EP4739686A1 - Smarca2 inhibitor useful for the treatment of smarca4 deficient cancers - Google Patents

Abstract

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

Description

JAB7161 -1- SMARCA2 INHIBITOR USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS FIELD OF THE INVENTION [0001] The invention relates to a pharmaceutical compound and pharmaceutical compositions comprising said compound, to processes for the preparation of said compound and to the use of said compound as inhibitor of the SMARCA2 protein and to its use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC). BACKGROUND OF THE INVENTION [0002] The Switch/Sucrose Non-Fermentable (SWI/SNF), also known as BAF complex, is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase/ATPase catalytic subunits: SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI/ SNF-Related, Matrix- Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression. [0003] Mutations in the genes encoding the twenty canonical SWI/SNF subunits are observed in nearly 20% of all cancers with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4-deficiency, such as lack of expression), including, e.g., lung cancer (such as non- small cell lung cancer or NSCLC). [0004] SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4-related or -mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells depend exclusively on SMARCA2 activity – i.e., there is a greater JAB7161 -2- 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 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 3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4- fluoropyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)benzamide, or 3-chloro-5- ((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)benzamide having SMARCA2 modulating properties, and pharmaceutical compositions comprising this compound, to the use of said compound as inhibitor 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 JAB7161 -3- and pharmaceutically acceptable salts, isotopes, and stereoisomers thereof. [0012] An additional embodiment of the invention is a method of treating cancer or non- small-cell lung carcinoma (NSCLC) in a subject comprising administering an effective amount of a pharmaceutical composition, or use of a pharmaceutical composition for treating cancer or non-small-cell lung carcinoma (NSCLC), or a pharmaceutical composition for such use, comprising: the compound of the present invention; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of said compound; and at least one pharmaceutically acceptable excipient. [0013] In some embodiments, such pharmaceutical compositions comprise a therapeutically effective amount of the compound of the present invention, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, or a pharmaceutically acceptable prodrug of said compound, or at least one pharmaceutically active metabolite ; and at least one pharmaceutically acceptable excipient. INCORPORATION BY REFERENCE [0014] 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 [0015] 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. JAB7161 -4- [0016] 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. [0017] 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. [0018] 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.” [0019] 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. [0020] 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. [0021] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. [0022] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. JAB7161 -5- [0023] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York. [0024] 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. [0025] 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. [0026] 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. [0027] 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. [0028] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. JAB7161 -6- [0029] 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. [0030] 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. [0031] 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. [0032] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins. [0033] 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. [0034] 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. [0035] 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. [0036] 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. [0037] 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 JAB7161 -7- reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal. [0038] 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. [0039] 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. [0040] 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, JAB7161 -8- invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. [0041] As used herein, the term “cancer” refers to a malignant neoplasm. [0042] 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). [0043] 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 [0044] Hereinbefore and hereinafter, the term “3-chloro-5-((difluoromethyl)sulfonyl)-N- ((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthyridin-7- yl)methyl)benzamide”, “3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6- dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6-naphthyridin-7-yl)methyl)benzamide”, the JAB7161 -9- compound of formula the present disclosure or invention”, “compound presented herein”, or similar terms or expressions, is meant to include the addition salts, and the stereoisomers thereof. [0045] In certain embodiments, the compound presented herein possesses one or more stereocenters and each center independently exists in either the R or S configuration. The compound presented herein includes 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. [0046] In some situations, the compound may exist as tautomers. All tautomers are included within the scope of the compound presented herein. [0047] 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 [0048] Such forms in so far as they may exist, are intended to be included within the scope of the compound presented herein. It follows that a single compound may exist in both stereoisomeric and tautomeric form. [0049] 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”, JAB7161 -10- 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” isomers of 2,6-dimethyl-morpholine. There is one possible relative configuration based on the relative positions of the two substituents, whether they are on the same side or opposite faces of the cyclic structure. [0050] For example: [0051] The present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible. [0052] 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. [0053] The methods and formulations described herein include the use of N-oxides (if appropriate), pharmaceutically acceptable salts, and combinations thereof, of the compound having the structure presented herein and having the same type of activity. [0054] The salt forms of the compound 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 compound of the invention, also form part of the invention. JAB7161 -11- [0055] 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 compound described herein are able to form. [0056] 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 the compound 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 compound of the invention may exist as mono- or di-salts depending upon the pKa of the acid from which the salt is formed. [0057] 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. [0058] Appropriate anions comprise, for example, acetate, 2,2-dichloroacetate, adipate, alginate, ascorbate (e.g. L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4- acetamidobenzoate, butanoate, bicarbonate, bitartrate, bromide, (+) camphorate, camphor- sulphonate, (+)-(1S)-camphor-10-sulphonate, calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecylsulphate, edetate, estolate, esylate, ethane-1,2-disulphonate, ethanesulphonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g. D-glucuronate), glutamate (e.g. L-glutamate), α-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, methylsulfate, mucate, naphthalene-sulphonate (e.g.naphthalene-2-sulphonate), naphthalene- 1,5-disulphonate, 1-hydroxy-2-naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate/diphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, JAB7161 -12- stearate, subacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g. p-toluenesulphonate), tosylate, triethiodide, undecylenate, valeric acids, as well as acylated amino acids and cation exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. [0059] The compound 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(CH ) +, + + 3 4 and substituted ammonium ions (e.g., NH3R , 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 compound described herein contain an amine function, this 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 compound is within the scope of the compound presented herein. [0060] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form. [0061] In some embodiments, sites on the compound 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. [0062] The compound of the present disclosure includes compounds that are isotopically labeled, i.e., with one or more isotopic substitutions. These compounds are identical to those recited in the formula and structure 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 JAB7161 -13- 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, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from the group of 2H, 3H, 11C 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. Synthesis of Compounds [0063] 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 Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of the 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. [0064] The starting materials and reagents used for the synthesis of the compound described herein may be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics. [0065] 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 JAB7161 -14- 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. [0066] 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. [0067] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (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. [0068] 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 Pd0- 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. [0069] Typically blocking/protecting groups may be selected from: JAB7161 -15- Me Bn alloc Cbz t-butyl Fmoc [0070] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosure. General synthetic pathways SCHEME 1 [0071] According to SCHEME 1, a commercially available ester of formula (I) can be reacted with sodium methanesulfinate, in the presence of a suitable catalyst such as, for example, copper (I) iodide, in the presence of a suitable ligand such as, for example, (L)-proline, in a JAB7161 -16- suitable solvent such as, for example, DMSO, at a suitable temperature such as, for example, 100 °C, to afford a methylsulfonylbenzoyl ester (II). A methylsulfonylbenzoyl ester of formula (II) can be converted to an intermediate of formula (III) by reaction with 2,2,2- trifluoroethyl trifluoroacetate (CAS [407-38-5]) in the presence of a suitable base such as, for example, LiHMDS, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, -78 °C. An intermediate of formula (III) can be fluorinated by reaction with a suitable fluorinating agent such as, for example, 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate (CAS [140681-55-6]), in a suitable solvent such as, for example, ACN, at a suitable temperature such as, for example, 60 °C, to afford an intermediate of formula (IV). An intermediate of formula (IV) can be converted to an ester of formula (V) by reacting with a suitable base such as, for example, DIPEA, in a suitable solvent such as, for example, a mixture of THF and water, at a suitable temperature such as, for example, room temperature. [0072] Alternatively, a commercially available ester of formula (I) can be converted to a thioacetate of formula (VI) by reacting with potassium thioacetate, in the presence of a suitable catalyst such as, for example, Pd2(dba)3 (CAS [51364-51-3]), in the presence of a suitable ligand such as, for example, Xantphos (CAS [161265-03-8]), in a suitable in a suitable solvent such as, for example, toluene or a mixture of toluene and acetone, at a suitable temperature such as, for example, 70 °C. A thioacetate of formula (VI) can be deacetylated in the presence of suitable base such as, for example, potassium carbonate, in a suitable solvent such as, for example, methanol, at a suitable temperature such as, for example, room temperature, to afford a thiol of formula (VII). A thiol of formula (VII) can be difluoromethylated by reaction with a suitable reagent such as sodium 2-chloro-2,2- difluoroacetate (CAS [1895-39-2]), in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as, for example, DMF, at a suitable temperature such as, for example, 95 °C, to give a difluoromethylsulfide of formula (VIII). A difluoromethylsulfide of formula (VIII) can be oxidized by reaction with oxone (CAS [70693- 62-8]), in a suitable solvent such as, for example, a mixture of methanol and water, at a suitable temperature such as, for example, 0 °C or room temperature, to afford an ester of formula (V). [0073] According to SCHEME 1, an ester compound of formula (V) can be reacted under basic conditions such as NaOH, LiOH, KOH, and the like; in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or a mixture thereof; at a suitable JAB7161 -17- temperature such as room temperature or 60 °C to 80 °C; to afford an acid compound of formula (IX). SCHEME 2 [0074] According to SCHEME 2, a compound of formula (XI) can be prepared in a metal mediated coupling reaction of a commercially available or synthetically accessible compound of formula (X), where Hal is a suitable halogen such as Br (bromine); with a boronic acid or boronic ester such as potassium trifluoro(vinyl)borate; in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) chloride, and the like; a base such as Cs₂CO₃, and the like; in a suitable solvent such as THF, 1,4-dioxane, toluene, water, or a mixture thereof; at temperatures ranging from 70 °C to 100 °C; for a period of 12-18 h. Halogenation of a compound of formula (XI), employing a chlorinating agent such as POCl3, and the like, in a suitable solvent such as 1,2-dichloroethane, chloroform, and the like, at temperatures ranging from 70-90 °C, can afford a compound of formula (XII). A compound of formula (XII) can be oxidized by treatment with osmium tetroxide and NaIO4, in a suitable solvent such as 1,4-dioxane, THF, water, or a mixture thereof, to provide a compound of formula (XIII). Reduction of a compound of formula (XIII) can be achieved employing a suitable reducing agent such as NaBH4, and the like; in a suitable solvent, such as MeOH, EtOH, and the like; to provide a compound of formula (XIV). Subsequent mesylation of the hydroxy compound of formula (XIV) can be achieved employing methanesulfonyl chloride (mesyl chloride), a suitable base such as triethylamine (TEA), in a suitable solvent such as DCM, and the like, to provide a compound of formula (XV). An azide compound of formula (XVI) can be prepared from a compound of formula (XV) employing azidation conditions known to one skilled in the art. In a preferred method, a compound of formula (XV) can be reacted with sodium azide, in a suitable solvent such as DMF, and the like, at room JAB7161 -18- temperature, for a period of 18 h, to provide a compound of formula (XVI). A compound of formula (XVII) can be prepared by reacting a compound of formula (XVI) with a suitable reductant such as, for example, triphenylphosphine, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, room temperature. A compound of formula (XVII) can be protected with a Boc protecting group, employing conditions known to one skilled in the art, for example, by reacting a compound of formula (XVII) with Boc- anhydride, in the presence of a suitable base such as, for example, Et3N; at room temperature; for a period of about 4-7 h, to provide a compound of formula (XVIII), where P1 is Boc. SCHEME 3 [0075] According to SCHEME 3, a compound of formula (X), where Hal is Cl, can undergo a palladium-catalyzed cyanation employing conditions known to one skilled in the art. For example, a compound of formula (X), can be reacted with a palladium catalyst such as Pd(dppf)Cl₂.CH₂Cl₂, and the like; and zinc cyanide as the nucleophile; in a suitable solvent such as DMA, N,N-dimethylformamide (DMF), and the like; at a temperature of about 100 °C; for a period of 2-6 h; to provide a cyano compound of formula (XIX). Halogenation of a compound of formula (XIX) can be achieved employing methods previously described, such as using POCl3, to afford a compound of formula (XX). A compound of formula (XX) can be reduced using a suitable reducing agent such as DIBAL-H; in a suitable solvent such as DCM, toluene, and the like; at a temperature of -78 °C to room temperature; subsequent reaction with a suitable protecting group precursor such as, for example, Boc anhydride, in a suitable solvent such as, for example, DCM, at a suitable temperature such as, for example, room temperature can afford a compound of formula (XVIII). SCHEME 4 [0076] According to SCHEME 4, a compound of formula (XVIII), where R3 is H, Hal is Cl, and P1 is Boc, can be reacted with a suitable sulfinate such as, for example, sodium 1- methyl 3-sulfinopropanoate (CAS [90030-48-1]); in the presence of a suitable catalyst such as, for example, CuI; in a suitable solvent such as, for example, DMSO, and the like; at a JAB7161 -19- suitable temperature such as, for example, 110 °C; to provide a compound of formula (XXI). A compound of formula (XXI) can be reacted with a commercially available or synthetically accessible suitably substituted 2-halogeno-R5, such as, for example, (cis)-4-(6-bromo-4- fluoropyridin-2-yl)-2,6-dimethylmorpholine; in the presence of a suitable phosphonium salt such as di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3]); in the presence of a suitable base such as, for example, K2CO3, and the like; in the presence of a suitable catalyst such as, for example, Pd(OAc)2, and the like; in a suitable solvent such as, for example, 1,4-dioxane; at a suitable temperature such as, for example, 150 °C; to provide a compound of formula (XXII). Deprotection of the Boc protecting group on a compound of formula (XXII) can be achieved employing acidic conditions known to one skilled in the art or as previously described to provide a compound of formula (XXIII). SCHEME 5 [0077] According to SCHEME 5, a compound of formula (XXIII) can be reacted with a suitable carboxylic acid, employing conventional amide bond forming techniques such as coupling reactions which are well known to those skilled in the art. For example, a compound of formula (XXIII), where R5 is 6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl, can be reacted with a suitable carboxylic acid of formula (IX), in the presence of a suitable coupling agent such as, for example, HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HBTU, or 1-propanephosphonic anhydride; in the presence of a suitable base such as, for example, N-ethyldiisopropylamine (DIPEA), triethylamine (TEA), and the like; in a suitable solvent such as, for example, DCM, THF, DMF, and the like; at a suitable temperature such as, for example, ranging from 0 °C to room temperature, to provide a compound of Formula (I). Alternatively, Compounds of Formula (I) can be prepared by reacting a compound of formula (XXIII) with a suitable activated form of a carboxylic acid, such as, for example, an acyl chloride, or its corresponding anhydride, in the presence of a suitable base such as, for example, DIPEA or Et₃N, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, 0 °C or room temperature. [0078] The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound. JAB7161 -20- [0079] 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. [0080] 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. [0081] 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. [0082] 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. [0083] The compound 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 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, and the pharmaceutically acceptable addition salts thereof, involves liquid chromatography using a chiral stationary phase e.g. by supercritical fluid chromatography. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereo specifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. [0084] 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. JAB7161 -21- Methods of Treatment and Medical Uses, Pharmaceutical compositions, and combinations [0085] 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. [0086] The subject being treated is a mammal. The subject may be a human. The subject may be a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. The subject may be a companion animal such as a dog or cat. The subject may be a livestock animal such as a cow, pig, horse, sheep, or goat. The subject may be a zoo animal. The subject may be a research animal such as a rodent, dog, or non-human primate. The subject may be a non-human transgenic animal such as a transgenic mouse or transgenic pig. [0087] The proliferative disease to be treated or prevented using the compounddescribed herein 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 compound of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, inhibits the activity of SMARCA2 and may be useful in treating and/or preventing proliferative diseases. [0088] 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 compound 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. [0089] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer. JAB7161 -22- [0090] 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. [0091] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject. [0092] In yet another aspect, the present invention provides the compound 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 compound described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting cell growth. The compound described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inducing apoptosis in a cell. The compound described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting transcription. [0093] One skilled in the art will recognize that a therapeutically effective amount of the compound 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 the 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. [0094] 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 compound according to the invention is preferably formulated prior to administration. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. [0095] 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 JAB7161 -23- 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. [0096] 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 (18th 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. JAB7161 -24- [0097] 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. [0098] 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. [0099] 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. [0100] 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. [0101] 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 JAB7161 -25- 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. [0102] 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. [0103] 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 [0104] 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 JAB7161 -26- sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific. [0105] When a stereocenter is indicated with ‘RS’ this means that a racemic mixture was obtained. [0106] For intermediates that may be used in a next reaction step as a crude or as a partially purified intermediate, theoretical mol amounts may be indicated in the reaction protocols described below. [0107] Hereinafter, “DCM” and “CH₂Cl₂”means dichloromethane; “r.t.” means room temperature; “Boc” means tert-butoxycarbonyl; “CH3CN”and “ACN” means acetonitrile; “MeOH” means methanol; “EtOH” means ethanol; “iPrOH” means isopropanol; “DMF” means dimethylformamide; “iPrNH₂” means isopropylamine; “SOCl₂” means thionylchloride; “Et3N” means triethylamine; “NH4OAc” means ammonium acetate; “NH4OH” means ammonium hydroxide; “NH4Cl” means ammonium chloride; “NaBH(OAc)₃” means sodium triacetoxyborohydride; “POCl₃” means phosphorus oxychloride; “RuPhos Pd G3” means (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1’- biphenyl)(2-(2’-amino-1,1’-biphenyl))palladium(II) methanesulfonate; “Na2CO3” means sodium carbonate; “KHSO₄” means potassium hydrogenasulfate, “HBTU” means 2-(1H- Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; “EA” means ethylamine; “NH4HCO3” means ammonium bicarbonate; “TFA” means trifluoroacetic acid; “THF” means tetrahydrofuran; “h” means hours; “RM” means reaction mixture; “SFC” means Supercritical fluid chromatography; “Bredereck’s reagent” means tert-Butoxy bis(dimethylamino)methane; ”AcOEt” means ethyl acetate; “K2CO3” means potassium carbonate; “MgSO4” means magnesium sulfate; “Boc2O” means di-tert-butyl decarbonate. [0108] Example A: Preparation of the Intermediates and the final Compounds, and characterization thereof [0109] Several methods for preparing the Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods. Table 1: Abbreviations. Abbreviation Meaning ACN acetonitrile AcOH acetic acid JAB7161 -27- Abbreviation Meaning Celite® diatomaceous earth Co Compound Co. No. Compound Number DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIBALH di-isobutylaluminiumhydride DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DEA diethylamine DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide eq. equivalent(s) Et3N or TEA triethylamine EtOAc ethyl acetate EtOH ethanol HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HPLC high performance liquid chromatography iPrNH2 isopropylamine iPrOH isopropanol LED light-emitting diode mCPBA meta-chloroperoxybenzoic acid Me methyl MeOH methanol MsCl methanesulfonyl chloride NaBH(OAc)₃ sodium triacetoxyborohydride PPh₃ triphenylphosphine quant. quantitative rac racemic RP reversed phase JAB7161 -28- Abbreviation Meaning SFC supercritical fluid chromatography TBAF tetrabutylammonium fluoride TBDMSCl tert-butyldimethylsilyl chloride TBDPSCl tert-butyldiphenylsilyl chloride TFA trifluoroacetic acid THF tetrahydrofuran [0110] As understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities. [0111] 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. [0112] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context. [0113] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated. [0114] Unless otherwise stated, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. Where solutions were “dried,” they were generally dried over a drying agent such as Na₂SO₄ or MgSO₄. Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure. [0115] The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M- JAB7161 -29- 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. [0116] 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 (1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Experiments were performed at ambient temperature (298.6 K), unless otherwise mentioned. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Definitions for multiplicity are as follows: s = singlet, d = doublet, t= triplet, q = quartet, p = pentet, hept = heptet, dd = doublet of doublets, dt = doublet of triplets, dq = double of quartets, dp = doublet of pentets, td = triplet of doublets, tt = triplet of triplets, ddd = doublet of doublet of doublets, m = multiplet, br = broad. It will be understood that for compounds comprising an exchangeable proton, said proton may or may not be visible on an NMR spectrum depending on the choice of solvent used for running the NMR spectrum and the concentration of the compound in the solution. Preparation of intermediates [0117] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below. [0118] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye). Intermediate 1: (2-chloro-1,6-naphthyridin-7-yl)methanamine. [0119] Step A: 7-vinyl-1,6-naphthyridin-2(1H)-one.7-Bromo-1,6-naphthyridin-2(1H)- one (CAS [1574395-48-4], 2.32 g, 10.309 mmol), potassium trifluoro(vinyl)borate (CAS [13682-77-4], 1.657 g, 12.371 mmol, 1.2 eq.), bis(triphenylphosphine)palladium(II) chloride JAB7161 -30- (CAS [13965-03-2], 434 mg, 0.619 mmol, 0.06 eq.), and Cs₂CO₃ (10.077 g, 30.928 mmol, 3 eq.) were dissolved in THF (40 mL) and water (10 mL) under nitrogen atmosphere. The mixture was stirred at 80 ºC for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and water was added. The layers were separated, and the organic layer was dried on MgSO₄, filtered, and evaporated. The residue was purified by flash column chromatography (80 g; SiO2; EtOAc/heptane 10/90 to 100/0) to yield the title compound (1150 mg, yield: 64 %) as a white solid. [0120] Step B: 2-chloro-7-vinyl-1,6-naphthyridine. POCl₃ (1.86 mL, 20.037 mmol, 3 eq.) was added to a suspension of 7-vinyl-1,6-naphthyridin-2(1H)-one (1.15 g, 6.679 mmol) in 1,2-dichloroethane (34 mL). The mixture was stirred at 80 ºC for 16 h. The mixture was diluted with aqueous Na₂CO₃ and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 x). The combined organic layer was dried (MgSO4), filtered, and evaporated to yield the title compound (1.16 g, yield: 90 %) as an orange solid, used without further purification. [0121] Step C: 2-chloro-1,6-naphthyridine-7-carbaldehyde.2-chloro-7-vinyl-1,6- naphthyridine (1.16 g, 6.064 mmol) and 2,6-lutidine (1.41 mL, 12.128 mmol, 2 eq.) were dissolved in water (6 mL) and 1,4-dioxane (23 mL). NaIO₄ (5.19 g, 24.257 mmol, 4 eq.) and OsO₄ (38 mg, 0.152 mmol, 0.025 eq.) were added at 0 ºC. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM several times. The combined organic layer was dried over MgSO4, filtered, and evaporated to yield the title compound (820 mg, yield: 63 %) as a dark brown solid used without further purification. [0122] Step D: (2-chloro-1,6-naphthyridin-7-yl)methanol. A solution of 2-chloro-1,6- naphthyridine-7-carbaldehyde (820 mg, 3.832 mmol) in EtOH (30 mL) was cooled to 0 ºC and NaBH₄ (72 mg, 1.916 mmol, 0.5 eq.) was added. The reaction mixture was stirred at room temperature for 20 min. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and evaporated. The residue was purified by flash column chromatography (80 g SiO₂; DCM:MeOH (9:1) in DCM 0/100 to 20/80) to yield the title compound (387 mg, yield: 51 %) as a white solid. [0123] Step E: (2-chloro-1,6-naphthyridin-7-yl)methyl methanesulfonate. Et3N (114 µL, 0.832 mmol, 1.2 eq.) was added to a solution of (2-chloro-1,6-naphthyridin-7-yl)methanol (135 mg, 0.694 mmol) in DCM (5 mL) at room temperature. Then, MsCl (59 µL, 0.763 mmol, 1.1 eq.) was added portion-wise at 0 ºC and the mixture was stirred at room JAB7161 -31- temperature for 16 h. The reaction mixture was concentrated in vacuo to yield the title compound (190 mg, yield: 95 %) as a brown oil, used without further purification. [0124] Step F: 7-(azidomethyl)-2-chloro-1,6-naphthyridine. Sodium azide (59 mg, 0.906 mmol, 1.3 eq.) was added to a solution of (2-chloro-1,6-naphthyridin-7-yl)methyl methanesulfonate (190 mg, 0.697 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated in vacuo to yield the title compound as a brown oil. The product was used as such in next step. [0125] Step G: (2-chloro-1,6-naphthyridin-7-yl)methanamine. Triphenylphosphine (252 mg, 0.963 mmol, 1.4 eq.) was added to a solution of 7-(azidomethyl)-2-chloro-1,6- naphthyridine (151 mg, 0.688 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 1 h. Additional triphenylphosphine (90 mg, 0.343 mmol, 0.5 eq.) was added and the mixture was stirred at room temperature for 1.5 h. Water (2 mL) was added and the mixture was stirred at room temperature for 16 h. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (12 g silica; gradient of DCM/MeOH/NH3 (9/1/0.25) in DCM from 0 to 60 %) to yield the title compound (50 mg, yield: 38 %) as a brown oil. Intermediate 2: tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate. Method 1: [0126] Boc anhydride (7.486 g, 34.301 mmol, 1.1 eq.) followed by Et₃N (13 mL, 93.548 mmol, 3 eq.) were added portion wise to a suspension of (2-chloro-1,6-naphthyridin-7- yl)methanamine (Intermediate 1, HCl salt, 7.175 g, 31.183 mmol) in dry DCM (200 mL) at room temperature under nitrogen atmosphere. The resulting solution was stirred at room temperature for 2.5 h. The reaction mixture was diluted with DCM and water and the layers were separated. The aqueous layer was extracted again with DCM. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane:EtOH/EtOAc 1/3100:0 to 20:80) to give the title compound (6.1 g, yield: 67 %) as a white solid. Method 2: JAB7161 -32- [0127] Step A: 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile. Into a 3-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DMA (2.24 L), Pd(dppf)Cl2.CH2Cl2 (CAS [95464-05-4], 22.4 g, 0.1 eq.), 7-chloro-1H-1,6- naphthyridin-2-one (CAS [1345091-18-0], 224 g, 1240.37 mmol), zinc (16.22 g, 248.07 mmol, 0.2 eq.), and zinc cyanide (145.65 g, 1240.37 mmol, 1 eq.). The resulting solution was stirred for 4 h at 100 °C. The reaction mixture was cooled to room temperature. The solids were filtered out and washed with 2 x 100 mL of DMA. The reaction was then quenched by the addition of 5 L of water/ice. The solids were collected by filtration to afford the title compound (147 g, yield: 69 %) as a brown solid. [0128] Step B: 2-chloro-1,6-naphthyridine-7-carbonitrile. Into a 2-L 3-necked round- bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed phosphorus oxychloride (1.47 L) and 2-oxo-1,2-dihydro-1,6-naphthyridine-7-carbonitrile (147.00 g, 858.85 mmol). The resulting solution was stirred for 3 h at 80 °C. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then quenched by the addition of 4 L of water/ice. The resulting solution was extracted with 3 x 3 L of DCM, the organic layer was dried over Na2SO4, and concentrated to afford the title compound (58 g, yield: 36 %) as a yellow solid. [0129] Step C: tert-butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate. Into a 5-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DCM (1.74 L), 2-chloro-1,6-naphthyridine-7-carbonitrile (58 g, 305.90 mmol). This was followed by the dropwise addition over 30 min of DIBAL-H (1 N, 765 mL, 2.5 eq.) while stirring at -78 °C. The resulting solution was stirred for 2 h at -78 °C. To this was added potassium sodium tartrate (Rochelle Salt) (257 g, 1224 mmol, 4 eq.) at -78 °C. The resulting solution was stirred for 1 h at room temperature. This was followed by the addition of di-tert- butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 eq.). The resulting solution was stirred overnight at room temperature. The solids were filtered out and washed with 3 x 300 mL of DCM. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (EtOAc/petroleum ether 1/3 to 1/2) to afford the title compound (60.9 g, yield: 68 %) as a yellow solid. JAB7161 -33- Intermediate 3: methyl 3-((7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridin-2- yl)sulfonyl)propanoate. [0130] tert-Butyl ((2-chloro-1,6-naphthyridin-7-yl)methyl)carbamate (Intermediate 2) (1.03 g, 3.506 mmol) was added to a solution of sodium 1-methyl 3-sulfinopropanoate (CAS [90030-48-1], 1.22 g, 7.013 mmol, 2 eq.) and copper iodide (1.34 g, 7.013 mmol, 2 eq.) in DMSO (10 mL). The reaction mixture was stirred under nitrogen atmosphere at 110 ºC for 1 h. After cooling, the reaction mixture was diluted with EtOAc and washed with water containing aqueous NH₃ (1 mL). The organic layer was separated, dried over MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g column, gradient of EtOAc/heptane from 0/100 to 100/0) to give Intermediate 3 (801 mg, yield: 53 %) as an orange solid. Intermediate 4: (cis)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine. CIS [0131] Step A: (cis)-4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine.2,6- Dibromo-4-nitropyridine (CAS [175422-04-5], 5 g, 17.737 mmol) and 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 MgSO4, 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 the title compound (3.2 g, yield: 56 %) as an orange solid. JAB7161 -34- [0132] Step B: (cis)-4-(6-bromo-4-fluoropyridin-2-yl)-2,6-dimethylmorpholine. Tetramethylammonium fluoride (CAS [373-68-2], 663 mg, 7.117 mmol, 1.5 eq.) was added to a solution of (cis)-4-(6-bromo-4-nitropyridin-2-yl)-2,6-dimethylmorpholine (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred for 3 h at 65 ºC. 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 4 (1139 mg, yield: 81 %) as an orange solid. Intermediate 5: tert-butyl ((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)carbamate. CIS [0133] Intermediate 3 (950 mg, 2.32 mmol), Intermediate 4 (1006 mg, 3.48 mmol, 1.5 eq.), and K2CO3 (481 mg, 3.48 mmol, 1.5 eq.) were dissolved in 1,4-dioxane (24 mL) in a sealed tube under a nitrogen stream. Di-tert-butyl(methyl)phosphonium tetrafluoroborate (CAS [870777-30-3], 58 mg, 0.232 mmol, 0.1 eq.) and Pd(OAc)₂ (CAS [3375-31-3], 26 mg, 0.116 mmol, 0.05 eq.) were added and the reaction mixture was stirred at 150 ºC for 4 h. The mixture was cooled to room temperature, diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography over silica gel (25 g column, gradient of EtOAc/heptane from 0/100 to 100/0) to give Intermediate 5 (428 mg, yield: 39 %) as a yellow solid. Intermediate 6: (2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6- naphthyridin-7-yl)methanamine. JAB7161 -35- CIS [0134] Intermediate 5 (428 mg, 0.906 mmol) was dissolved in a solution of HCl (4 M in 1,4-dioxane, 2.27 mL, 9.063 mmol, 10 eq.) and 1,4-dioxane (40 mL) and the reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue was triturated in Et₂O to yield Intermediate 6 (HCl salt, 406 mg, quantitative) as an orange solid. Intermediate 7: 3-chloro-5-((difluoromethyl)sulfonyl)benzoic acid. [0135] Step A: methyl 3-chloro-5-((3,3,3-trifluoro-2-oxopropyl)sulfonyl)benzoate. A homogeneous solution of methyl 3-chloro-5-(methylsulfonyl)benzoate (CAS [151104-62-0], 6.541 g, 26.302 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS [407-38-5], 7.0 mL, 52.273 mmol) in dry THF (200 mL) was cooled to -78 °C under a nitrogen atmosphere and treated dropwise with LiHMDS (CAS [4039-32-1], 40 mL, 40 mmol, 1 M in THF). After stirring at -78 °C for 5 min, the reaction mixture was allowed to slowly warm to room temperature over the course of 1 h. The mixture was cooled to 0 °C and saturated aqueous NaHCO₃ was added. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSO4), filtered, concentrated, and dried under high vacuum to yield the title compound, used without further purification. [0136] Step B: methyl 3-chloro-5-((1,1,3,3,3-pentafluoro-2- oxopropyl)sulfonyl)benzoate. A solution of methyl 3-chloro-5-((3,3,3-trifluoro-2- oxopropyl)sulfonyl)benzoate (10.29 g) in ACN (200 mL) was cooled to 0 °C and treated with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS [140681-55-6], 24.223 g, 68.376 mmol) in one portion. The reaction mixture was stirred at 60 °C for 40 min. After cooling, the mixture was concentrated and the crude material was suspended in EtOAc (100 mL), sonicated to break up all particulates, filtered through Celite®, and concentrated to yield the title compound which was used directly in the next step without further purification. [0137] Step C: methyl 3-chloro-5-((difluoromethyl)sulfonyl)benzoate. A solution of methyl 3-chloro-5-((1,1,3,3,3-pentafluoro-2-oxopropyl)sulfonyl)benzoate in THF/H₂O (10/1, 220 mL) was treated with DIPEA (9.0 mL) and was stirred at room temperature for 1.5 h. The JAB7161 -36- reaction mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated to yield the title compound (6.85 g, yield: 88 % over 3 steps) as a pale yellow solid, used without further purification. [0138] Step D: 3-chloro-5-((difluoromethyl)sulfonyl)benzoic acid. A solution of methyl 3-chloro-5-((difluoromethyl)sulfonyl)benzoate (6.85 g, 24.063 mmol) in THF (100 mL) and water (100 mL) was cooled to 0 °C and treated with LiOH (0.85 g, 35.493 mmol). After stirring at 0 °C for 1 h, the reaction was quenched by addition of HCl (30 mL, 30 mmol, 1 M in H₂O). The reaction mixture was diluted with EtOAc (300 mL) and washed twice with brine. The organic layer was dried (MgSO4), filtered, and concentrated to yield Intermediate 7 (6.08 g, yield: 93 %) as a pale yellow solid, used without further purification. Compound 1: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,6- naphthyridin-7-yl)methyl)-3-(1,1,2,2-tetrafluoroethoxy)benzamide. [0139] 1-Propanephosphonic anhydride solution (CAS [68957-94-8], 50 % solution in EtOAc, 177 µL, 0.297 mmol, 1.3 eq.) was added to a suspension of Intermediate 6 (107 mg, 0.228 mmol) and Intermediate 7 (74 mg, 0.274 mmol, 1.2 eq.) in dry DCM (5 mL) at room temperature. Triethylamine (159 µL, 1.142 mmol, 5 eq.) was then added dropwise to the suspension. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: AcOEt/EtOH 3/1:heptanes from 0:100 to 80:20) to give Compound 1 (93 mg, yield: 66 %) as a yellow solid, dried under vacuum at 45 °C. Example B: Analytical characterization methods of Intermediates and Compound NMR [0140] 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 JAB7161 -37- out using a Bruker Avance III 400 spectrometer, using internal deuterium lock and equipped with reverse double-resonance (1H, 13C, SEI) probe head with z gradients and operating at 400 MHz for the proton. Experiments were performed at ambient temperature (298.6 K), unless otherwise mentioned. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Table 2: 1H NMR Results. Cmpd NMR peaks list ID 1H NMR (400 MHz, DMSO-d6) ^ (ppm) 9.77 (t, 1H, J=5.8 Hz), 9.43 (s, 1H), 8.7- 1 8.7 (m, 1H), 8.61 (d, 1H, J=8.6 Hz), 8.59 (t, 1H, J=1.7 Hz), 8.50 (t, 1H, J=1.4 Hz), 8.22 (t, 1H, J=1.8 Hz), 7.91 (s, 1H), 7.65 (dd, 1H, J=1.9, 9.6 Hz), 7.44 (t, 1H, J=51.9 Hz), 6.90 (dd, 1H, J=1.9, 12.4 Hz), 4.84 (d, 2H, J=5.7 Hz), 4.34 (br d, 2H, J=11.9 Hz), 3.6-3.7 (m, 2H), 2.5-2.6 (m, 2H), 1.21 (d, 6H, J=6.2 Hz) LC-MS LCMS General procedure The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time…) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+ (protonated molecule) and/or [M-H]- (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]-, etc). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “DAD” Diode Array Detector, ”HSS” High Strength silica. LCMS Method Codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes): JAB7161 -38- Table 3: LC-MS Methods. Method Instrument column mobile gradient Flow Run Code phase ------- time Col T A: 0.1% Waters: From 100 % A Waters :BE NH4HCO3 Acquity® to 5 % A in 2.10 0.6 1 H in 95 % UPLC® - min, to 0 % A in ------- 3.5 (1.8 µm, 2.1 H₂O + 5 % DAD and 0.9min, to 5 % A 55 * 100 mm) CH3CN SQD in 0.5 min B: CH3CN Table 4: LCMS Results (RT means retention time, in min) Cmpd ID Molecular LCMS results Weight 1 619.12 confirms the MW (RT: 2.28, [M+H]+ 620, LCMS Method 1) Example C: Pharmacological Assays [0141] 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 GloTM 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: [0142] 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 MgCl₂ (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 JAB7161 -39- 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 μM ATP and 2.5 nM Biotin-GatC2 nucleosomes (Epicypher, cat# 16- 4112). [0143] The compound dissolved in DMSO or vehicle controls and 3 µL 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 µL 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 µL of ADP-GloTM reagent, supplemented with 14.5 mM MgCl₂ and 0.1% CHAPS (G Biosciences, cta# DG097), was added. Then, plates were centrifuged for 1 min at 1000 rpm and incubated for 60 minutes at room temperature. Ultimately, 6 µL 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. [0144] Results (indicated as IC50, in µM) obtained from testing the compounds of the present disclosure in the above-described assays are indicated in the Table 5 below. Table 5: Biochemical Assay Results. Cmpd # SMARCA2 ADP-Glo IC₅₀ (nM) SMARCA4 ADP-Glo IC₅₀ (nM) 1 0.87 4.9 Example D: Prophetic formulations [0145] “Active ingredient” (a.i.) as used throughout these examples relates to the compound of the present invention, including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt thereof. 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 JAB7161 -40- 2. Suspension An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml. 3. Injectable A parenteral composition is prepared by stirring 1.5 % (weight/volume) of active ingredient in 0.9 % NaCl solution or in 10 % by volume propylene glycol in water. 4. Ointment Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g White petroleum 15 g Water ad 100 g

Claims

JAB7161 -41- CLAIMS 1. A compound of the formula, , and pharmaceutically acceptable salts thereof. 2. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1; and at least one pharmaceutically acceptable excipient. 3. A compound according to any one of claims 1 to 2 for use in therapy. 4. A compound according to any one of claims 1 to 2 for use in the treatment of a SMARCA4 deficient cancer. 5. The compound for the use of claim 4, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC). 6. A compound according to any one of claims 1 to 2 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein. 7. The compound for the use of claim 6, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC). 8. Use of a compound as defined in any one of claims 1 to 2 for the manufacture of a medicament for the treatment of cancer or NSCLC. 9. 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 2. 10. 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 2. 11. The method of claim 10, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC. 12. 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 2. JAB7161 -42- 13. The method of claim 12, wherein the disease or condition is selected from a cancer or NSCLC. 14. The method of any one of claims 10 to 13, wherein the subject is a mammal.