropyridine-2-boronic acid pinacol ester (CAS[842136-58-7], 1.329 g, 5.958 mmol), and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 0.299 g, 0.409 mmol) were suspended in degassed 1,4-di oxane (29 mL) and degassed aqueous K2CO3 (11 mL, 22 mmol, 2 M) under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 40 min. After cooling, the mixture was diluted with EtOAc, washed with brine, dried (MgSCU), filtered, and concentrated. The crude product was triturated in ACN with sonication. The resulting solid was isolated via filtration, rinsed with additional ACN, and dried under high vacuum to yield Intermediate 15 (0.902 g, yield: 84 %) as a dark gray solid.

Intermediate 11 : tert-butyl 2-(6-(6-fluoropyridin-2-yl)isoquinolin-3-yl)acetate.

Procedure A:

[0196] Into a 2 L 3-necked flask was added Intermediate 10 (23.6 g, 91.2 mmol, 1.00 eq.), XPhos Pd G2 (CAS [1310584-14-5], 14.4 g, 18.2 mmol, 0.20 eq.), THF (944 mL), and 2-tert- butoxy-2-oxoethylzinc bromide (CAS [51656-70-3], 118.8 g, 456.2 mmol, 5.00 eq.). The system was evacuated and refilled with nitrogen three times. The reaction mixture was heated to 70 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (600 mL) and washed with saturated aqueous NH4CI (3 x 300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (EtOAc:petroleum ether 1 : 10) to afford Intermediate 11 (25 g, yield: 81 %) as a yellow solid.

Procedure B:

[0197] Intermediate 10 b (0.096 g, 0.371 mmol) and XPhos Pd G2 (CAS [1310584-14-5], 0.031 g, 0.0394 mmol) were suspended in degassed, dry THF (5 mL) under a nitrogen atmosphere. 2-Tert-butoxy-2-oxoethylzinc bromide (CAS [51656-70-3], 4.0 mL, 2.0 mmol, 0.5 M in Et2O) was added and the reaction mixture was stirred at 70 °C for 1 h. After cooling, the reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated. The crude residue was purified by flash column chromatography (12 g SiO2, 0 - 10 % 2 N NHVMeOH in DCM) to yield Intermediate 16 (0.12 g, yield: 91 %, 95 % pure) as a yellow solid. Intermediate 12: tert-butyl 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3- yl)acetate.

Procedure A:

[0198] Into a 2 L 3-necked flask were added Intermediate 11 (25 g, 73.9 mmol, 1.00 eq.), DMSO (1250 mL), DIPEA (38.2 g, 295.5 mmol, 4.00 eq.), and (2R,6S)-2,6- dimethylmorpholine (CAS [6485-55-8], 17.0 g, 147.8 mmol, 2.00 eq.). The reaction mixture was stirred at 110 °C overnight. Then, an additional portion of DIPEA (9.1 g, 73.9 mmol, 1.00 eq.) and (2R,6S)-2,6-dimethylmorpholine (8.5 g, 73.9 mmol, 1.00 eq.) were added. The mixture was stirred at 110 °C overnight. The resulting mixture was diluted with EtOAc (2 L) and washed with brine (3 x 1 L). The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc:petroleum ether 1 :5) to afford Intermediate 12 (24.4 g, yield: 76 %) as a yellow solid.

Procedure B:

[0199] A solution of Intermediate 11b (0.631 g, 1.865 mmol), cis-2,6-dimethylmorpholine (CAS [6485-55-8], 0.7 mL, 5.512 mmol), and DIPEA (1.5 mL, 8.704 mmol) in dry DMSO (10 mL) was stirred at 110 °C for 16 h. After cooling, the reaction mixture was diluted with 5 % Et2OZEtOAc, washed twice with water and once with brine. The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified by flash column chromatograpy (40 g SiO2, EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 19 (0.741 g, yield: 82 %, 90 % purity).

Intermediate 13 : 2-(6-(6-((2R, 6S)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3- yl)acetic acid dihydrochloride.

[0200] Into a 500 mL 3-necked flask were added Intermediate 12 (24.4 g, 56.3 mmol, 1.00 eq.), DCM (244 mL), and HC1 (140 mL, 4 M in 1,4-dioxane). The mixture was stirred overnight at room temperature. The mixture was diluted with Et2O (200 mL) and filtered to collect the solid. The yellow solid was washed with Et2O (2 x 30 mL) and dried under vacuum to give Intermediate 13 (18.723 g, yield: 88 %) as a yellow solid.

Intermediate 14: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-

N-((R)-piperidin-3-yl)acetamide.

[0201] Intermediate 4 (200 mg, 0.528 mmol), HATU (CAS [148893-10-1], 241 mg, 0.634 mmol), and EtsN (0.184 mL, 1.321 mmol) were added to a vial with DCM (3 mL). The mixture was stirred for 5 min at room temperature. (R)-l-Boc-3 -aminopiperidine (CAS [188111-79-7], 116 mg, 0.581 mmol) was added and the mixture was stirred at room temperature for 1 h. Volatiles were removed under vacuum. The residue was dissolved in 2 mL DCM, filtered, and TFA (1 mL) was added. After 15 min, volatiles were removed. The residue was dissolved in DCM and neutralized with saturated aqueous NaHCCh. The organic layer was extracted with HC1 (1 M in water). This acidic aqueous layer was neutralized with saturated aqueous NaHCOs and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, and evaporated to give Intermediate 14 as a yellow solid (220 mg, yield: 90 %).

Intermediate 17: 2-(6-(6-fluoropyridin-2-yl)isoquinolin-3-yl)acetic acid.

[0202] A solution of Intermediate 11 (0.12 g, 0.337 mmol, 95 % purity) in DCM (4 mL) was treated with HC1 (3.0 mL, 12 mmol, 4 M in 1,4-dioxane) at room temperature under a nitrogen atmosphere. After 1 week, the reaction mixture was concentrated and dried under high vacuum to yield Intermediate 17 (0.115 g, yield: 96 %, bis-HCl salt) as a white solid. Intermediate 18: 2-(6-(6-fluoropyridin-2-yl)isoquinolin-3-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)acetamide.

[0203] A suspension of Intermediate 17 (0.115 g, 0.324 mmol, bis-HCl salt), 3- methanesulfonyl-4-methylaniline (CAS [307989-41-9], 0.075 g, 0.405 mmol), and HATU (CAS [148893-10-1], 0.146 g, 0.384 mmol) in ACN (5 mL) was treated with DIPEA (0.3 mL, 1.741 mmol) and stirred at room temperature for 20 min. The reaction mixture was concentrated and the residue was purified by flash column chromatography (12 g SiCL, 0 - 10 % 2 N NHs/MeOH in DCM), followed by another flash column chromatography (12 g SiCL, EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 18 (0.143 g, yield: 73 %, 74 % pure).

Intermediate 21 : tert-butyl (4-methyl-3-(methylthio)phenyl)carbamate.

H M eS N

XT T b

[0204] A suspension of tert-butyl (3-bromo-4-methylphenyl)carbamate (CAS [515813-02-2], 0.249 g, 0.87 mmol) and Xantphos Pd G4 (CAS [1621274-19-8], 0.076 g, 0.079 mmol) in dry 1,4-dioxane (5 mL) was treated with sodium methanethiolate (CAS [5188-07-8], 0.112 g, 1.518 mmol) followed by DIPEA (0.4 mL, 2.321 mmol) at room temperature while stirring under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried (MgSCU), filtered, and concentrated. The crude product was purified by flash column chromatography (40 g SiCL, isocratic DCM) to yield Intermediate 21 (0.058 g, yield: 26 %).

Intermediate 22: tert-butyl (4-methyl-3-(S-methylsulfonimidoyl)phenyl)carbamate.

[0205] A solution of Intermediate 21 (0.058 g, 0.229 mmol) in MeOH (3 mL) was treated with (diacetoxyiodo)benzene (CAS [3240-34-4], 0.188 g, 0.584 mmol) followed by ammonium carbamate (CAS [1111-78-0], 0.038 g, 0.487 mmol) while stirring at room temperature. After 30 min, the reaction mixture was concentrated and the residue was purified by flash column chromatography (12 g SiCh, EtOAc/DCM from 0/100 to 100/0) to yield Intermediate 22 (0.041 g, yield: 63 %).

Intermediate 23 : (5-amino-2-methylphenyl)(imino)(methyl)-16-sulfanone.

[0206] A solution of Intermediate 22 (0.041 g, 0.144 mmol) in DCM (5 mL) was treated with HC1 (0.25 mL, 1 mmol, 4 M in 1,4-di oxane) while stirring at room temperature. After 16 h, additional HC1 (0.5 mL, 2 mmol, 4 M in 1,4-di oxane) was added and the reaction mixture was stirred at 50 °C for 90 min. After cooling, the reaction mixture was concentrated, and further dried under high vacuum to yield Intermediate 23 (0.054 g, quantitative, 78 % purity) as a tris-HCl salt.

Intermediate 24: 2,5-dioxopyrrolidin-l-yl 2-(2-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)acetate.

[0207] Intermediate 4 (110 mg, 0.194 mmol), A-hydroxysuccinimide (CAS [6066-82-6], 25 mg, 0.213 mmol), DMAP (2 mg, 0.0136 mmol) were dissolved in DMF (1.3 mL) and cooled to 0 °C. EDCI (CAS [25952-53-8], 56 mg, 0.291 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and DIPEA (0.17 mL, 0.97 mmol), EDCI (74 mg, 0.388 mmol), and A-hydroxysuccinimide (0.045 g, 0.388 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (25 mL) and washed with 1 : 1 brine/water (25 mL). The aqueous layer was further extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (4 x 50 mL), NaHCOs (2 x 50 mL), and brine (20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford Intermediate 24 as a brown oil, used without further purification.

Intermediate 25: 2-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)acetic acid.

[0208] HC1 (4 M in 1,4 -dioxane, 5 mL, 20 mmol) was added to a solution of Intermediate 2 (150 mg, 0.442 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness. The residue was taken up in saturated aqueous NaHCCf (2 mL) and extracted with EtOAc (2 x 8 mL). The combined organic layer was dried with Na2SO4, filtered, and evaporated to give Intermediate 25 (130 mg, quantitative) as a yellow solid, used without further purification.

Intermediate 26: 2-(2-(6-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-methyl-3 - (methylsulfonyl)phenyl)acetamide.

[0209] T3P (CAS [68957-94-8], 50 % in EtOAc, 0.51 mL, 0.857 mmol) was added to a solution of Intermediate 25 (120 mg, 0.424 mmol) and 4-methyl-3-

(methylsulfonyl)benzenamine (CAS [307989-41-9], 79 mg, 0.427 mmol) in DCM (5 mL) was added DIPEA (0.38 mL, 2.182 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL). 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 50/50) to give Intermediate 26 (100 mg, yield: 52 %) as a yellow solid. Intermediate 27: tert-butyl 7-(6-(7-(2-((4-methyl-3-(methylsulfonyl)phenyl)amino)-2- oxoethyl)-l,6-naphthyridin-2-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate.

[0210] DIPEA (0.3 mL, 1.741 mmol) was added to a solution of Intermediate 26 (90 mg, 0.2 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate (CAS [674792-08-6], 148 mg, 0.7 mmol) in DMSO (4 mL). The reaction mixture was stirred at 145 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The organic layer was concentrated in vacuum and the residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 1/1) to give Intermediate 27 (232 mg, quantitative) as brown oil.

Intermediate 28: (cis)-4-(6-bromo-4-nitropyri din-2 -yl)-2,6-dimethylmorpholine.

[0211] 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 28 (3.2 g, yield: 56 %) as an orange solid. Intermediate 29: (cis)-4-(6-bromo-4-fluoropyri din-2 -yl)-2,6-dimethylmorpholine.

[0212] Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 eq.) was added to a solution of Intermediate 28 (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 MgSO4, 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 29 (1139 mg, yield: 81 %) as an orange solid.

Intermediate 30: (cis)-4-(4-fluoro-6-(tributylstannyl)pyridin-2-yl)-2,6-dimethylmorpholine

[0213] Pd2(dba)s (CAS [51364-51-3], 100 mg, 0.109 mmol), tricyclohexylphosphine (CAS [2622-14-2], 60 mg, 0.214 mmol), and LiCl (132 mg, 3.114 mmol) were added to a solution of Intermediate 29 (300 mg, 1.038 mmol) and 1,1,1,2,2,2-hexabutyldistannane (CAS [813-19- 4], 2.270 g, 3.913 mmol) in l,4-dioxane(6 mL). The mixture was stirred at 105 °C for 12h under nitrogen atmosphere. Saturated aqueous KF (10 mL) was added dropwise at 0 °C. The mixture was stirred at room temperature for 10 min., then was filtered over a pad of celite. The filtrate was extracted with EtOAc (20 mL * 3). The combined organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography over silica gel (EtOAc/petroleum ether from 0/100 to 10/90) to give Intermediate 30 (600 mg, 75 % pure, yield: 86 %) as a yellow oil. Intermediate 31 : tert-butyl 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)acetate.

[0214] PyBroP (CAS [132705-51-2], 324 mg, 0.695 mmol) and DBU (CAS [6674-22-2], 180 mg, 1.182 mmol) were added to a solution of Intermediate 1 (150 mg, 0.576 mmol) in 1,4- dioxane (6 mL) under nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 30 min. Then, Intermediate 30 (350 mg, 0.523 mmol), LiCl(78 mg, 1.840 mmol), Pd2(dba)s (CAS [51364-51-3], 54 mg, 0.059 mmol), and tricyclohexylphosphine (CAS [2622-14-2], 30 mg, 0.107 mmol) were added to the mixture under nitrogen atmosphere at room temperature. The reaction mixture was stirred at 105°C for 12 h. The mixture was filtered, concentrated under vacuum, and purified by column chromatography over silica gel (EtOAc/petroleum ether from 0/100 to 60/40) to give Intermediate 31 (150 mg, 69 % pure) as a yellow solid, used without further purification.

Intermediate 32: 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6- naphthyridin-7-yl)acetic acid

[0215] Intermediate 32 was prepared following the same procedure as Intermediate 6, using Intermediate 31 instead of Intermediate 5.

Intermediate 33 : 3-(cyclopropylsulfonyl)bicyclo[l .1. l]pentan-l -amine.

[0216] A solution of dibutyl phosphate (CAS [107-66-4], 53 pL, 0.27 mmol) in DMA (0.8 mL) and ACN (0.8 mL) was added to a mixture of l,3-dihydro-l,3-dioxo-2J7-isoindol-2-yl 3- [[(1, l-dimethylethoxy)carbonyl]amino]bicyclo[l .1. l]pentane-l -carboxylate (CAS [2248340- 09-0], 50 mg, 0.13 mmol), sodium cyclopropanesulfinate (CAS [910209-21-1], 35 mg, 0.28 mmol), 4CZIPN (CAS [1416881-52-1], 2 mg, 0.0003 mmol), and copper(II) trifluoromethanesulfonate (CAS [34946-82-2], 10 mg, 0.027 mmol) under nitrogen atmosphere. The mixture was irradiated in a Penn reactor (Blue LED (100 %), 6800 FAN) for 12 h. The solvent was evaporated and the residue was taken up with water (1.5 mL) and DCM (1.5 mL). The mixture was stirred at room temperature for 10 min and put in an Isolute separtor cartridge, eluting with DCM. The filtrate was concentrated in vacuo. The residue was dissolved in DCM (0.5 mL), then TFA (0.1 mL, 1.31 mmol) was added. The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. The residue was dissolved in MeOH and passed through a SCX-2 ion exchange cartridge, eluting with ammonia (7 N in MeOH) to give Intermediate 33 (25 mg, quantitative), used without further purification.

Intermediate 34: 6-chloro-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)isoquinoline.

[0217] 2-Bromo-4-chlorobenzaldehyde (CAS [84459-33-6], 4.4 g, 20.2 mmol), EtsN (5.6 mL, 40.5 mmol) and tert-butylamine (CAS [75-64-9], 6.4 mL, 61 mmol) were dissolved in ACN (60 mL) in a sealed tube at room temperature. Then, tetrahydro-2-(2-propynyloxy)-27/-pyran (CAS [6089-04-9], 4.3mL, 31 mmol) was added and the reaction mixture reaction was bubbled with nitrogen for 5 min. 1,2-Bis(diphenylphosphino)ethane nickel (II) chloride (CAS [14647-23-5], 1.0 g, 2.0 mmol) was added and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (x 3). The combined organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; AcOEt/heptane from 0/100 to 30/70) to afford Intermediate 34 (1 g, yield: 18 %) as an orange oil. Intermediate 35: (6-chloroisoquinolin-3-yl)methanol.

[0218] p-Toluenesulfonic acid monohydrate (CAS [6192-52-5], 685 mg, 3.6 mmol) was added to a stirred solution of Intermediate 34 (1 g, 3.6 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with EtOAc and washed with water. The aqueous layer was neutralized with aqueous Na2COs (I M) and extracted with EtOAc (x 3). The combined organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 40 g; AcOEt/heptane from 0/100 to 80/20) to yield Intermediate 35 (462 mg, 66 %) as a white solid.

Intermediate 36: 6-chloro-3-(chloromethyl)isoquinoline.

[0219] p-Toluenesulfonyl chloride (CAS [98-59-9], 589 mg, 3.1 mmol) was added to a stirred solution of Intermediate 35 (460 mg, 2.38 mmol), DIPEA (0.869 mL, 5.0 mmol), and DMAP (CAS [1122-58-3], 58 mg, 0.47 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 5 h. The mixture was diluted with water, extracted with AcOEt, and the organic layer was washed with brine (x 2). The organic layer was dried on MgSCU, filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; AcOEt/heptane from 0/100 to 50/50) to yield Intermediate 36 (293 mg, yield: 58 %) as a white solid.

Intermediate 37: 2-(6-chloroisoquinolin-3-yl)acetonitrile.

[0220] Sodium cyanide (118 mg, 2.40 mmol) was added to a stirred solution of Intermediate 36 (285 mg, 1.34 mmol) in DMSO (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with AcOEt, and the organic layer was washed with brine (x 2). The organic layer was dried on MgSO4, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; AcOEt/heptane from 0/100 to 50/50) to yield Intermediate 37 (180 mg, yield: 65 %) as a brown solid.

Intermediate 38: 2-(6-chloroisoquinolin-3-yl)acetic acid.

[0221] Intermediate 37 (175 mg, 0.86 mmol) was dissolved in NaOH (2.5 M in water, 20mL). The mixture was stirred at 115 °C for 16 h. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was acidified to pH=l with HC1 (1 M in water) and then extracted with EtOAc (x 2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 38 (181 mg, yield: 95 %) as a yellow solid.

Intermediate 39: 2-(6-chloroisoquinolin-3-yl)-N-(l-(methylsulfonyl)piperidin-3-yl)acetamide.

[0222] HATU (CAS [148893-10-1], 140 mg, 0.37 mmol) was added to a stirred solution of Intermediate 38 (180 mg, 0.81 mmol), 1-methanesulfonylpiperi din-3 -ylamine (CAS [934107- 80-9], 145 mg, 0.81 mmol), and DIPEA (0.567 mL, 3.2 mmol) in DCM (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water, extracted with DCM, and the organic layer was washed with brine (x 2). The organic layer was dried on MgSCU, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 12g; EtOAc/heptane from 0/100 to 100/0) to yield Intermediate 39 (197 mg, yield: 63 %) as a white solid.

Intermediate 40: methyl 2-(6-chloroisoquinolin-3-yl)acetate.

[0223] Sulfuric acid (95 %, 0.132 mL, 2.5 mmol) was added to a solution of Intermediate 38 (55 mg, 0.25 mmol) in MeOH (1 mL) and the mixture was stirred for 16 h at 50 °C. The solvent was evaporated and the residue was diluted with water and EtOAc and basified to pH=9-10 with saturated aqueous Na2COs. The mixture was extracted with EtOAc, the organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 12 g; AcOEt/heptane from 0/100 to 80/20) to afford Intermediate 40 (60 mg, yield: 98 %) as a yellow oil.

Intermediate 41 : methyl 2-(6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-3- yl)acetate.

[0224] A mixture of Intermediate 40 (60 mg, 0.24 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 123 mg, 0.48 mmol), and potassium acetate (74 mg, 0.751 mmol) in 1,4- di oxane (2 mL) was degassed by bubbling nitrogen for 15 min. Then, Xphos Pd G3 (CAS [1445085-55-1], 21 mg, 0.024 mmol) and Xphos (CAS [564483-18-7], 23 mg, 0.05 mmol) were added and the mixture was stirred at 70 °C for 16 h. After cooling, the mixture was filtered through a pad of celite and the solvents were evaporated in vacuo. The residue was purified by flash column chromatography (80 g silica; EtOAc/heptane from 0/100 to 70/30) to afford Intermediate 41 (72 mg, yield: 86 %) as a colorless oil.

Intermediate 42: 6-chloro-2-((cis)-2,6-dimethylmorpholino)-3-methylpyrimidin-4(3H)-one.

[0225] Cis-2,6-dimethylmorpholine (CAS [6485-55-8], 0.45 mL, 3.6 mmol) was added to a stirred solution of 2,6-dichloro-3-methyl-4(3J7)-pyrimidinone (812 mg, 4.5 mmol) and DIPEA (2.2 mL, 13.6 mmol) in DMSO (8 mL). The mixture was stirred at 130 °C for 16 h. The mixture was diluted with water and extracted with EtOAc (x 3). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; EtOAc/heptane from 0/100 to 70/30) to yield Intermediate 42 (870 mg, 74 %) as yellow solid. Intermediate 43: methyl 2-(6-(2-((cis)-2,6-dimethylmorpholino)-l-methyl-6-oxo-l,6- dihydropyrimidin-4-yl)isoquinolin-3-yl)acetate.

[0226] PdCh dppf) (CAS [95464-05-4], 8 mg, 0.01 mmol) was added to a stirred solution of Intermediate 41 (68 mg, 0.21 mmol), Intermediate 42 (53 mg, 0.21 mmol) and sodium bicarbonate (35 mg, 0.41 mmol) in 1,4-dioxane (1 mL) and water (0.25 mL) in a sealed tube and under nitrogen atmosphere. The mixture was stirred at 90 °C for 16 h. After cooling, the mixture was filtered through a pad of celite, diluted with water, and extracted with AcOEt. The organic layer was washed with brine (x 2). The organic layer was evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90) to yield Intermediate 43 (181 mg, yield: 63 %) as a brown oil.

Intermediate 44: 2-(6-(2-((cis)-2,6-dimethylmorpholino)-l-methyl-6-oxo-l,6- dihydropyrimidin-4-yl)isoquinolin-3-yl)acetic acid.

Sodium hydroxide (2.5 M in water, 0.5 mL, 1.3 mmol) was added to a stirred solution of

Interrmediate 43 (18 Omg, 0.43 mmol) in MeOH (12 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with HC1 (1 M in water) to pH=5 and then extracted with EtOAc (x 2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo to yield Intermediate 44 (144 mg, yield: 82 %) as a beige solid. Intermediate 45: methyl 2-(6-phenylisoquinolin-3-yl)acetate.

[0227] PdCh dppf) (CAS [95464-05-4], 103 mg, 0.13 mmol) was added to a stirred solution of Intermediate 41 (827 mg, 2.5 mmol), bromobenzene (CAS [108-86-1], 266 mg, 2.5 mmol), and sodium bicarbonate (425 mg, 5.1 mmol) in 1,4-dioxane (4 mL) and water (1 mL) in a sealed tube and under nitrogen atmosphere. The mixture was stirred at 90 °C for 16 h. After cooling, the mixture was filtered through a pad of celite, diluted with water, and extracted with AcOEt. The organic layer was washed with brine (x 2) and evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90) to yield Intermediate 45 (864 mg, yield: 86 %) as a brown solid.

Intermediate 46: 2-(6-phenylisoquinolin-3-yl)acetic acid.

[0228] Sodium hydroxide (1 M in water, 6.5 mL, 6.5 mmol) was added to a stirred solution of Intermediate 45 (604 mg, 2.18 mmol) in MeOH (3 mL) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was acidified with HC1 (1 M in water) to pH=4 and then concentrated in vacuo. The residue was purified by flash column chromatography (40 g silica; MeOH (with acetic acid) in DCM from 0/100 to 10/90) to afford Intermediate 46 (307 mg, yield: 53 %) as a yellow solid.

Intermediate 47: (3-aminophenyl)(difluoromethyl)(imino)-X⁶-sulfanone; Intermediate 48: (*R)-(3-aminophenyl)(difluoromethyl)(imino)- /J’-sulfanone and Intermediate 49: (*S)-(3- aminophenyl)(difluoromethyl)(imino)- X⁶-sulfanone.

(rac) Intermediate 47 (*R) Intermediate 48 (*S) Intermediate 49

[0229] Iron powder (130 g, 2.33 mol, 5.0 eq.) was added in batches to a solution of (difluoromethyl)(imino)(3-nitrophenyl)-X⁶-sulfanone (CAS [2361945-66-4], 110 g, 465 mmol) and NH4CI (124 g, 2.33 mol, 5.0 eq.) in THF (500 mL), MeOH (500 mL), and water (500 mL). The reaction mixture was stirred at 60 °C for 6 h. The reaction mixture was then filtered and the filter cake was rinsed several times with EtOAc. The filtrate was evaporated. The residue was diluted with water (400 mL) and extracted with EtOAc (600 mL x 3). The combined organic layer was washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica Flash Column; from 25 to 28 % EtOAc in petroleum ether) to give Intermediate 47 (70.0 g, yield: 71 %) as a yellow solid.

[0230] A batch of Intermediate 47 was separated into its stereoisomers by SFC (Regis Reflect i-Cellulose-C 250 x 30 mm 5 um; from 80 % of CO2 - 20 % IPA + 0.1 % DEA to 80 % of CO2 - 20 % IPA + 0.1 % DEA) to give Intermediate 48 and Intermediate 49.

Intermediate 50: 3-(cyclopropylsulfonyl)cyclobutan-l-amine.

[0231] Intermediate 50 was prepared following same procedure as Intermediate 33, using 1,3- dihydro- 1 ,3 -di oxo-27/-i soi ndol -2-yl 3 -[[( 1 , 1 - dimethylethoxy)carbonyl]amino]cyclobutanecarboxylate (CAS [2248324-36-7]) instead of 1 ,3 -dihydro- 1 ,3 -di oxo-27/-i soi ndol -2-yl 3 - [[( 1 , 1 - dimethylethoxy)carbonyl]amino]bicyclo[l .1. l]pentane-l -carboxylate.

Intermediate 51 : 3-(methylsulfonyl)cyclohexan-l-amine.

[0232] Intermediate 51 was prepared following the same procedure as Intermediate 33, using rel- 1 , 3 -dihydro- 1 , 3 -di oxo-27/-i soindol -2-yl ( 1 R, 3 S)-3 -[ [( 1 , 1 - dimethylethoxy)carbonyl]amino]cyclohexanecarboxylate (CAS [2248335-83-1]) instead of 1 ,3 -dihydro- 1 ,3 -di oxo-27/-i soi ndol -2-yl 3 - [[( 1 , 1 - dimethylethoxy)carbonyl]amino]bicyclo[l .1. l]pentane-l -carboxylate, and sodium methanesulfmate (CAS [20277-69-4] instead of sodium cyclopropanesulfinate. Intermediate 52: 3-(cyclopropylsulfonyl)cyclohexan-l-amine.

[0233] Intermediate 52 was prepared following same procedure as Intermediate 33, using rel-

1.3 -dihydro- 1 , 3 -di oxo-2//-i soindol-2-yl ( 1 R, 3 S)-3 -[ [( 1 , 1 - dimethylethoxy)carbonyl]amino]cyclohexanecarboxylate (CAS [2248335-83-1]) instead of

1.3 -dihydro- 1 ,3 -di oxo-27/-i soi ndol -2-yl 3 - [[( 1 , 1 - dimethylethoxy)carbonyl]amino]bicyclo[l .1. l]pentane-l -carboxylate.

Preparation of Examples

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

[0234] Step A: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)acetic acid. To a solution of Intermediate 3 (104 mg, 0.24 mmol) in DCM (2 mL) was added TFA (0.5 mL). After 16 h at room temperature, the solution was concentrated in vacuo. [0235] Step B: To 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)acetic acid was added DMF (3 mL), DIPEA (0.24 mL, 1.41 mmol), HATU (134 mg, 0.35 mmol) and 3-methanesulfonyl-4-methylaniline (65 mg, 0.35 mmol) and this mixture was stirred for 2 h at room temperature. EtOAc and Et2O were added, the solution washed with water and brine, dried over MgSCU, filtered, and concentrated in vacuo. Purification by HPLC (150 mm x 30 mm C18 column, eluting with 10 to 80 % ACN/FFO + 0.1 % TFA) afforded the title compound (16 mg, yield: 12 %).

[0236] The following compounds were made according to the procedures above, substituting the appropriate reagents in the appropriate steps: Example 2: 2-(2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide.

[0237] Purification of Example 3 by RP HPLC: 0.1% TFA in water and ACN, 16 min run (s: 10% ACN slow ramp to 50% over 8 min then a fast ramp to 100% to the end), Column: (OOD-4633-UO-AX Kinetex 5umEV0 cl 8 100) afforded the title compound and Example 9.

Example 3: (Racemic) 2-(2-(6-((3S,5R)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)- l,6-naphthyridin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide.

[0238] The title compound was prepared in a manner analogous to Intermediate 12, using racemic 3,5-dimethyl-4-piperidinol, CAS RN 373603-93-1 instead of (2R, 6S)-2,6- dimethylmorpholine and Intermediate 26 instead of Intermediate 11.

Example 4: 2-(2-(6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(l-

(methylsulfonyl)indolin-6-yl)acetamide.

[0239] Step A: 2-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(l- (methylsulfonyl)indolin-6-yl)acetamide. The title compound was prepared in a manner analogous to Intermediate 18, using 1 -(methyl sulfonyl)indolin-6-amine for 3- methanesulfonyl-4-methylaniline.

[0240] Step B: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N- (l-(methylsulfonyl)indolin-6-yl)acetamide. The title compound was prepared in a manner analogous to Intermediate 12, using 2-(2-(6-fluoropyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(l- (methylsulfonyl)indolin-6-yl)acetamide instead of Intermediate 11. Example 5: N-(4-methyl-3-(methylsulfonyl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6- naphthyridin-7-yl)acetamide.

[0241] Intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)acetic acid) was dissolved in DMF (2 mL) and treated with DIPEA (0.095 mL, 0.55 mmol), HATU (79 mg, 0.21 mmol), and 3-methanesulfonyl-4-methylaniline (CAS [307989-41-9], 38 mg, 0.21 mmol) and the reaction mixture was stirred for 2 h at room temperature. Water was added, the solution was extracted with DCM, dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by HPLC (150 mm x 30 mm C18 column, eluting with 10 to 80 % ACN/H2O + 0.1 % TFA) to obtain the title compound (14 mg, yield: 21 %) as a solid.

Example 6: N-(3-(2-hydroxypropan-2-yl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6- naphthyridin-7-yl)acetamide.

[0242] The title compound was prepared in a manner analogous to Example 5 using Intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)acetic acid) and 2-(3- aminophenyl)propan-2-ol (CAS [23243-05-2]).

Example 7: N-(5-(methylsulfonyl)pyridin-3-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6- naphthyridin-7-yl)acetamide

[0243] The title compound was prepared in a manner analogous to Example 5 using Intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)acetic acid) and 5- (methylsulfonyl)pyridin-3-amine (CAS [1067530-19-1]).

Example 8: N-(l-(methylsulfonyl)indolin-6-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6- naphthyridin-7-yl)acetamide.

[0244] The title compound was prepared in a manner analogous to Example 5 using Intermediate 6 (2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7-yl)acetic acid) and 2,3- dihydro-1 -(methyl sulfonyl)- lJ/-indol-6-amine (CAS [620985-93-5]).

Example 9: 2-(2-(6-((3a,4a,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6- naphthyridin-7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide.

(3a, 4a, 5a)

[0245] Example 9 was isolated from RP HPLC (same method as Example 2) of Example 3.

Example 10: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-

(3-((2 -hydroxy ethyl)sulfonyl)-4-methylphenyl)acetamide.

Method E

[0246] DIPEA (0.2 mL, 1.148 mmol) and T3P (CAS [68957-94-8], 50 % in EtOAc, 0.3 mL, 0.504 mmol) were added to a solution of Intermediate 4 (85 mg, 0.225 mmol) and 2-((5- amino-2-methylphenyl)sulfonyl)ethanol (CAS [41506-69-8], 48 mg, 0.225 mmol) in DCM (4 mL) at room temperature and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL). The organic layer was concentrated in vacuum and the residue was purified by preparative HPLC (Boston Green ODS 150 * 30 mm * 5 um; water (FA)/ACN from 60/40 to 30/70) to afford the title compound (25 mg, yield: 19 % yield) as a yellow solid. [0247] The compounds in Table 3. were prepared following Method E, using the indicated amine:

Table 3.

Example 11 : 2-(2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-

(4-methyl-3-(methylsulfonyl)phenyl)acetamide.

[0248] TFA (3 mL) was added dropwise to a suspension of Intermediate 27 (190 mg, 0.296 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 2). The organic layer was concentrated in vacuum and the residue was purified by column chromatography over silica gel (DCM/MeOH 10/1), followed by preparative HPLC (Boston Green ODS 150 * 30 mm * 5 um; water (FA)/ACN from 87/13 to 57/43) to afford the title compound (36 mg, yield: 21 %) as a yellow solid. Example 23 : 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-l,6-naphthyridin- 7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide.

[0249] The title compound was prepared in a manner analogous to Example 10, Method E, using Intermediate 32 instead of Intermediate 4, and 4-methyl-3-(methylsulfonyl)aniline (CAS [307989-41-9]) instead of 2-((5-amino-2-methylphenyl)sulfonyl)ethanol.

Example 26: 2-(6-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)isoquinolin-3-yl)-N-(4- methyl-3-(methylsulfonyl)phenyl)acetamide.

[0250] A solution of Intermediate 18 (0.07 g, 0.115 mmol), tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate (CAS [6747492-08-6], 0.064 g, 0.301 mmol), and DIPEA (0.1 mL, 0.58 mmol) in dry DMSO (4 mL) was stirred at 130 °C for 48 h. After cooling, the reaction mixture was treated with TFA (0.1 mL, 1.307 mmol) and was stirred at room temperature for 6 h, followed by heating at 100 °C for 16 h. After cooling, the reaction mixture was directly purified by reverse phase HPLC (Waters XB ridge BEH Cl 8, 5 um, 19 x 150 mm, 30-65 % ACN/H2O with 10 mM NH4OH), followed by another reverse phase HPLC (Waters XSelect CSH Fluoro Phenyl, 5 um, 19 x 150 mm, 10-4 0% ACN/H2O with 0.16 % TFA) to afford the title compound (11 mg, yield: 15 %, TFA-salt) as a yellow solid.

Example 27: 2-(6-(6-((3a, 40, 5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyri din-2 - yl)isoquinolin-3-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide.

(3a, 40, 5a) -in¬

[0251] The title compound was prepared in a manner analogous to that of Example 26, using (3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidine (CAS [374067-78-4]) instead of tert-butyl 4,7- diazaspiro[2.5]octane-4-carboxylate, and omitting the TFA deprotection step.

Example 28: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3-yl)-N-(4- methyl-3-(methylsulfonyl)phenyl)acetamide.

[0252] A suspension of Intermediate 13 (0.052 g, 0.115 mmol, bis-HCl salt), 3- methanesulfonyl-4-methylaniline (CAS [307989-41-9], 0.027 g, 0.146 mmol), and HATU (CAS [148893-10-1], 0.047 g, 0.124 mmol) in ACN (4 mL) was treated with DIPEA (0.1 mL, 0.58 mmol) while stirring at room temperature. After 10 min, the reaction mixture was filtered and directly purified by reverse phase HPLC (Waters XB ridge BEH Cl 8, 5 um, 19 x 150 mm, 40-75 % ACN/H2O with 10 mM NH4OH) to afford the title compound (29 mg, yield: 45 %) as a tan solid.

Example 29 : 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 -((2- hydroxy ethyl)sulfonyl)-4-methylphenyl)acetamide.

[0253] The title compound was prepared in a manner analogous to that of Example 28, using 2-[(5-amino-2-methylphenyl)sulfonyl]ethanol (CAS [41506-69-8]) instead of 3- methanesulfonyl-4-methylaniline.

Example 30: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N- (5-(methylsulfonyl)pyridin-3-yl)acetamide.

[0254] The title compound was prepared following the same procedure as Example 28 using Intermediate 4 and 5-(methylsulfonyl)pyridin-3-amine (CAS [1067530-19-1]).

Example 35: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

Method A [0255] To a vial containing 3 -difluoromethanesulfonylaniline (CAS [24906-76-1], 20 mg,

0.065 mmol) was added a solution of Intermediate 4 (32 mg, 0.078 mmol) and DIPEA (0.07 mL, 0.39 mmol) in DMF (0.4 mL). A solution of HATU (CAS [148893-10-1], 58 mg, 0.15 mmol) in DMF (0.4 mL) was added. The reaction mixture was stirred at room temperature for 4 h. Purification of the crude reaction mixture by HPLC (19 x 100 mm Cl 8 column, from 35 to 75 % ACN/H2O + 0.1 % NH3) afforded the title compound (8 mg, yield: 19 %).

[0256] The compounds in Table 4 were prepared from Intermediate 4 and the corresponding amine following the procedure in Example 35, Method A.

Table 4.

Example 53 : 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-

(l-(methylsulfonyl)piperidin-3-yl)acetamide.

[0257] DIPEA (0.05 mL, 0.29 mmol) followed by 1-methanesulfonylpiperi din-3 -amine (CAS [934107-80-9], 34 mg, 0.193 mmol) was added to a solution of Intermediate 24 (46 mg, 0.097 mmol) in ACN (1 mL). The vial was sealed and the reaction mixture was stirred at 60 °C for 30 min. The reaction mixture was filtered and the filtrate was directly purified by reverse phase column chromatography (Waters XBridge BEH C18, 5um, 19 x 150 mm; Water + pH 10 NH4OH / ACN + pH 10 NH4OH from 30 to 65 % ACN) to afford the title compound. Example 56: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide.

Method B

[0258] To a vial containing 3 -difluoromethanesulfonylaniline (CAS [24906-76-1], 30 mg, 0.146 mmol) was added a solution of Intermediate 13 (50 mg, 0.132 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (0.5 mL). A solution of HATU ((CAS [148893-10-1], 76 mg, 0.20 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature for 5 h. Purification by HPLC (19 x 100 mm Cl 8 column, eluting with 10 to 90 % ACN/H2O + 0.1 % NH3) afforded the title compound (36 mg, yield: 48 %).

Example 57 and Example 58: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)-N-((*R)-l-(methylsulfonyl)piperidin-3-yl)acetamide and 2-(2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((*S)-l-

(methylsulfonyl)piperidin-3-yl)acetamide.

(*S), (CIS)

[0259] The chiral separation of the stereoisomers of Example 53 by SFC (Waters 150AP (B41-1116); IB (30 x 250 mm ID, 5 urn); isocratic 20 % MeOH w/ 0.1 % NH₄OH - 80 % CO2) gave Example 57 and Example 58. Example 59 and Example 60: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)-N-((*R)-l-(methylsulfonyl)piperidin-3-yl)acetamide and 2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((*S)-l-(methylsulfonyl)piperidin- 3-yl)acetamide.

(*S), (CIS)

[0260] DIPEA (0.11 mL, 0.636 mmol) and HATU (CAS [148893-10-1], 73 mg, 0.191 mmol) were added to a solution of Intermediate 13 (60 mg, 0.159 mmol) and 1- methanesulfonylpiperidin-3-amine (CAS [934107-80-9], 31 mg, 0.175 mmol) in DMF. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was filtered and directly separated into stereoisomers by SFC chiral separation (Waters 150AP (B41-1116); IB (30 x 250 mm ID, 5 urn); 20 % MeOH w/ 0.1% NH₄OH - 80 % CO₂) to give Example 59 and Example 60.

Example 61 : 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-

(4-methyl-3-(S-methylsulfonimidoyl)phenyl)acetamide.

[0261] The title compound was prepared in a manner analogous to that of Example 28, using Intermediate 4 instead of Intermediate 13, and Intermediate 23 instead of 3-methanesulfonyl- 4-methylaniline. Example 62: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3-yl)-N- ((3R,6R)-6-methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide.

CIS

[0262] Step A: tert-butyl (2R,5R)-5-(2-(6-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)acetamido)-2-methylpiperidine-l-carboxylate. The title compound was prepared in a manner analogous to that of Example 28 using tert-butyl (2R,5R)-5-amino-2- methylpiperidine-1 -carboxylate (CAS [1807773-56-3]) instead of 3-methanesulfonyl-4- methylaniline. Purification by flash column chromatography (2 N NHs/MeOH in DCM) afforded the title compound (244 mg, yield: 98 %) as a pale yellow solid.

[0263] Step B: 2-(6-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N- ((3R,6R)-6-methylpiperidin-3-yl)acetamide. The title compound was prepared in a manner analogous to that of Intermediate 13, to yield the title compound as an HC1 salt (260 g, quantitative, 4 * HC1 salt).

[0264] Step C: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N- ((3R,6R)-6-methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide. A homogeneous solution of 2-(6-(6-((2S,6R)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3-yl)-N-((3 R,6R)-6- m ethylpiperi din-3 -yl)acetamide (260 mg, 0.42 mmol, 4*HC1 salt) and DIPEA (0.4 mL, 2.321 mmol) in DCM (10 mL) was cooled to 0 °C under nitrogen atmosphere. Methanesulfonyl chloride (CAS [124-63-0], 0.05 mL, 0.644 mmol) was slowly added while stirring. After 15 min, the reaction mixture was concentrated to dryness and the residue was purified by flash column chromatography (40 g SiCL, 0-10 % 2 N NHs/MeOH in DCM) to yield the title compound (150 g, yield: 63 %) as an off-white solid.

[0265] The compounds in Table 5 were prepared from Intermediate 13 and the corresponding amine following the procedure in Method A or Method B.

Table 5.

Example 63 and Example 64: N-((*R)-l-((difluoromethyl)sulfonyl)piperi din-3 -yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide and N-((*S)-1- ((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-!, 6-naphthyridin-7-yl)acetamide.

(*S), (CIS)

Method C

[0266] Step A: tert-butyl (l-((difluoromethyl)sulfonyl)piperi din-3 -yl)carbamate. To a solution of 3-Boc-aminopiperidine (CAS [172603-05-3], 200 mg, 0.97 mmol) in THF (5 mL) was added K2CO3 (2 eq.). Difluoromethanesulfonyl chloride (CAS [1512-30-7], 0.09 mL, 1.02 mmol) was added dropwise to the stirred suspension. The mixture was stirred at room temperature overnight, then filtered. Volatiles were removed from the filtrate under vacuum to afford the title compound which was used without further purification in the next step.

[0267] Step B: l-((difluoromethyl)sulfonyl)piperi din-3 -amine. tert-Butyl (1- ((difluoromethyl)sulfonyl)piperidin-3-yl)carbamate was dissolved in DCM (2 mL) and HC1 was added (3 M in CPME, 10 eq.). After stirring overnight, volatiles were removed under vacuum.

[0268] Step C: N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide and N-((*S)-1- ((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide. To l-((difluoromethyl)sulfonyl)piperi din-3 -amine was added DMF (1 mL), DIPEA (3 eq.), and Intermediate 4 (400 mg, 1 mmol). HATU (CAS [148893-10-1], 600 mg, 1.6 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was purified directly by reverse phase HPLC (19 x 100 mm C18 column, eluting with 10 to 90 % ACN/H2O + 0.1 % NH3), followed by SFC purification (OD 21 x 250 mm ID, 5 mm column, eluting with 13 % MeOH - 87 % CO2) to give Example 63 and Example 64.

Example 65 and Example 66: N-((*R)-l-((difluoromethyl)sulfonyl)piperi din-3 -yl)-2-(6-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide and N-((*S)-1- ((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)acetamide.

(*S), (CIS)

[0269] Example 65 and Example 66 were prepared in a manner analogous to Examples 63 and 64; by using Intermediate 13 in Step C. The enantiomers were separated by SFC (AD (21 x 250 mm ID, 5 pm) column; isocratic 30 % IPA/ACN - 70 % CO2).

Example 67 and Example 68: N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide and N-((*S)-1- ((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide.

(*S), (CIS)

[0270] Examples 67 and 68 were prepared in a manner analogous to Examples 63 and 64, using 3-(tert-butoxycarbonylamino)pyrrolidine (CAS [99724-19-3]) instead of 3-Boc- aminopiperidine in Step A. Enantiomers were separated by SFC (AD (21 x 250 mm ID, 5 pm) column; eluting with 35 % EtOH - CO2).

Example 69 and Example 70: N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide and N-((*S)-1- ((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)acetamide.

(*S), (CIS)

[0271] The title compounds were prepared in a manner analogous to Examples 63 and 64 using 3-(tert-butoxycarbonylamino)pyrrolidine (CAS 99724-19-3) instead of 3-Boc- aminopiperidine in Step A; and Intermediate 13 instead of Intermediate 4 in Step C.

Enantiomers were separated by SFC (IG (21 x 250 mm ID, 5 pm) column; eluting with 35 % IPA/ACN - CO₂). Example 71, Example 72, Example 73, and Example 74: 2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*R,3*R)-3-

(methylsulfonyl)cyclohexyl)acetamide and 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)-N-((l*S,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide and 2-(2- (6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*R,3*S)-3- (methylsulfonyl)cyclohexyl)acetamide and -(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)-N-((l*S,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide.

(*S), (*S), (CIS)

[0272] The title compounds were isolated from the same reaction mixture and were prepared in a manner analogous to that of Example 28, using Intermediate 4 instead of Intermediate 13, and racemic 3-methanesulfonylcyclohexan-l-amine hydrochloride (CAS [1334147-71-5]) instead of 3 -methanesulfonyl-4-m ethylaniline. Purification by SFC (IH, 21 x 250 mm, 25 % (1 : 1 ACN/iPrOH) / 75 % CO2) gave Example 71 (19 mg, yield: 9 %), Example 72 (23 mg, yield: 11 %), Example 73 (22 mg, yield: 10 %), and Example 74 (26 mg, yield: 12 %). Example 75: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N- ((3S,6R)-6-methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide.

[0273] The title compound was prepared in a manner analogous to that of Example 62, using tert-butyl (2R,5S)-5-amino-2-methylpiperidine-l-carboxylate (CAS [2306249-72-7]) instead of tert-butyl (2R,5R)-5-amino-2-methylpiperidine-l-carboxylate in Step A.

Example 76 : 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N - ((3S,6R)-6-methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide.

(2S,5R), (CIS)

[0274] The title compound was prepared in a manner analogous to that of Example 62, using tert-butyl (2S,5R)-5-amino-2-methylpiperidine-l-carboxylate (CAS [1450891-27-6]) instead of tert-butyl (2R,5R)-5-amino-2-methylpiperidine-l-carboxylate in Step A.

Example 77, Example 78, Example 79, and Example 80: 2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((l*R,3*R)-3- (methylsulfonyl)cyclohexyl)acetamide and 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)-N-((l*S,3*R)-3-(methylsulfonyl)cyclohexyl)acetamide and 2-(6-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((l*R,3*S)-3- (methylsulfonyl)cyclohexyl)acetamide and 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)-N-((l*S,3*S)-3-(methylsulfonyl)cyclohexyl)acetamide.

(*R), (*R), (CIS)

(*S), (*S), (CIS)

[0275] The title compounds were isolated from the same reaction mixture and were prepared in a manner analogous to that of Example 28, substituting racemic 3- methanesulfonylcyclohexan-1 -amine hydrochloride (CAS [1334147-71-5]) in place of 3- methanesulfonyl-4-methylaniline. Purification by SFC (IG, 30 x 250 mm, 45 % (MeOH w/ 0.1 % DEA) / 55 % CO2), followed by further purification by SFC (IH, 21 x 250 mm, 20 % MeOH / 80 % CO2) gave Example 77, Example 78, Example 79, and Example 80. [0276] The compounds in Table 6 were prepared from Intermediate 4 and the corresponding amine following the procedure in Method C.

Table 6.

[0277] The compounds in Table 7. were prepared from Intermediate 4 and the corresponding amine following the procedure in Method C using MsCl (CAS [124-63-0]) instead of difluoromethanesulfonyl chloride.

Table 7.

Example 81 : 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N- ((R)-l -((tri fluoromethyl)sulfonyl)piperi din-3 -yl)acetamide.

Method D [0278] A solution of Intermediate 14 (28 mg, 0.058 mmol) and DIPEA (0.02 mL, 0.116 mmol) in DCM (0.5 mL) was cooled to 0 °C. Triflic anhydride (CAS [358-23-6], 1 M in DCM, 60 pL, 0.060 mmol) was added dropwise. After stirring for 10 min, volatiles were removed and the residue was purified by HPLC (19 x 100 mm Cl 8 column, eluting with 10 to 90 % ACN/H2O + 0.1 % NH3) to afford the title compound as a yellow solid (9 mg, yield: 26 %). Example 82: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N- ((S)-l -((tri fluoromethyl)sulfonyl)piperi din-3 -yl)acetamide.

[0279] The title compound was synthesized following the same synthetic pathways as Example 81, starting from Intermediate 4 and using tert-butyl (3S)-3-amino-l- piperidinecarboxylate (CAS 216854-23-8) instead of (R)-l-Boc-3 -aminopiperidine [CAS 188111-79-7],

Example 99: N-((R)-l-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

(R), (CIS)

[0280] Intermediate 14 (30 mg, 0.065 mmol), difluoroacetic acid (0.006 mL, 0.1 mmol), HATU (CAS [148893-10-1], 50 mg, 0.13 mmol), and DIPEA (0.034 mL, 0.2 mmol) were dissolved in DMF (0.5 mL). After stirring overnight, the mixture was directly purified by HPLC (19 x 100 mm Cl 8 column, eluting with 10 to 90 % ACN/ILO + 0.1 % NH3) afford the title compound as an orange solid (10 mg, yield: 28 %).

Example 98: N-((S)-l-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

(S), (CIS)

[0281] The title compound was prepared following a similar synthetic pathway as Example 99, starting from Intermediate 4 and using tert-butyl (3 S)-3 -amino- 1 -piperidinecarboxylate (CAS [216854-23-8) instead of (R)-l-Boc-3 -aminopiperidine. Example 100: N-(l-(2,2-difluoroacetyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

[0282] Step A: tert-butyl (l-(2,2-difluoroacetyl)pyrrolidin-3-yl)carbamate. DIPEA (0.278 mL, 1.611 mmol) was added to a solution of difluoroacetic acid ([CAS 381-73-7], 51 pL, 0.805 mmol) in DCM (1.5 mL). HATU (CAS [148893-10-1], 408 mg, 1.074 mmol) was added and the solution was stirred at room temperature for 5 min. DL-3-(Boc-amino)pyrrolidine (CAS [99724-19-3], 100 mg, 0.537 mmol) was added and the mixture was stirred at room temperature for 2 h. The mixture was filtered through a plug of silica and solvent was evaporated, used without further purification in the next step.

[0283] Step B: l-(3-aminopyrrolidin-l-yl)-2,2-difhioroethan-l-one. To tert-butyl (l-(2,2- difluoroacetyl)pyrrolidin-3-yl)carbamate was added DCM (7 mL) and HC1 (4 M in 1,4- di oxane, 0.8 mL, 3.2 mmol) was added. The solution was stirred at room temperature for 48 h. Volatiles were removed under vacuum and used without further purification in the next step.

[0284] Step C: N-(l-(2,2-difluoroacetyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)acetamide. l-(3-Aminopyrrolidin-l- yl)-2,2-difluoroethan-l-one was dissolved in DMF (1.5 mL) and Intermediate 4 (70 mg, 0.185 mmol) was added, followed by DIPEA (0.19 mL, 1.1 mmol) and HATU (141 mg, 0.37 mmol). The reaction mixture was stirred at room temperature for 30 min then directly purified by HPLC (19 x 100 mm C18 column, eluting with 10 to 90 % ACN/H2O + 0.1 % NH3) to give the title compound as an orange solid (29 mg, yield: 24 %). Example 113: N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

[0285] Step A: tert-butyl (3S,5R)-3-(2-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-

1.6-naphthyridin-7-yl)acetamido)-5-hydroxypiperidine-l-carboxylate. Intermediate 4 (60 mg, 0.159 mmol) and (3 S,5R)-3-amino-5-hydroxy-piperidine-l -carboxylic acid tert-butyl ester (CAS [1312798-21-2], 34 mg, 0.159 mmol) were dissolved in ACN (1.3 mL). EtsN (132 pL, 0.951 mmol) was added, followed by T3P (CAS [68957-94-8], 50 % in 2- methyltetrahydrofuran, 97 pL, 0.159 mmol), and the mixture was stirred at room temperature for 1 h. The mixture was filtered and volatiles were removed under vacuum, the resulting title compound was used without further purification in the next step.

[0286] Step B: 2-(2-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7- yl)-N-((3S,5R)-5-hydroxypiperidin-3-yl)acetamide. tert-Butyl (3S,5R)-3-(2-(2-(6-((2R,6S)-

2.6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamido)-5- hydroxypiperidine-1 -carboxylate was dissolved in DCM (1 mL) and HC1 (4 M in 1,4-dioxane, 0.396 mL, 1.586 mmol) was added. After 3 h at room temperature, volatiles were removed under vacuum and used without further purification in the next step.

[0287] Step C: N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide. 2-(2-(6- ((2R,6S)-2,6-Dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((3 S,5R)-5- hy droxypiperi din-3 -yl)acetamide was dissolved in THF (1 mL) and K2CO3 (83 mg, 0.6 mmol) was added. Difluoromethanesulfonyl chloride (CAS [1512-30-7], 27 pL, 0.3 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was purified by HPLC (19 x 100 mm C18 column, eluting with 10 to 90 % ACN/H2O + 0.1 % NH3) to afford the title compound (4 mg, yield: 5 %) as a yellow solid. Example 136: N-(l-(2,2-difhioroethyl)-5-fluoro-6-oxo-l,6-dihydropyridin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

[0288] HATU (CAS [94790-37-1], 105 mg, 0.28 mmol) was added to a stirred solution of 5- amino-l-(2,2-difluoroethyl)-3-fluoro-2(U7)-pyridinone (CAS [2409117-63-9], 63 mg, 0.33 mmol), Intermediate 4 (100 mg, 0.22 mmol), and DIPEA (0.15 mL, 0.87 mmol) in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCOs. The organic layer was dried over MgSCU, filtered, and concentrated. The crude product was purified by flash column chromatography (silica 12 g, MeOH in DCM from 0/100 to 20/80), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x l00 mm 5 pm; from 59 % [25 mM NH4HCO3] - 41 % [ACN: MeOH 1 : 1] to 17 % [25 mM NH4HCO3] - 83 % [ACN: MeOH 1 : 1]) to afford the title compound (14 mg, yield: 11 %) as a yellow solid.

Example 150: N-((R)-l-(difluoromethyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide.

(R), (CIS)

[0289] The title compound was prepared analogously to Example 113 using tert-butyl (5R)-5- amino-3,3-difluoropiperidine-l-carboxylate (CAS 1392473-32-3) instead of (3S,5R)-3-

[0290] The compounds in Table 8 were prepared from Intermediate 14 and the corresponding sulfonyl chloride following the procedure in Method D. Example 108 was synthesized starting from Intermediate 4 and using tert-butyl (3 S)-3 -amino- 1 -piperidinecarboxylate (CAS 216854-23-8) instead of (R)-l-Boc-3 -aminopiperidine [CAS 188111-79-7],

Table 8.

Example 162: (*R)-N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3- yl)acetamide.

(*R)

[0291] The title compound was isolated by SFC (Phenomenex amylose-1 250 x 30 mm 5 um; from 35 % of CO₂ - 65 % (EtOH + 0.1 % DEA) to 35 % of CO₂ - 65 % (EtOH + 0.1 %

DEA) purification of Example 156 both as a white solid.

Example 167: 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3-yl)-N-(l-

(methylsulfonyl)piperidin-4-yl)acetamide.

Method F [0292] K2CO3 (46.372 mg, 0.336 mmol) and methanesulfonyl chloride (0.026 mL, 0.335 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (CAS [73874-95-0], 35 mg, 0.168 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was treated with HC1 (3 M in CPME, 0.5 mL, 1.5 mmol). The solution was stirred overnight then volatiles were removed under vacuum. To the residue was added DIPEA (0.2 mL, 1.16 mmol), DMF (1 mL), Intermediate 13 (32 mg, 0.084 mmol), and HATU (CAS [148893-10-1], 48 mg, 0.126 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was directly purified by HPLC (19 x 100 mm C18 column, eluting with 10 to 90 % ACN/H2O + 0.1 % NH3) to afford the title compound (6 mg, yield: 7 %) as a light yellow solid.

[0293] The compounds in Table 9 were prepared from Intermediate 13 and the corresponding sulfonyl chloride following the procedure in Method F.

Table 10.

Example 152: methyl 3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3- yl)acetamido)bicyclo[l .1. l]pentane-l -carboxylate.

(CIS)

[0294] DIPEA (0.46 mL, 2.65 mmol) and methyl 3-aminobicyclo[l.l.l]pentane-l- carboxylate hydrochloride (CAS [676371-65-6], 241 mg, 1.46 mmol) were added to a stirred solution of Intermediate 13 (500 mg, 1.32 mmol) and HATU (CAS [148893-10-1], 756 mg, 1.99 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 h. More methyl 3 -aminobicyclo[l. l.l]pentane-l -carboxylate hydrochloride (200 mg, 1.13 mmol), HATU (504 mg, 1.32 mmol), and DIPEA (0.46 mL, 2.65 mmol) were added and the mixture was stirred at 40 °C for 5 h. The solvent was evaporated in vacuo. Water (30 mL) and DCM (30 mL) were added. The mixture was stirred at room temperature for 10 min. The mixture was put in an Isolute separator cartridge, eluting with DCM. The filtrate was concentrated and the residue was purified by flash column chromatography (silica, EtOAc/DCM from 0/100 to 100/0) to afford the title compound (381 mg, yield: 57 %) as a light brown foam.

Example 153: methyl (ls,3s)-3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)acetamido)cyclobutane-l-carboxylate.

(CIS), (CIS)

[0295] The title compound was prepared following the same procedure as Example 152, using cis-methyl 3 -aminocyclobutanecarboxylate hydrochloride (CAS [1212304-86-3]) instead of methyl 3 -aminobicyclo[l.l. l]pentane-l -carboxylate hydrochloride.

Example 154: N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(6-(6-

((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide.

(3S, 4S), (CIS) [0296] Step A: tert-butyl (3S,4S)-3-(2-(6-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2- yl)isoquinolin-3-yl)acetamido)-4-hydroxypyrrolidine-l-carboxylate. (3S,4S)-N-Boc-3-amino- 4-hydroxypyrrolidine (CAS [190792-74-6], 200 mg, 0.99 mmol), Intermediate 13 (485 mg, 1.29 mmol), and HATU (CAS [148893-10-1], 564 mg, 1.48 mmol) were dissolved in DMF (5 mL). DIPEA (0.51 mL, 2.97 mmol) was added and the reaction mixture was stirred at room temperature overnight. More (3S,4S)-N-Boc-3-amino-4-hydroxypyrrolidine (87 mg, 0.43 mmol) was added, and the reaction was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the organic layer was washed with brine (3 x) and with saturated aqueous NaHCCh. The combined aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse phase column chromatography (30 x 100 C18 Gemini, 38 - 58 % ACN:H₂O (10 mM NH₄OH)).

[0297] Step B: 2-(6-(6-((2R, 6S)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3 -yl)-N- ((3S,4S)-4-hydroxypyrrolidin-3-yl)acetamide. tert-Butyl (3S,4S)-3-(2-(6-(6-((2R,6S)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamido)-4-hydroxypyrrolidine-l- carboxylate was dissolved in DCM (2.5 mL). TFA (0.19 mL, 2.53 mmol) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were removed under vacuum to give the title compound.

[0298] Step C: N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(6-(6- ((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)acetamide. 2-(6-(6-((2R, 6 S)-2, 6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3S,4S)-4-hydroxypyrrolidin-3- yl)acetamide (233 mg, 0.51 mmol) and K2CO3 (349 mg, 2.53 mmol) were dissolved in Me- THF (5 mL). Difluoromethanesulfonyl chloride (CAS [1512-30-7], 0.13 mL, 1.52 mmol) was added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 3 days. The solvent was evaporated and more difluoromethanesulfonyl chloride (0.13 mL, 1.52 mmol) and K2CO3 (349 mg, 2.53 mmol) were added, along with Me- THF (5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was dried on MgSO₄, filtered, and evaporated. The resulting residue was purified by preparative HPLC (30 x 100 C18 Gemini column, 34 - 54 % ACN:H₂O (10 mM NH₄OH)) to give the title compound. Example 155: N-(3-(cyclopropylsulfonyl)bicyclo[l. l.l]pentan-l-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide.

[0299] DIPEA (0.047 mL, 0.27 mmol) and Intermediate 33 (25 mg, 0.13 mmol) were added to a stirred solution of Intermediate 13 (26 mg, 0.068 mmol) and HATU (CAS [148893-10-1], 65 mg, 0.17 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo. Water (2 mL) and DCM (2 mL) were added. The mixture was stirred at room temperature for 10 min. The mixture was put in an Isolute separator cartridge, eluting with DCM. The filtrate was concentrated in vacuo and the residue was purified by reverse phase HPLC (C18 XBridge 30 x 100 mm 10 pm; NH4HCO3 0.25 % in water and ACN) to afford the title compound (5 mg, yield: 14 %).

Example 156: N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide.

[0300] PdC12(dppf).CH2C12 (CAS [95464-05-4], 21 mg, 0.026 mmol) was added to a stirred solution of Intermediate 39 (195 mg, 0.51 mmol), phenyl boronic acid (CAS [98-80-6], 125 mg, 0.61 mmol), and sodium bicarbonate (86 mg, 1 mmol) in 1,4-di oxane (4 mL) and water (1 mL) in a sealed tube under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 16 h. After cooling, the mixture was diluted with water, extracted with EtOAc, and the organic layer was washed with brine (x 2). The organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 12 g; EtOAc/heptane from 0/100 to 60/20), followed by reverse phase column chromatography (Phenom enex Gemini C18 30 x l00 mm 5 pm; from 81 % [25 mM NH4HCO3] - 19 % ACN to 45 % [25 mM NH4HCO3] - 55 % ACN) to afford the title compound (22 mg, yield: 10 %) and unreacted Intermediate 39 (115 mg, yield: 58 %), both as white solids. Example 157: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide.

[0301] HATU (CAS [148893-10-1], 14 mg, 0.037 mmol) was added to a stirred solution of Intermediate 44 (10 mg, 0.024 mmol), 3-[(difluoromethyl)sulfonyl]benzenamine (CAS [24906-76-1], 5 mg, 0.024 mmol), and DIPEA (0.013 mL, 0.07 mmol) in DCM (1 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 (x 3). The combined organic layer was dried over MgSCU, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica 12 g; DCM:MeOH (9: 1) in DCM from 0/100 to 4/96) to afford the title compound (6 mg, yield: 40 %) as a yellow solid.

Example 158: N-(3-(S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-phenylisoquinolin-3- yl)acetamide.

[0302] Intermediate 47 (79 mg, 0.38 mmol) was added to a stirred solution of Intermediate 46 (98 mg, 0.35 mmol), HATU (CAS [148893-10-1], 0.200 g; 0.52 mmol), and DIPEA (0.24 mL, 1.4 mmol) in DMF (3 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with AcOEt. The organic layer was washed with brine (x 2), filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90), followed by reverse phase HPLC (Phenomenex Gemini C18 I.D. (mm) 100 x 21.2, 5 urn; from 72 % of H₂O (0.1 % HCOOH)- 28 % ACN: MeOH 1 : 1 to 36 % of H₂O (0.1 % HCOOH)- 64 % ACN: MeOH 1 : 1) to afford the title compound (2 Img, yield: 13 %) as a white powder. Example 159: 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - (methylsulfonyl)cyclobutyl)acetamide.

[0303] The title compound was prepared following the same procedure as Example 155, using 3-(methylsulfonyl)cyclobutanamine (CAS [1824081-10-8]) instead of Intermediate 33.

Example 160: (R)-N-(l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3- yl)acetamide.

[0304] The title compound was prepared following the same procedure as Example 158, using (3R)-l-[(difluoromethyl)sulfonyl]-3-piperidinamine (CAS [1704939-33-2]) instead of Intermediate 47.

Example 161 : N-(3-(*S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-phenylisoquinolin-3- yl)acetamide.

[0305] HATU (CAS [148893-10-1;], 122 mg; 0.32 mmol) was added to a stirred solution of Intermediate 46 (60 mg, 0.214 mmol), Intermediate 49 (49 mg, 0.24 mmol), and DIPEA (0.10 mL, 0.64 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (x 2), dried on MgSCU, filtered, and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica 24 g; MeOH/DCM from 0/100 to 10/90) to afford the title compound (69 mg, yield: 70 %) as a yellow solid. Example 163: (*S)-N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3- yl)acetamide.

[0306] The title compound was isolated by SFC purification of Example 156: SFC (Phenomenex amylose-1 250 x 30 mm 5 um; from 35 % of CO2 - 65 % (EtOH + 0.1 % DEA) to 35 % of CO2 - 65 % (EtOH + 0.1 % DEA) as a white solid.

Example 164: (*R)-N-(3-(S-(difluoromethyl)sulfinimidoyl)phenyl)-2-(6-phenylisoquinolin-3- yl)acetamide.

[0307] The title compound was prepared in a manner analogous to Example 161, using

Intermediate 48 instead of Intermediate 49.

Example 165: N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-phenylisoquinolin-3- yl)acetamide.

[0308] The title compound was prepared in a manner analogous to Example 158, using N-(2- aminoethyl)-l, 1 -diflu orom ethanesulfonamide hydrochloride (CAS [2260936-13-6]) instead of Intermediate 47. Example 166: N-(3-(cyclopropylsulfonyl)cyclobutyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide.

[0309] The title compound was prepared in a manner analogous to Example 155, using Intermediate 50 instead of Intermediate 33.

Example 181 : 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(3-

(methylsulfonyl)cyclohexyl)acetamide.

[0310] The title compound was prepared following the same procedure as Example 155, using Intermediate 51 instead of Intermediate 33.

Example 182: N-(3-(cyclopropylsulfonyl)cyclohexyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide.

[0311] The title compound was prepared in a manner analogous to Example 155, using Intermediate 52 instead of Intermediate 33. Example 183: N-(3-((*R)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide.

(*R), (CIS)

[0312] The title compound was prepared following the same procedure as Example 161, using Intermediate 48 instead of Intermediate 49, and Intermediate 44 instead of Intermediate

46.

Example 184: N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide.

(*S), (CIS)

[0313] The title compound was prepared in a manner analogous to Example 161, using Intermediate 44 instead of Intermediate 46.

Example B: Analytical characterization methods of Intermediates and Compounds

LC-MS methods

[0314] 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).

[0315] 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. [0316] 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.

[0317] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective

Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica.

LCMS Method Codes (Flow expressed in mL/min; column temperature (T) in °C; Run time Table 11. LCMS Methods

Table 12: LC-MS Results

SFC methods

[0318] 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. Table 13. SFC methods.

SFC Results

Table 14: 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.

NMR

[0319] Some NMR experiments were carried out using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with z gradients and operating at 500 MHz for the proton and 125 MHz for carbon. Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer, using internal deuterium lock, and equipped with reverse double-resonance (^XH, ¹³C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Experiments were performed at ambient temperature (298.6 K), unless otherwise mentioned. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, 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, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution.

Table 15: ‘H NMR results

Melting points

[0320] For melting points, values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method. Melting points were determined with a Mettler-Toledo MP50 or FP62 apparatus. Melting points were measured with a temperature gradient of 10°C/minute. Maximum temperature was 300°C.

Table 16. Melting Point

High Resolution Mass Spectrometry

Agilent 1260 Infinity DAD TOF-LC/MS G6224A; Column: YMC-pack ODS-AQ Cl 8 (50 x 4.6 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 2.6 mL/min: Temperature 35 °C; Run time : 6.8 min.

Table 17: HRMS results:

Optical rotation

[0321] Optical rotations were measured at 20°C or 23°C on a Perkin Elmer 341 digital polarimeter with a sodium lamp, 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). The rotation is reported in degrees.

Table 18: Optical Rotation

Example C: Pharmacological Assays

[0322] 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 or 4/SMARCC1/SMARCC2/SMARCB1 ADP-Glo Assays: [0323] 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).

[0324] 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.

[0325] Results (indicated as IC50, in nM) obtained from testing the compounds of the present disclosure in the present assays are indicated in the Table 19 below.

Table 19: SMARCA2 or 4/SMARCC1/SMARCC2/SMARCB1 ADP-Glo Assay Results.

Example D: Prophetic formulations

[0326] “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. [0327] Typical examples of recipes for the formulation of the invention are as follows:

1. Tablets

Active ingredient 5 to 50 mg

Di-calcium phosphate 20 mg

Lactose 30 mg

Talcum 10 mg

Magnesium stearate 5 mg

Potato starch ad 200 mg

2. Suspension

[0328] An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

[0329] A parenteral composition is prepared by stirring 1.5 % (weight/volume) of active ingredient in 0.9 % NaCl solution or in 10 % by volume propylene glycol in water.

4. Ointment

Active ingredient 5 to 1000 mg

Stearyl alcohol 3 g

Lanoline 5 g

White petroleum 15 g

Water ad 100 g

[0330] In this Example, active ingredient may be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

Claims

1. A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

R¹ is selected from the group consisting of:

R^c is halo, Ci-4alkyl, or OCi-4alkyl;

R^f is halo, Ci-4alkyl, or O-Ci-4alkyl;

R^h is Ci-4alkyl;

(ii) C_2.3alkyl substituted

wherein R¹ is SO₂-Ci-4haloalkyl, NH-SO₂-Ci-4haloalkyl, N(CH₃)-SO₂-Ci-4haloalkyl, or

SO₂-N(CH₃)₂, (iii) 5 or 6-membered heteroaryl selected from:

wherein Rⁿ is SO₂CH₃, CH₂C(OH)(CH₃)₂, CH₂CH₂SO₂CH₃;

R^p is SO₂CH₃ or CH₂CH₂CN; or

R^q is H or CH₃; (iv) C₃-6cycloalkyl or bridged-C5-7cycloalkyl each substituted with SO₂Ci-4alkyl, SO₂-C₃-6cycloalkyl. CO₂CH₃, or NH-SO₂Ci-4haloalkyl; or,

(v) carbon linked pyrrolidine, piperidine, or azepane: each independently substituted with one or two substituents selected from: halo, Ci-4alkyl, Ci-4haloalkyl, CH₂OH, OH, OCi- 4alkyl, SO₂Ci-4alkyl, SO₂Ci-4haloalkyl, SO₂CH₂CH₂OH, and C(=O)Ci-4haloalkyl; or 5- azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane, and 3- azabicyclo[3.1.0]hexane each independently substituted with SO₂Ci-4haloalkyl;

(vi)

R⁵ is an optionally substituted 6-membered ring selected from:

and X is CH or N.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

(i) R¹ is:

(ii) R¹ is:

(vi) R¹ is:

3. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the Formula (IA),

4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the Formula (IB),

wherein,

R¹ is (i)

R¹ is (vi)

5. 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, wherein: X is N.

7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is CH.

8. A compound of claim 1 selected from the group consisting of: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-m ethyl -

3-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((3S,5R)-4-hydroxy-3, 5-dimethylpiperi din-l-yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(l- (methylsulfonyl)indolin-6-yl)acetamide;

N-(4-methyl-3-(methylsulfonyl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-l, 6-naphthyri din-7- yl)acetamide;

N-(3-(2-hydroxypropan-2-yl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)acetamide;

N-(5-(methylsulfonyl)pyridin-3-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)acetamide;

N-(l -(methylsulfonyl)indolin-6-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-l, 6-naphthyri din-7- yl)acetamide;

2-(2-(6-((3a, 4a, 5a)-4-hydroxy-3, 5-dimethylpiperi din-l-yl)pyri din-2 -yl)-l, 6-naphthyri din- 7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(3-((2- hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(3-fluoro-5- (methylsulfonyl)phenyl)acetamide;

N-(4-chl oro-3 -(methylsulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2- yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)-lH-pyrazol-4-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(4- (methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l, 1- dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3- (ethylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(4-fluoro-3- (methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(2-(N, N- dimethylsulfamoyl)ethyl)acetamide;

N-(2-(2-oxabicyclo[2.1.1]hexan-l-yl)ethyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(l-(2-cyanoethyl)-5-methyl-lH-pyrazol-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(l-(2- (methylsulfonyl)ethyl)-lH-pyrazol-4-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4- methyl-3-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)-lH-pyrazol-3-yl)acetamide;

N-(6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

2-(6-(6-(4, 7 -diazaspiro[2.5 ]octan-7 -yl)pyridin-2-yl)i soquinolin-3 -yl)-N -(4-m ethyl -3 - (methylsulfonyl)phenyl)acetamide;

2-(6-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)isoquinolin-3-yl)- N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 -((2- hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(5- (methylsulfonyl)pyridin-3-yl)acetamide;

N-(3-(cyanomethoxy)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(3-methyl- 5-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(4-methoxy- 3-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(2,2- dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)acetamide;

N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-(l, 1- dioxidoisothi azolidin-2 -yl)phenyl)acetamide;

N-(3-(cyclopropylsulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(3-methoxy- 5-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)-lH-pyrrol-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3- ((trifluoromethyl)sulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(2 -methyl- 5-(methylsulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-(N, N- dimethylsulfamoyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-((2- hydroxyethyl)sulfonyl)phenyl)acetamide;

N-(3-(2-cyanopropan-2-yl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)acetamide;

N-(2,2-dimethylchroman-7-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3- (tetrahydrofuran-3-yl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-oxo- 2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(l-(2- hydroxy -2 -methylpropyl)-lH-pyrazol-4-yl)acetamide;

N-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2- yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(l -methyl- l-oxido-3H-114-benzo[d]isothiazol-5-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(3-(2,5- dioxopyrrolidin-l-yl)-4-fluorophenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)piperidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-(2- methyloxetan-2-yl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(6- (methylsulfonyl)pyridin-2-yl)acetamide;

N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((*R)-l - (methylsulfonyl)piperidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((* S)-l- (methylsulfonyl)piperidin-3-yl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3-yl)-N-((*R)-l - (methylsulfonyl)piperidin-3-yl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((*S)-l- (methylsulfonyl)piperidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-m ethyl - 3-(S-methylsulfonimidoyl)phenyl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)i soquinolin-3 -yl)-N-((3 R,6R)-6- methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide;

N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*S)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((*S)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((*S)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((*S)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*R,3*R)-

3-(methylsulfonyl)cyclohexyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*S,3*R)-

3-(methylsulfonyl)cyclohexyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*R,3*S)-

3-(methylsulfonyl)cyclohexyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*S,3*S)-

3-(methylsulfonyl)cyclohexyl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3S,6R)-6- methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -((3R, 6 S)-6- methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(( 1 *R,3 *R)-3 - (methylsulfonyl)cyclohexyl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((l*S,3*R)-3-

(methylsulfonyl)cyclohexyl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(( 1 *R, 3 * S)-3 - (methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N-(( 1 * S, 3 * S)-3 - (methylsulfonyl)cyclohexyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((*R)-l - ((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((* S)-l- ((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)pyrrolidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((R)-l - (methylsulfonyl)pyrrolidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((S)-l- (methylsulfonyl)pyrrolidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((ls,3s)-3- (methylsulfonyl)cyclobutyl)acetamide;

N-(2-((difluoromethyl)sulfonyl)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide;

N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(3-((difluoromethyl)sulfonamido)propyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(3-((difluoromethyl)sulfonyl)propyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide;

N-(3-((dimethyl(oxo)-16-sulfaneylidene)amino)phenyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(2-((difluoromethyl)sulfonyl)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide;

N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2 -y 1 )i soquinolin-3 -yl)acetamide;

N-(3-((difluoromethyl)sulfonamido)propyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(4-(S- methylsulfonimidoyl)phenyl)acetamide; N-(3-((difluoromethyl)sulfonyl)propyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide;

N-(3-((dimethyl(oxo)-16-sulfaneylidene)amino)phenyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((S)-l-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((R)-l-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(l-(2,2-difluoroacetyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-(S- methylsulfonimidoyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(3- ((fluoromethyl)sulfonyl)phenyl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - ((fluoromethyl)sulfonyl)phenyl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-((l- (methylsulfonyl)piperidin-4-yl)methyl)acetamide;

N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((R)-l-((2- hydroxy ethyl)sulfonyl)piperidin-3-yl)acetamide;

N-((R)-l-((3,3-difluoropropyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((S)-l-((2- hydroxyethyl)sulfonyl)piperidin-3-yl)acetamide;

N-((3R,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,4R)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((R)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((S)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((R)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((S)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(l-((2,2-difluoroethyl)sulfonyl)piperidin-4-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((3 R,5R)-5- fluoro-l-(methylsulfonyl)piperidin-3-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((3R,5S)-5- fluoro-l-(methylsulfonyl)piperidin-3-yl)acetamide;

N-((3R,5R)-5-(difluoromethyl)-l-(methylsulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(5-((difluoromethyl)sulfonyl)-5-azaspiro[2.5]octan-7-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(6-((difluoromethyl)sulfonyl)-6-azaspiro[3.5]nonan-8-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3S,5S)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((S)-l-((difluoromethyl)sulfonyl)-5,5-dimethylpiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5R)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)-

2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(l-(2,2-difluoroethyl)-5-fluoro-6-oxo-l,6-dihydropyridin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(2-((l,l-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((lR,2S)-2-((difluoromethyl)sulfonamido)cyclobutyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((lR,2R)-2-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(5-((difluoromethyl)sulfonamido)bicyclo[3.1.1]heptan-l-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((lR,2R)-2-((difluoromethyl)sulfonamido)cyclobutyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(((S)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)methyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(2-((difluoromethyl)sulfonyl)-2-azabicyclo[2.1. l]hexan-4-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lS,2S)-2-((difluoromethyl)sulfonamido)cyclopropyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((l-((difluoromethyl)sulfonyl)piperidin-3-yl)methyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((lR,2S)-2-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(3-(l,l,2,2- tetrafluoroethoxy)phenyl)acetamide;

N-(4-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide;

N-((R)-l-(difluoromethyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((lR,5S)-3-((difluoromethyl)sulfonyl)-3-azabicyclo[3.1.0]hexan-l-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; methyl 3-(2-(6-(6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3 - yl)acetamido)bicyclo[l .1. l]pentane-l -carboxylate; methyl (ls,3s)-3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3- yl)acetamido)cyclobutane-l -carboxylate;

N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-(3-(cyclopropylsulfonyl)bicyclo[l.l.l]pentan-l-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide;

N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-l-methyl-

6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide;

N-(3-(S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-phenylisoquinolin-3-yl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - (methylsulfonyl)cyclobutyl)acetamide;

(R)-N-(l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide;

(*R)-N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide; (*S)-N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide;

(*R)-N-(3-(S-(difluoromethyl)sulfinimidoyl)phenyl)-2-(6-phenylisoquinolin-3- yl)acetamide;

N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-phenylisoquinolin-3-yl)acetamide;

N-(3-(cyclopropylsulfonyl)cyclobutyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -( 1 - (methylsulfonyl)piperidin-4-yl)acetamide;

N-(l-((difluoromethyl)sulfonyl)piperidin-4-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -( 1 -((2- hydroxyethyl)sulfonyl)piperidin-4-yl)acetamide;

N-((3S,4R)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3R,4R)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3R,4S)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-methoxypyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,5S)-l-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - (methylsulfonyl)cyclohexyl)acetamide;

N-(3-(cyclopropylsulfonyl)cyclohexyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide;

N-(3-((*R)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide; and

N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide; and pharmaceutically acceptable salts or stereoisomers thereof.

9. A compound of claim 1 selected from the group consisting of:

N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-

2 -y 1 )i soquinolin-3 -yl)acetamide;

N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide;

N-((R)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((R)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide;

N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide;

N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; and

N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; 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.