SMARCA2 inhibitors useful for treating SMARCA4-deficient cancers

Abstract

The present invention relates to a pharmaceutical compound and a pharmaceutical composition comprising the compound, a process for preparing the compound, the use of the compound as an inhibitor of the SMARCA2 protein, and its use in the treatment of SMARCA4-deficient cancers, such as SMARCA4-deficient non-small cell lung cancer (NSCLC). [Case 1] TIFF2026522022000027.tif25128

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical compound and a pharmaceutical composition comprising the compound, a process for preparing the compound, the use of the compound as an inhibitor of the SMARCA2 protein, and its use in the treatment of SMARCA4-deficient cancers, such as SMARCA4-deficient non-small cell lung cancer (NSCLC). [Background technology]

[0002] Switch / Sucrose Non-Fermentable (SWI / SNF), also known as the BAF complex, is a multi-subunit complex that regulates color 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 regulatory subunits ATP hydrolysis to perturbations of histone-DNA contacts, thereby providing access points to transcription factors and congeneral DNA elements that promote gene activation and repression.

[0003] Mutations in the genes encoding 20 standard SWI / SNF subunits are observed in nearly 20% of all cancers, with the highest frequency mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, and clear cell carcinomas of the esophagus and kidney. Despite their high degree of homology and presumed overlapping functions, SMARCA2 and SMARCA4 have been reported to have different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is rare in tumorigenesis. Indeed, numerous types of cancer, including lung cancer (such as non-small cell lung cancer or NSCLC), have been shown to be SMARCA4-related (e.g., cancers with SMARCA4 mutations or SMARCA4 deficiencies, e.g., lack of expression).

[0004] SMARCA2 has been demonstrated as one of the most important genes in SMARCA4-related or SMARCA4-mutated cancer cell lines. This is because SMARCA4-deficient patient populations or cells are exclusively dependent on SMARCA2 activity; that is, there is greater uptake of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Therefore, SMARCA2 can be targeted in SMARCA4-related / deficient cancers. The simultaneous occurrence of deficiencies in the expression of two (or more) genes that lead to cell death is known as synthetic lethality. Therefore, synthetic lethality can be utilized in the treatment of certain SMARCA2 / SMARCA4-related cancers.

[0005] There is a continuing need for effective treatments for diseases treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, nonspecific effects and the inability to selectively target and modulate SMARCA2 remain obstacles to the development of effective treatments. Therefore, small molecule therapies targeting SMARCA2 are highly valuable.

[0006] The object of the present invention is to provide a compound that is more selective for SMARCA2 than for SMARCA4.

[0007] The object of the present invention is to provide a SMARCA2 inhibitor effective for the treatment of SMARCA4-deficient cancer.

[0008] The object of the present invention is to provide a SMARCA2 inhibitor effective for the treatment of SMARCA4-deficient NSCLC.

Summary of the Invention

Means for Solving the Problems

[0009] Embodiments of the present invention relate to the specific use and method 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 regulatory properties as described in the claims, and pharmaceutical compositions containing this compound, the use of the compound as an inhibitor of the SMARCA2 protein, and a method for treating SMARCA4-deficient cancer or use in the treatment of SMARCA4-deficient cancer.

[0010] Additional embodiments, features, and advantages of the present invention will become apparent from the following "Modes for Carrying Out the Invention" and through the practice of the present invention.

[0011] Embodiments of the present invention relate to a compound of the formula

[0012]

Chemical formula

[0013] Additional embodiments of the present invention include a method for treating cancer or non-small-cell lung carcinoma (NSCLC) in a subject, comprising administering an effective amount of the pharmaceutical composition, or the use of a pharmaceutical composition for treating cancer or non-small-cell lung carcinoma (NSCLC), or a pharmaceutical composition for such use, comprising a compound of the present invention, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of the compound, and at least one pharmaceutically acceptable additive.

[0014] In some embodiments, such a pharmaceutical composition comprises 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 the compound, or at least one pharmaceutically active metabolite, and at least one pharmaceutically acceptable additive.

[0015] Embedding by reference All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referenced herein are incorporated by reference to the same extent that each individual publication, patent, patent application, or published nucleotide and amino acid sequence is specifically and individually indicated as being incorporated by reference. [Modes for carrying out the invention]

[0016] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood in relation to the subject matter claimed. Where URLs or other such identifiers or addresses are referenced, it is understood that such identifiers may change, and certain information on the Internet may shift, but equivalent information can be found by searching the Internet. References to these are evidence of the existence and public dissemination of such information.

[0017] Please understand that the general description above and the detailed description below are illustrative and descriptive only and do not limit the subject matter to which the claims are made.

[0018] In this application, unless otherwise specifically stated, the use of the singular form includes the plural. Note that, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple objects unless otherwise clearly indicated by the surrounding context. In this application, unless otherwise specifically stated, the use of "or" means "and / or."

[0019] When a value is expressed as an approximation using the antecedent “about,” it should 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 stated value, including the endpoints. For example, the phrase “about 8” comprehensively refers to values ​​from 7.2 to 8.8, and as another example, the phrase “about 8%” comprehensively refers to values ​​from 7.2% to 8.8%. All ranges, where present, are comprehensive and combinable. For example, when listing the range “1 to 5,” the listed range should be interpreted as including ranges such as “1 to 4,” “1 to 3,” “1 to 2,” “1 to 2 and 4 to 5,” and “1 to 3 and 5.” Furthermore, where a list of substitutes is explicitly provided, such a list may also include embodiments in which any of the substitutes may be excluded. For example, when describing the range “1 to 5,” such description may support situations in which 1, 2, 3, 4, or 5 is excluded. Therefore, the statement "1-5" may support the interpretation of "1 and 3-5, but not 2" or simply "2 is not included."

[0020] Some of the quantitative expressions given herein are not modified by the term “approximately.” Whether or not the term “approximately” is explicitly used, all quantities shown herein mean the actual values ​​shown, and are understood to also mean approximations of such shown values ​​that can be reasonably estimated based on the ordinary skill in the art, including approximations of such shown values ​​based on experimental and / or measurement conditions and permissible errors.

[0021] As used herein, the expression "one or more" means, whenever possible, at least one, for example, one, two, three, four, five or more, depending on the context.

[0022] Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limited to these.

[0023] The chapter headings used herein are for structural purposes only and should not be interpreted as limiting the subjects described.

[0024] The standard definitions of chemical terms are found in Carey and Sundberg's "Advanced Organic Chemistry 4". th This can be found in references including, but not limited to, "Ed." Vols. A (2000) and B (2001), Plenum Press, New York.

[0025] Unless otherwise specified, the nomenclature, experimental procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, and pharmaceutical and pharmaceutical chemistry described herein are recognized in the art. Standard methods can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, as well as for patient treatment. Standard methods can be used for recombinant DNA and oligonucleotide synthesis, as well as for tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques can be carried out, for example, using kits specified by the manufacturer, or as commonly achieved in the art, or as described herein. The aforementioned techniques and procedures can generally be carried out by conventional methods, as described in the various general and more specific references cited and discussed throughout this specification.

[0026] The methods and compositions described herein are not limited to the specific methodologies, protocols, cell lines, constructs, and reagents described herein, and should therefore be understood to be subject to change. Furthermore, the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit the scope of the methods, compounds, and compositions described herein.

[0027] The terms "optional" or "optionally" mean that the event described after them may or may not occur. This term encompasses both cases where the event occurs and cases where it does not.

[0028] In the compounds disclosed herein, in the depicted formula, * The carbon atom indicated by " is a chiral center. * When a carbon atom is indicated as "(S)", it means it is a pure enantiomer, but it is unclear whether it is an R or S enantiomer. Similarly, when a carbon atom is indicated as "(S * When indicated by )", it means it is a pure enantiomer, but it is unclear whether it is an R or S enantiomer.

[0029] The terms "bond" or "single bond" refer to a chemical bond between two atoms, or a chemical bond between two parts when the atoms linked by the bond are considered part of a larger substructure.

[0030] The term "part" refers to a specific segment or functional group of a molecule. Chemical parts are often perceived as chemical entities embedded within or attached to a molecule.

[0031] As used herein, the term “therapeutic dose” means the amount of active compound or medicinal product that, when administered to a mammal in need, is effective in at least partially improving or at least partially preventing the disease, disorder, or condition described herein.

[0032] As used herein, the term “composition” is intended to encompass products containing a particular component in a specific amount, as well as any products resulting directly or indirectly from a combination of a particular amount of a particular component.

[0033] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0034] As used herein, the term “antagonist” refers to a small molecule drug that binds to a receptor and subsequently reduces the receptor’s agonist-induced transcriptional activity.

[0035] As used herein, the term “agonist” refers to a small molecule drug that binds to a receptor and subsequently increases receptor transcriptional activity in the absence of a known agonist.

[0036] As used herein, the term “inverse agonist” refers to a small molecule drug that binds to a receptor and subsequently reduces the baseline level of receptor transcriptional activity present in the absence of a known agonist.

[0037] As used herein, the term “modulate” means to interact with a target directly or indirectly in such a way as to alter its activity, including, for example, enhancing, inhibiting, limiting, or prolonging the activity of the target.

[0038] The terms “subject” or “patient” encompass 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, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human. Those skilled in the art will recognize that a therapy that reduces the severity of a condition in one species of mammal may predict the effect of that therapy in another species of mammal.

[0039] The terms “treat,” “treating,” or “treatment,” as used herein, include alleviating, reducing or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, for example, stopping the onset of a disease or condition, reducing a disease or condition, causing a regression of a disease or condition, reducing a condition caused by a disease or condition, or preventing and / or therapeutically cessating the symptoms of a disease or condition.

[0040] "Proliferative disorders" refer to diseases resulting from abnormal growth or expansion due to cell proliferation. Proliferative disorders may be associated with: 1) pathological proliferation of cells that are normally quiescent; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); or 4) pathological angiogenesis, such as in proliferative retinopathy and tumor metastasis. Exemplary proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

[0041] The terms “neoplasm” and “tumor” are used interchangeably herein and refer to an abnormal mass of tissue whose growth exceeds and does not coordinate with the growth of normal tissue. Neoplasms or tumors may be “benign” or “malignant” depending on the following characteristics: degree of cellular differentiation (including morphology and function), growth rate, local invasion, and metastasis. “Benign neoplasms” are generally highly differentiated, grow more slowly than malignant neoplasms, and remain localized to the site of origin. In addition, benign neoplasms do not have the ability to invade, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipomas, chondromes, adenomas, filamentous fibromas, senile angiomas, seborrheic keratosis, lentigo, and sebaceous gland hyperplasia. In some cases, certain “benign” tumors may later develop into malignant neoplasms, which may be due to additional genetic changes in a subpopulation of neoplastic cells in the tumor; these tumors are called “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, "malignant neoplasms" are generally poorly differentiated (anaplastic) and characterized by rapid growth accompanied by progressive invasion, infiltration, and destruction of surrounding tissues. Furthermore, malignant neoplasms generally have the ability to metastasize to distant sites.

[0042] As used herein, the term "cancer" refers to a malignant neoplasm.

[0043] The term "angiogenesis" refers to the formation and growth of new blood vessels. Normal angiogenesis occurs in a healthy body for wound healing and restoring blood flow to damaged tissue. A healthy body controls angiogenesis through several means, such as angiogenic growth factors and angiogenic inhibitors. Many pathological conditions, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal angiogenesis (i.e., increased or excessive). Abnormal angiogenesis refers to angiogenesis that is greater than that in a normal body, especially in adults unrelated to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that nourish diseased tissue and / or destroy normal tissue, and in the case of cancer, new blood vessels can allow tumor cells to escape into the circulatory system and remain in other organs (tumor metastasis).

[0044] The term “biological specimen” refers to any specimen containing tissue specimens (such as tissue sections and needle biopsies); cell specimens (e.g., cytological smears (e.g., Pap or blood smears) or cell specimens obtained by microdissection); whole organism specimens (e.g., yeast or bacterial specimens); or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and separating their components by centrifugation or other means). Other examples of biological specimens include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (e.g., cheek swabs), or any substance containing biomolecules derived from the first biological specimen. Biological specimens also include transgenic biological specimens such as transgenic oocytes, spermatids, blastocysts, embryos, fetuses, donor cells, or cell nuclei.

[0045] Isomers, salts, N-oxides, isotope-labeled derivatives In this specification, before and after this point, "3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide", "3-chloro-5-((difluoromethyl)sulfonyl)-N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)benzamide", formula

[0046] [ka] The terms "compounds of this disclosure or / or the present invention," "compounds presented herein," or similar terms or expressions, mean that they include their addition salts and stereoisomers.

[0047] In certain embodiments, the compounds presented herein have one or more stereocenters, each independently existing in either an R or S configuration. The compounds presented herein include all diastereomers, enantiomers, atropisomers, and epimer forms, as well as suitable mixtures thereof. Stereoiomers are obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatography column. In some embodiments, the compounds of the disclosure are used as single enantiomers. In some embodiments, the compounds of the disclosure are used as racemic mixtures. In some embodiments, the compounds of the disclosure have rotational hindrance around a single bond resulting in atropisomers.

[0048] Under certain circumstances, compounds may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0049] To avoid misunderstanding, a compound may exist in one of several geometric isomers or tautomers, and if only one is specifically described or shown, all others are nevertheless encompassed. Examples of tautomers include, for example, the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / endiamine, nitroso / oxime, thioketone / enthiol, and nitro / ac-nitro, such as the keto, enol, and enolate forms.

[0050] [ka]

[0051] Such forms are intended to be included within the range of compounds presented herein, to the extent that they exist. Thus, a single compound may exist in both stereoisomer and tautomer forms.

[0052] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers can 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 identified, for example, as "cis," this means that the two groups point in the same direction with respect to the plane of the ring. In the "trans" isomer, they point in opposite directions. The "cis" isomer of 2,6-dimethylmorpholine is illustrated below. Based on the relative positions of the two substituents, there is one possible relative configuration, regardless of whether they are on the same side or opposite side of the cyclic structure.

[0053] [ka]

[0054] for example,

[0055] [ka]

[0056] This disclosure includes, whenever chemically possible, enantiomers, atrop isomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof.

[0057] The meanings of all terms, namely enantiomer, atropisomer, diastereomer, racemate, E isomer, Z isomer, cis isomer, trans isomer, and mixtures thereof, are known to those skilled in the art.

[0058] The methods and formulations described herein involve the use of N-oxides (where appropriate), pharmaceutically acceptable salts, and combinations thereof of compounds having the structure presented herein and the same type of activity.

[0059] The salt forms of the compounds presented herein are typically pharmaceutically acceptable salts, examples of which are discussed in Berge et al. (1977) "Pharmaceutically Acceptable Salts", J.Pharm.Sci., Vol.66, pp.1-19. However, pharmaceutically unacceptable salts may also be prepared as intermediate forms and subsequently converted to pharmaceutically acceptable salts. For example, such pharmaceutically unacceptable salt forms, which may be useful in the purification or separation of the compounds of the present invention, also form part of the present invention.

[0060] Medicinally acceptable salts include pharmaceutically acceptable acid and base addition salts, and include therapeutically active, non-toxic acid and base addition salt forms that the compounds described herein can form.

[0061] The salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods, such as those described in "Pharmaceutical Salts: Properties, Selection, and Use," edited by P. Heinrich Stahl and Camille G. Wermuth, ISBN: 3-90639-026-8, hardcover, page 388, August 2002. Generally, such salts can be prepared by reacting the free acidic or basic form of these compounds with a suitable base or acid in water, an organic solvent, or a mixture thereof, typically using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. The compounds of the present invention may exist as monosaltes or disaltes, depending on the pKa of the acid in which the salt is formed.

[0062] Medicinally acceptable acid addition salts can be easily obtained by treating the salt form with a suitable inorganic acid in an anionic form (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) or an organic acid (e.g., acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid, etc.).

[0063] Suitable anions include, for example, acetate, 2,2-dichloroacetate, adipine, alginate, ascorbate (e.g., L-ascorbate), L-aspartate, benzenesulfonate, benzoate, 4-acetamidebenzoate, butanoate, bicarbonate, bicarbonate, bromide, (+)camphorate, camphor sulfonate, (+)-(1S)-camphor-10-sulfonate, calcium edetate, and camphor. Salts, caprinates, caproates, caprylates, carbonates, chlorides, cinnamic acid, citrates, cyclamates, dihydrochlorides, dodecyl sulfates, edetates, estates, esylates, ethane-1,2-disulfonates, ethanesulfonates, formate, fumarates, galactarates, gentisinates, glucoheptones, gluceptates, gluconates, D-gluconates, glucuronates (e.g., D-glucuronic acid), g Glutamate (e.g., L-glutamate), α-oxoglutarate, glycolate, glycolylarsanilate, hexylresorcinate, hippurate, hydravamin, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isethionate, lactate (e.g., (+)-L-lactate, (±)-DL-lactate), lactobionate, malate, (-)-L-malate, maleate, malonate, mandelate, (±)-DL-mandelate, mesylate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, naphthalene sulfonate (e.g., naphthalene-2-sulfonate), naphthalene-1,5-disulfonate, 1-hydroxy-2-naphthoate, naphthylate, nicotinate, nitrate, oleate, orotate, oxalate, oxalate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate / diphosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, diacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, theophylline salt, thiocyanate, toluenesulfonate (e.g., p-toluenesulfonate), tosylate, triethiodide, undecylenate, valeric acid, and acylated amino acids and cation exchange resins. Conversely, the above salt forms can be converted to the free base form by treatment with an appropriate base.,

[0064] The compounds of the present disclosure containing acidic protons may be converted to their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases in cationic form. Suitable basic salts are 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, and tromethamine; ammonium ions (i.e., NH4 + ), quaternary ammonium ions N(CH3)4 + , and substituted ammonium ions (e.g., NH3R + , NH2R2 + , NHR3 + , NR4 +This includes compounds formed from ) and compounds formed from metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. If the compounds described herein contain an amine functional group, this can form a quaternary ammonium salt by reaction with an alkylating agent, for example, according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the range of compounds presented herein.

[0065] Conversely, the salt form can be converted back to the free form by treatment with an appropriate acid.

[0066] In some embodiments, the sites on the compounds disclosed herein are susceptible to various metabolic reactions. Therefore, incorporating appropriate substituents at the sites of metabolic reactions reduces, minimizes, or eliminates metabolic pathways. In certain embodiments, suitable substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions are, to name just a few, halogens, deuterium, or alkyl groups.

[0067] The compounds of this disclosure include isotope-labeled compounds, i.e., compounds having one or more isotopic substitutions. These compounds are identical to those enumerated in the formulas and structures presented herein, but in practice, one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. References to specific elements include, within their scope, all isotopes of the element that exist naturally or are synthetically produced, either in natural abundance or in isotopic enrichment forms. For example, references to hydrogen include, within their scope... 1 H, 2 H(D), and 3 H(T) is included. Similarly, references to carbon and oxygen are within their respective ranges. 12 C, 13 C and 14 C, and 16 O and 18Each contains O. These isotopes may be radioactive or non-radioactive. In one embodiment, the compound does not contain radioactive isotopes. In another embodiment, the compound may contain one or more radioactive isotopes. Compounds containing such radioactive isotopes may be useful in diagnostic settings. The radiolabeled compounds described herein are 2 H, 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 It may contain radioactive isotopes selected from the group including Br. Preferably, the radioactive isotopes are 2 H, 3 H, 11 C, and 18 Selected from the group F. More preferably, the radioactive isotope is 2 It is H. In particular, deuterium compounds are intended to be included within the scope of the present invention. In some embodiments, the metabolic sites on the compounds described herein are deuterated.

[0068] Compound synthesis The synthesis of the compounds described herein is achieved by means of the chemical literature, by the methods described herein, or by a combination thereof. In addition, the solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the art include, for example, 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 4. th Ed.,(Wiley 1992);Carey and Sundberg,Advanced Organic Chemistry 4 th Ed.,Vols.A and B(Plenum 2000,2001), and Green and Wuts,Protective Groups in Organic Synthesis 3 rd The details are described in Ed., (Wiley 1999) (both of these documents are incorporated by reference to their disclosures). General methods for preparing the compounds disclosed herein may be derived from reactions and modified by using appropriate reagents and conditions to introduce the various parts found in the formulas provided herein.

[0069] The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, including but not limited to Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0070] In the reactions described herein, it may be necessary to protect reactive functional groups, such as hydroxyl groups, amino groups, imino groups, thio groups, or carboxyl groups, if desired in the final product, to avoid their undesirable involvement in the reaction. Protecting groups are used to block some or all of the reactive moieties, preventing such groups from participating in the chemical reaction until the protecting group is removed. Preferably, each protecting group can be removed by different means. Protecting groups that are cleaved under completely different reaction conditions satisfy different removal requirements.

[0071] Protecting groups can be removed by acids, bases, reducing conditions (e.g., hydrolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl can be used to protect carboxy and hydroxy-reactive moieties in the presence of amino groups protected by acid-unstable and hydrolytically removable Cbz groups and base-unstable Fmoc groups. Carboxylic acid and hydroxy-reactive moieties can be blocked by acid-unstable groups such as t-butyl carbamate, or by base-unstable groups such as methyl, ethyl, and acetyl, in the presence of amines blocked by carbamates that are stable to both acids and bases but hydrolytically removable.

[0072] The carboxylic acid and hydroxyl-reactive moieties may also be blocked with hydrolytically removable protecting groups, such as benzyl groups, while amine groups that can hydrogenate with acids may be blocked with base-unstable groups, such as acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethylene-oxycarbonyl (Fmoc). The carboxylic acid-reactive moieties may be protected by conversion to simple ester compounds, such as those exemplified herein, including conversion to alkyl esters, or they may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-unstable silylcarbamates.

[0073] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups because the former are stable and can then be removed with a metal or π-acid catalyst. For example, allyl-blocked carboxylic acids can be protected in the presence of acid-unstable t-butyl carbamate or base-unstable amine acetate protecting groups, and Pd 0 Deprotection can be achieved using catalytic reactions. Another form of protecting group is a resin to which a compound or intermediate can be bound. As long as the residue is bound to the resin, its functional group is blocked and cannot react. Once released from the resin, the functional group becomes available for reaction.

[0074] Typically, blocking / protecting groups can be selected from the following:

[0075] [ka]

[0076] A detailed description of other protecting groups, as well as techniques applicable to the fabrication and removal of protecting groups, is provided in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, Hoboken, New Jersey, 2007, which is incorporated herein by reference for such disclosures.

[0077] General synthesis route Scheme 1

[0078] [ka]

[0079] 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 copper(I) iodide, a suitable ligand such as (L)-proline, a suitable solvent such as DMSO, and at a suitable temperature such as 100°C to obtain methylsulfonylbenzoyl ester (II). The methylsulfonylbenzoyl ester of formula (II) can be converted to the intermediate of formula (III) by reaction with 2,2,2-trifluoroethyltrifluoroacetate (CAS[407-38-5]) in the presence of a suitable base such as LiHMDS, a suitable solvent such as THF, and at a suitable temperature such as -78°C. The intermediate of formula (III) can be fluorinated in a suitable solvent, such as ACN, at a suitable temperature, such as 60°C, with a suitable fluorinating agent, such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate (CAS[140681-55-6])) to obtain the intermediate of formula (IV). The intermediate of formula (IV) can be converted to the ester of formula (V) by reacting it with a suitable base, such as DIPEA, in a suitable solvent, such as a mixture of THF and water, at a suitable temperature, such as room temperature.

[0080] Alternatively, a commercially available ester of formula (I) can be converted to the thioacetate of formula (VI) by reacting it with potassium thioacetate in a suitable solvent, such as toluene or a mixture of toluene and acetone, in the presence of a suitable catalyst, such as Pd2(dba)3 (CAS[51364-51-3]), a suitable ligand, such as Xantphos (CAS[161265-03-8]), and at a suitable temperature, such as 70°C. The thioacetate of formula (VI) can then be deacetylated in a suitable solvent, such as methanol, and at a suitable temperature, such as room temperature, in the presence of a suitable base, such as potassium carbonate, to obtain the thiol of formula (VII). The 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 DMF, and at a suitable temperature such as 95°C, to obtain the difluoromethyl sulfide of formula (VIII). The difluoromethyl sulfide of formula (VIII) can be oxidized by reaction with oxone (CAS[70693-62-8]) in a suitable solvent such as a mixture of methanol and water, and at a suitable temperature such as 0°C or room temperature, to obtain the ester of formula (V).

[0081] According to Scheme 1, the ester compound of formula (V) can be reacted under basic conditions such as NaOH, LiOH, or KOH in a suitable solvent such as methanol (MeOH), ethanol (EtOH), THF, ACN, H2O, or a mixture thereof, at room temperature or a suitable temperature such as 60°C to 80°C, to obtain the acid compound of formula (IX).

[0082] Scheme 2

[0083] [ka]

[0084] According to Scheme 2, the compound of formula (XI) can be prepared by reacting a commercially available or synthetically obtainable compound of formula (X) (wherein Hal is a suitable halogen such as Br (bromine)) with a boronic acid or boronic acid ester, such as potassium trifluoro(vinyl)borate, in a metal-mediated coupling reaction over a period of 12 to 18 hours at a temperature range of 70°C to 100°C in a suitable solvent such as THF, 1,4-dioxane, toluene, water, or a mixture thereof, in the presence of a catalyst such as bis(triphenylphosphine)palladium(II) dichloride and a base such as Cs2CO3. For example, the compound of formula (XII) can be obtained by halogenating the compound of formula (XI) using a chlorinating agent such as POCl3 at a temperature range of 70 to 90°C in a suitable solvent such as 1,2-dichloroethane or chloroform. The compound of formula (XII) can be oxidized to the compound of formula (XIII) by treatment with osmium tetroxide and NaIO4 in a suitable solvent such as 1,4-dioxane, THF, water, or a mixture thereof. The compound of formula (XIII) can be reduced to the compound of formula (XIV) in a suitable solvent such as MeOH or EtOH using a suitable reducing agent such as NaBH4. The subsequent mesylation of the hydroxy compound of formula (XIV) can be achieved in a suitable solvent such as DCM using a suitable base such as methanesulfonyl chloride (mesyl chloride) or triethylamine (TEA) to obtain the compound of formula (XV). The azide compound of formula (XVI) can be prepared from the compound of formula (XV) using azide conditions known to those skilled in the art. In a preferred method, the compound of formula (XV) can be reacted with sodium azide in a suitable solvent such as DMF at room temperature for 18 hours to obtain the compound of formula (XVI). The compound of formula (XVII) can be prepared by reacting the intermediate of formula (XVI) with a suitable reducing agent, such as triphenylphosphine, in a suitable solvent, such as THF, at a suitable temperature, such as room temperature.The compound of formula (XVII) can be protected with a Boc protecting group by reacting the compound of formula (XVII) with Boc anhydride at room temperature for about 4-7 hours under conditions known to those skilled in the art, for example, in the presence of a suitable base such as Et3N, and P. 1 We can provide compounds of formula (XVIII) where is Boc.

[0085] Scheme 3

[0086] [ka]

[0087] According to Scheme 3, the compound of formula (X) (wherein Hal is Cl) can be subjected to palladium-catalyzed cyanation using conditions known to those skilled in the art. For example, the compound of formula (X) can be reacted with a palladium catalyst such as Pd(dppf)Cl2·CH2Cl2 and zinc cyanide as a nucleophile in a suitable solvent such as DMA or N,N-dimethylformamide (DMF) at a temperature of about 100°C for 2 to 6 hours to obtain the cyano compound of formula (XIX). The halogenation of the compound of formula (XIX) can be achieved using previously described methods, such as using POCl3, to obtain the compound of formula (XX). The compound of formula (XX) can be reduced using a suitable reducing agent such as DIBAL-H in a suitable solvent such as DCM or toluene at a temperature from -78°C to room temperature, and then reacted with a suitable protecting group precursor such as Boc anhydride in a suitable solvent such as DCM at a suitable temperature such as room temperature to obtain the compound of formula (XVIII).

[0088] Scheme 4

[0089] [ka]

[0090] According to Scheme 4, the compound of formula (XVIII) (wherein R 3H is H, Hal is Cl, and P 1 (where Boc is the compound) can be reacted with a suitable sulfinate, such as sodium 1-methyl-3-sulfinopropanoate (CAS[90030-48-1]), in the presence of a suitable catalyst, such as CuI, in a suitable solvent, such as DMSO, at a suitable temperature, such as 110°C, to obtain the compound of formula (XXI). The compound of formula (XXI) can be obtained from commercially available or synthetically available appropriately substituted 2-halogeno-R 5 For example, (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine can be reacted with 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 K2CO3, in the presence of a suitable catalyst such as Pd(OAc)2, in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as 150°C to obtain the compound of formula (XXII). Deprotection of the Boc protecting group on the compound of formula (XXII) can be achieved using acidic conditions known to those skilled in the art or the aforementioned acidic conditions to obtain the compound of formula (XXIII).

[0091] Scheme 5

[0092] [ka]

[0093] According to Scheme 5, the compound of formula (XXIII) can be reacted with a suitable carboxylic acid using conventional amide bond formation techniques such as coupling reactions, which are well known to those skilled in the art. For example, R in the formula 5Compounds of formula (XXIII), where is 6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl, can be reacted with a suitable carboxylic acid of formula (IX) in the presence of a suitable base such as N-ethyldiisopropylamine (DIPEA) or triethylamine (TEA), in a suitable solvent such as DCM, THF, or DFM, at a suitable temperature such as 0°C to room temperature, to obtain compounds of formula (I).

[0094] Alternatively, the compound of formula (I) can be prepared by reacting the compound of formula (XXXVIII) with a suitable activated form of a carboxylic acid, such as acyl chloride, or its corresponding anhydride, in the presence of a suitable base, such as DIPEA or Et3N, in a suitable solvent, such as DCM or DMF, at a suitable temperature, such as 0°C to room temperature.

[0095] Those skilled in the art will understand that another series of chemical reactions shown in the following scheme may also yield the desired compound.

[0096] Those skilled in the art will understand that the intermediates and final compounds shown in the following scheme can be further functionalized according to methods well known to those skilled in the art.

[0097] Those skilled in the art will recognize that in some cases, it may be recommended or necessary to carry out the reactions described in the scheme under an inert atmosphere, such as an N2 gas atmosphere.

[0098] It will be apparent to those skilled in the art that cooling of the reaction mixture may be necessary before the reaction (meaning a series of operations necessary to isolate and purify the products of the chemical reaction, such as quenching, column chromatography, or extraction).

[0099] Those skilled in the art will understand that heating a reaction mixture under stirring can enhance the reaction outcome. In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0100] The compounds of the present invention prepared by the processes described herein can be synthesized in the form of enantiomer mixtures, particularly racemic mixtures of enantiomers, which can be separated from each other by separation procedures known in the art. Racemic compounds containing a basic nitrogen atom can be converted to the corresponding diastereomer salt form by reaction with a suitable chiral acid. The diastereomer salt form is then separated, for example, by selective or fractional crystallization, and the enantiomer is liberated therefrom by alkali. Alternative methods for separating the enantiomer form and its pharmaceutically acceptable addition salt include liquid chromatography using a chiral stationary phase, for example, by supercritical fluid chromatography. The pure stereochemical isomer form may also be derived from the corresponding pure stereochemical isomer form of a suitable starting material, provided that the reaction occurs stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods will advantageously use enantiomerically pure starting materials.

[0101] In all of these preparations, the reaction product can be isolated from the reaction medium and, if necessary, further purified according to methodologies commonly known in the art (e.g., extraction, crystallization, trituration, and chromatography). The purity of the reaction product can be determined according to methods commonly known in the art, such as LC-MS, TLC, and HPLC.

[0102] Treatment methods and medical uses, pharmaceutical compositions, and combinations The present invention also provides methods for treating or preventing proliferative disorders (e.g., cancer, benign neoplasms, angiogenesis) in a subject. Such methods include administering an effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt, tautomer, stereoisomer, or isotope-labeled derivative thereof, or a pharmaceutical composition thereof, to a subject requiring administration.

[0103] The subjects being treated are mammals. The subjects may be humans. The subjects may be livestock such as dogs, cats, cattle, pigs, horses, sheep, or goats. The subjects may be companion animals such as dogs or cats. The subjects may be domesticated animals such as cattle, pigs, horses, sheep, or goats. The subjects may be zoo animals. The subjects may be research animals such as rodents, dogs, or non-human primates. The subjects may be non-human transgenic animals such as transgenic mice or transgenic pigs.

[0104] Proliferative disorders treated or prevented using the compounds described herein are typically associated with abnormal activity of SMARCA2. Abnormal activity of SMARCA2 may be elevated and / or inappropriate (e.g., abnormal) activity of SMARCA2. In certain embodiments, SMARCA2 is not overexpressed, and its activity is elevated and / or inappropriate. In certain other embodiments, SMARCA2 is overexpressed, and its activity is elevated and / or inappropriate. The compounds of this disclosure, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotope-labeled derivatives, and compositions, may inhibit SMARCA2 activity and be useful for treating and / or preventing proliferative disorders.

[0105] Proliferative disorders may also be associated with the inhibition of apoptosis of cells in biological specimens or subjects. All types of biological specimens described herein or known in the art are intended to be within the scope of the present invention. Inhibition of SMARCA2 activity is expected to cause cytotoxicity through the induction of apoptosis. The compounds of this disclosure, as well as their pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions, may be able to induce apoptosis and thus may be useful in the treatment and / or prevention of proliferative disorders.

[0106] In one embodiment, the proliferative disorder treated or prevented using the compounds of the present disclosure is cancer.

[0107] The cells described herein may be abnormal cells. This method may be carried out in vitro or in vivo. The cells may be proliferative cells.

[0108] In another embodiment, the present invention provides a method for downregulating the expression of SMARCA2 in a biological sample or subject.

[0109] In yet another embodiment, the present invention provides compounds of the present disclosure, as well as pharmaceutically acceptable salts, tautomers, stereoisomers, isotope-labeled derivatives, and compositions thereof, for use in treating proliferative disorders in a subject. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used to inhibit cell growth. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used to induce apoptosis in cells. The compounds described herein, as well as their pharmaceutically acceptable salts and compositions, may be used to inhibit transcription.

[0110] Those skilled in the art will understand that a therapeutically effective amount of the compound of the present invention is sufficient to have therapeutic activity, and that this amount varies, among other things, depending on the type of disease, the concentration of the compound in the therapeutic formulation, and the patient's condition. 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 basis by the attending physician.

[0111] Those skilled in the art in treating such diseases may determine an effective therapeutic daily dose from the test results shown below. The effective therapeutic daily dose may be approximately 0.005 mg / kg to 50 mg / kg body weight. The amount of the compound according to the present invention, also referred to herein as the active ingredient, required to achieve a therapeutic effect may vary on a case-by-case basis, for example, depending on the specific compound, route of administration, age and condition of the recipient, and the specific disorder or disease being treated. The treatment method may also involve administering the active ingredient in a regimen of 1 to 4 doses per day. In these treatment methods, the compound according to the present invention is preferably formulated before administration. As described below herein, a suitable pharmaceutical formulation is prepared by known procedures using well-known and readily available ingredients.

[0112] While the active ingredient can be administered alone, it is preferable to provide it as part of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition comprising the compound according to the present invention together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be "acceptable" in the sense that it is compatible with the other components of the composition and is not harmful to its recipient.

[0113] The pharmaceutical compositions of the present invention are, for example, Gennaro et al. Remington's Pharmaceutical Sciences (18 thThese pharmaceutical compositions can be prepared by any method well known in the field of pharmacy, such as those described in (see, in particular, Part 8: Pharmaceutical preparations and their Manufacture) of Mack Publishing Company, 1990. A therapeutically effective amount of a specific compound in base form or salt form, as the active ingredient, is closely mixed and combined with a pharmaceutically acceptable carrier, and can take on a wide variety of forms depending on the form of formulation preferred for administration. These pharmaceutical compositions are preferably in unit dosage forms suitable for systemic administration, such as oral, transdermal, or parenteral administration; or preferably in topical administration, such as inhalation or nasal spray. For example, when preparing an oral dosage form composition, any of the usual pharmaceutical media can be used, such as water, glycol, oil, or alcohol in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions; or, in the case of powders, pills, capsules, and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, and disintegrants. Tablets and capsules are the most advantageous oral unit dosage forms because they are easy to administer; in this case, it is clear that a solid pharmaceutical carrier is used. In the case of parenteral compositions, the carrier usually contains at least a large portion of sterile water, but may also contain other components (e.g., to aid solubility). For example, an injectable solution may be prepared in which the carrier contains physiological saline, glucose solution, or a mixture of physiological saline and glucose solution. An injectable suspension may also be prepared, in which case a suitable liquid carrier, suspending agent, etc., may be used. In compositions suitable for transdermal administration, the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, optionally in combination with some suitable additive that does not cause significant adverse effects on the skin in small amounts. Such additives can facilitate administration to the skin and / or may be useful in preparing the desired composition. These compositions can be administered in various ways, for example, as transdermal patches, spot-on treatments, or ointments.

[0114] The above-mentioned pharmaceutical compositions are particularly advantageous when formulated as unit dosage forms to facilitate administration and ensure uniformity of the dosage. As used herein and in the claims, a unit dosage form means a physically separated unit suitable as a single dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, together with the necessary pharmacological carrier. Examples of such unit dosage forms include tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons, and multiple portions thereof.

[0115] The precise dosage and frequency of administration depend, as is well known to those skilled in the art, on the specific compound of the present invention used, the specific medical condition being treated, the severity of the condition being treated, the age, weight, sex, degree of disability and overall health of the particular patient, and any other medications the individual may be taking. Furthermore, it is evident that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or on the assessment of the physician prescribing the compound of the present invention.

[0116] The methods described herein may also include a further step of administering one or more additional pharmaceuticals in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition comprising such compound or a pharmaceutically acceptable salt thereof. Thus, combinations of the compound or composition of the present invention with additional pharmaceuticals may be useful for treating proliferative disorders that are resistant to treatment using additional pharmaceuticals without the compound or composition of the present invention.

[0117] Combination therapy includes administering a single drug formulation containing the compound according to the present invention and one or more additional therapeutic agents, as well as administering the compound according to the present invention and each additional therapeutic agent in its own separate drug formulation. For example, the compound and therapeutic agents according to the present invention may be administered together to the patient in a single oral composition such as a tablet or capsule, or each drug may be administered in a separate oral formulation.

[0118] Accordingly, one embodiment of the present invention relates to a product comprising a compound according to the present invention as a first active ingredient and one or more anticancer agents as further active ingredients, as a combination preparation for simultaneous, separate, or sequential use in the treatment of a patient suffering from cancer.

[0119] One or more other drugs and compounds according to the present invention may be administered simultaneously (e.g., separately or in a single composition) or sequentially in any order. In the latter case, the two or more compounds are administered for a period of time and in a quantity and manner sufficient to ensure that a favorable or synergistic effect is achieved. It will be understood that the preferred method and order of administration, as well as the respective dosages and regimens, for each component of the combination will depend on the specific other drugs and compounds of the present invention being administered, their routes of administration, the specific tumor being treated, and the specific host being treated. The optimal method and order of administration, as well as the dosages and regimens, can be readily determined by those skilled in the art using conventional methods and taking into account the information described herein.

[0120] The weight ratio of the compound according to the present invention to one or more other anticancer agents when administered in combination can be determined by those skilled in the art. The ratio, as well as the exact dosage and frequency of administration, depends, as is well known to those skilled in the art, on the specific compound according to the present invention and the other anticancer agents used, the specific condition being treated, the severity of the condition being treated, the age, weight, sex, diet, administration time and general physical condition of the specific patient, the mode of administration, and other medications the individual may take. Furthermore, it is evident that the effective daily dose may be increased or decreased depending on the response of the subject being treated and / or the assessment of the physician prescribing the compound according to the present invention. The specific weight ratio of the compound of formula (I) to another anticancer agent may range from 1 / 10 to 1 / 10, more specifically from 1 / 5 to 1 / 5, and even more specifically from 1 / 3 to 1 / 3. [Examples]

[0121] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. These examples and all references to the literature throughout this specification are incorporated herein by reference for all legal purposes provided herein. The starting materials and reagents used in the synthesis of the compounds described herein may be synthesized or obtained from commercial sources, including but not limited to Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0122] When the stereocenter is indicated by "RS," it means that a racemic mixture has been obtained.

[0123] For intermediates that may be used in the next reaction step as crude or partially purified intermediates, the theoretical molar amounts may be shown in the reaction protocol described below.

[0124] Below, "DCM" and "CH2Cl2" mean dichloromethane. "rt" means room temperature. "Boc" means tert-butoxycarbonyl. "CH3CN" and "ACN" mean acetonitrile. "MeOH" means methanol, "EtOH" means ethanol, and "iPrOH" means isopropanol. "DMF" means dimethylformamide. "iPrNH2" means isopropylamine. "SOCl2" means thionyl chloride. "Et3N" means triethylamine. "NH4OAc" means ammonium acetate, NH4OH means ammonium hydroxide, and "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 bisulfate. "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 time. "RM" means reaction mixture. "SFC" means supercritical fluid chromatography. "Bredereck's "Reagent" means tert-butoxybis(dimethylamino)methane. "AcOEt" means ethyl acetate. "K2CO3" means potassium carbonate. "MgSO4" means magnesium sulfate. "Boc2O" means di-tert-butyl decarbonate.

[0125] Example A: Preparation of intermediate and final compounds, and their characterization. Several methods for preparing the compounds of the present invention are shown in the following examples. Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification, or can be synthesized by those skilled in the art using well-known methods.

[0126] [Table 1]

[0127] As will be understood by those skilled in the art, compounds synthesized using the indicated protocol may contain residual solvent or small amounts of impurities.

[0128] Those skilled in the art will understand, even if not explicitly mentioned in the following experimental protocol, that typically, after column chromatography purification, the desired fraction is collected and the solvent is evaporated.

[0129] If the stereochemistry is not shown, this means that it is a mixture of stereoisomers, unless otherwise specified or evident from the context.

[0130] In obtaining the compounds and corresponding analytical data described in the following examples, the following experimental and analytical protocols were followed unless otherwise specified.

[0131] Unless otherwise specified, reaction mixtures were magnetically stirred at room temperature (rt) under a nitrogen atmosphere. When solutions were “dried,” they were generally dried with a drying agent such as Na2SO4 or MgSO4. When mixtures, solutions, and extracts were “concentrated,” they were typically concentrated in a rotary evaporator under reduced pressure.

[0132] High-performance liquid chromatography (HPLC) measurements were performed using the LC pump, diode array (DAD), or UV detector and column specified for each method. Additional detectors were included as needed (see the table of methods below). The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting adjustment parameters (e.g., scanning range, residence time, etc.) to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) of the compounds is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. The compounds were analyzed based on their experimental retention time (R t ) and ions are described. Unless otherwise specified in the data table, the reported molecular ions are [M+H] + (protonated molecules) and / or [MH] - This corresponds to a (deprotonated molecule). If a compound cannot be directly ionized, its adduct form is identified (i.e., [M+NH4]). + [M+HCOO] - (etc.). For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained with respect to the lowest isotopic mass. All results are obtained with experimental uncertainty generally associated with the methods used.

[0133] Some NMR experiments were performed using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with a z-gradient, operating at 500 MHz for protons and 125 MHz for carbon. Some NMR experiments were performed using a Bruker Avance III 400 spectrometer with internal deuterium locking and inverse double resonance with a z-gradient. 1 H, 13The experiment was conducted using a C,SEI) probe head, operating at 400 MHz for protons. Unless otherwise noted, the experiment was performed at ambient temperature (298.6 K). Chemical shifts (d) are reported in parts per million (ppm). J values ​​are expressed in Hz. The definitions of 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 = doublet of quartets, dp = doublet of pentets, td = triplet of doublets, tt = triplet of triplets, ddd = doublet of doublets, m = multiplet, br = broad. For compounds containing interchangeable protons, it will be understood that these protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectroscopy and the concentration of the compound in solution.

[0134] Preparation of intermediates For intermediates used in subsequent reaction steps, either as crude or partially purified intermediates, the molar amount of such intermediate in the subsequent reaction step may not be mentioned, or an estimated or theoretical molar amount of such intermediate in the subsequent reaction step may be indicated in the reaction protocol described below.

[0135] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0136] Intermediate 1: (2-chloro-1,6-naphthyridine-7-yl)methaneamine.

[0137] [ka]

[0138] Step A: 7-Vinyl-1,6-naphthyrizine-2(1H)-one. 7-Bromo-1,6-naphthyrizine-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 equivalents), bis(triphenylphosphine)palladium(II) chloride (CAS[13965-03-2], 434 mg, 0.619 mmol, 0.06 equivalents), and Cs2CO3 (10.077 g, 30.928 mmol, 3 equivalents) were dissolved in THF (40 mL) and water (10 mL) under a nitrogen atmosphere. The mixture was stirred at 80°C for 16 hours. After cooling, the reaction mixture was diluted with toluene and water was added. The layers were separated, the organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified by flash column chromatography (80 g, SiO2, toluene / heptane 10 / 90-100:0) to obtain the title compound (1150 mg, yield: 64%) as a white solid.

[0139] Step B: 2-Chloro-7-vinyl-1,6-naphthiridine. POCl3 (1.86 mL, 20.037 mmol, 3 equivalents) was added to a suspension of 7-vinyl-1,6-naphthiridine-2(1H)-one (1.15 g, 6.679 mmol) in 1,2-dichloroethane (34 mL). The mixture was stirred at 80°C for 16 hours. The mixture was diluted with aqueous Na2CO3 and SiO2. The layers were separated, and the aqueous layer was extracted with SiO2 (3×). The combined organic layers were dried over (MgSO4), filtered, and evaporated to obtain the title compound (1.16 g, yield: 90%) as an orange solid, which was used without further purification.

[0140] Step C: 2-Chloro-1,6-naphthiridine-7-carbaldehyde. 2-Chloro-7-vinyl-1,6-naphthiridine (1.16 g, 6.064 mmol) and 2,6-lutidine (1.41 mL, 12.128 mmol, 2 equivalents) were dissolved in water (6 mL) and 1,4-dioxane (23 mL). NaIO4 (5.19 g, 24.257 mmol, 4 equivalents) and OsO4 (38 mg, 0.152 mmol, 0.025 equivalents) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with saturated NaHCO3 aqueous solution and extracted several times with DCM. The combined organic layer was dried over MgSO4, filtered, and evaporated to obtain the title compound (820 mg, yield: 63%) as a dark brown solid, which was used without further purification.

[0141] Step D: (2-chloro-1,6-naphthirizine-7-yl)methanol. A solution of 2-chloro-1,6-naphthirizine-7-carbaldehyde (820 mg, 3.832 mmol) in EtOH (30 mL) was cooled to 0°C, and NaBH4 (72 mg, 1.916 mmol, 0.5 equivalents) was added. The reaction mixture was stirred at room temperature for 20 minutes. The mixture was diluted with water and extracted with siRNA. The organic layer was dried over (Na2SO4), filtered, and evaporated. The residue was purified by flash column chromatography (80 g SiO2, in DCM, DCM:DCM in DCM / MeOH (9:1) 0 / 100~20 / 80) to obtain the title compound (387 mg, yield: 51%) as a white solid.

[0142] Step E: (2-chloro-1,6-naphthirizin-7-yl)methylmethanesulfonate. Et3N (114 μL, 0.832 mmol, 1.2 equivalents) was added at room temperature to a solution of (2-chloro-1,6-naphthirizin-7-yl)methanol (135 mg, 0.694 mmol) in DCM (5 mL). MsCl (59 μL, 0.763 mmol, 1.1 equivalents) was then added gradually at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum to obtain the title compound (190 mg, yield: 95%) as a brown oily substance, which was used without further purification.

[0143] Step F: 7-(azidomethyl)-2-chloro-1,6-naphthiridine. Sodium azide (59 mg, 0.906 mmol, 1.3 equivalents) was added to a solution of (2-chloro-1,6-naphthiridine-7-yl)methylmethanesulfonate (190 mg, 0.697 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the title compound as a brown liquid. The product was used directly in the next step.

[0144] Step G: (2-chloro-1,6-naphthirizine-7-yl)methaneamine. Triphenylphosphine (252 mg, 0.963 mmol, 1.4 equivalents) was added to a solution of 7-(azidomethyl)-2-chloro-1,6-naphthirizine (151 mg, 0.688 mmol) in dry THF (5 mL). The mixture was stirred at room temperature for 1 hour. Additional triphenylphosphine (90 mg, 0.343 mmol, 0.5 equivalents) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (2 mL) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under vacuum, and the residue was purified by flash column chromatography (12 g silica, 0-60% gradient of DCM / MeOH / NH39 / 1 / 0.25 in DCM) to obtain the title compound (50 mg, yield: 38%) as a brown oil.

[0145] Intermediate 2: Tert-butyl((2-chloro-1,6-naphthyridine-7-yl)methyl)carbamate.

[0146] [ka]

[0147] Method 1: Anhydrous Boc (7.486 g, 34.301 mmol, 1.1 equivalents), followed by Et3N (13 mL, 93.548 mmol, 3 equivalents), was gradually added to a suspension of (2-chloro-1,6-naphthyridine-7-yl)methaneamine (intermediate 1, HCl salt, 7.175 g, 31.183 mmol) in dry DCM (200 mL) under a nitrogen atmosphere at room temperature. The resulting solution was stirred at room temperature for 2.5 hours. 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 layers were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluate: heptane: siRNA 1 / 3 100:0~20:80) to obtain the title compound (6.1 g, yield: 67%) as a white solid.

[0148] Method 2: Step A: 2-Oxo-1,2-dihydro-1,6-naphthiridine-7-carbonitrile. In a 3 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, DMA (2.24 L), Pd(dppf)Cl2.CH2Cl2 (CAS[95464-05-4], 22.4 g, 0.1 equivalent), 7-chloro-1H-1,6-naphthiridine-2-one (CAS[1345091-18-0], 224 g, 1240.37 mmol), zinc (16.22 g, 248.07 mmol, 0.2 equivalent), and zinc cyanide (145.65 g, 1240.37 mmol, 1 equivalent) were added. The resulting solution was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature. The solid was filtered off and washed with 2 × 100 mL of DMA. The reaction was then stopped by adding 5 L of water / ice. The solid was collected by filtration, and the title compound (147 g, yield: 69%) was obtained as a brown solid.

[0149] Step B: 2-Chloro-1,6-naphthirizine-7-carbonitrile. In a 2 L three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, phosphorus oxychloride (1.47 L) and 2-oxo-1,2-dihydro-1,6-naphthirizine-7-carbonitrile (147.00 g, 858.85 mmol) were added. The resulting solution was stirred at 80°C for 3 hours. The reaction mixture was concentrated. The resulting solution was diluted with 2 L of DCM. The reaction was then stopped by adding 4 L of water / ice. The resulting solution was extracted with 3 × 3 L of DCM, the organic layer was dried over Na₂SO₄, and concentrated to obtain the title compound (58 g, yield: 36%) as a yellow solid.

[0150] Step C: tert-butyl((2-chloro-1,6-naphthirizine-7-yl)methyl)carbamate. In a 5 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 1.74 L of DCM and 58 g of 2-chloro-1,6-naphthirizine-7-carbonitrile (305.90 mmol) were added. Subsequently, DIBAL-H (1 N, 765 mL, 2.5 equivalents) was added dropwise over 30 minutes while stirring at -78°C. The resulting solution was stirred at -78°C for 2 hours. Potassium sodium tartrate (Rochelle salt) (257 g, 1224 mmol, 4 equivalents) was added at -78°C. The resulting solution was stirred at room temperature for 1 hour. Subsequently, di-tert-butyl dicarbonate (73.3 g, 336.50 mmol, 1.1 equivalents) was added. The resulting solution was stirred overnight at room temperature. The solid was filtered off and washed with 3 × 300 mL of DCM. The filtrate was concentrated. The residue was purified by column chromatography (Â1 / 3 to ½ Â1 / 2) on silica gel to obtain the title compound (60.9 g, yield: 68%) as a yellow solid.

[0151] Intermediate 3: Methyl 3-((7-(((tert-butoxycarbonyl)amino)methyl)-1,6-naphthyridine-2-yl)sulfonyl)propanoate.

[0152] [ka]

[0153] tert-butyl((2-chloro-1,6-naphthyridine-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 equivalents) and copper iodide (1.34 g, 7.013 mmol, 2 equivalents) in DMSO (10 mL). The reaction mixture was stirred at 110 °C for 1 hour under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with phenylethylamine and washed with water (1 mL) containing aqueous NH3 solution. The organic layer was separated, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25g column, 0 / 100 to 100 / 0 siRNA / heptane gradient) to obtain intermediate 3 (801 mg, yield: 53%) as an orange solid.

[0154] Intermediate 4: (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine.

[0155] [ka]

[0156] Step A: (cis)-4-(6-bromo-4-nitropyridine-2-yl)-2,6-dimethylmorpholine. 2,6-dibromo-4-nitropyridine (CAS[175422-04-5], 5g, 17.737 mmol) and cis-2,6-dimethylmorpholine (CAS[6485-55-8], 2.42 mL, 19.511 mmol, 1.1 equivalents) were dissolved in toluene (140 mL), and the solution was degassed by bubbling with nitrogen for 15 minutes. Next, Cs2CO3 (8.67 g, 26.606 mmol, 1.5 equivalents), rac-BINAP (CAS[98327-87-8], 1.10 g, 1.774 mmol, 0.1 equivalent), and Pd(OAc)2 (CAS[3375-31-3], 398 mg, 1.774 mmol, 0.1 equivalent) were added, and the resulting mixture was refluxed under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (120 g column, 0 / 100 to 40 / 60 siRNA / heptane gradient) to obtain the title compound (3.2 g, yield: 56%) as an orange solid.

[0157] Step B: (cis)-4-(6-bromo-4-fluoropyridine-2-yl)-2,6-dimethylmorpholine. Tetramethylammonium fluoride (CAS[373-68-2], 663 mg, 7.117 mmol, 1.5 equivalents) was added to a solution of (cis)-4-(6-bromo-4-nitropyridine-2-yl)-2,6-dimethylmorpholine (1500 mg, 4.745 mmol) in DMF (40 mL) in a sealed tube. The mixture was stirred at 65°C for 3 hours. The reaction was stopped by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (80g column, 0 / 100 to 30 / 70 siRNA / heptane gradient) to obtain intermediate 4 (1139mg, yield: 81%) as an orange solid.

[0158] Intermediate 5: tert-butyl((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)carbamate.

[0159] [ka]

[0160] Intermediate 3 (950 mg, 2.32 mmol), intermediate 4 (1006 mg, 3.48 mmol, 1.5 equivalents), and K2CO3 (481 mg, 3.48 mmol, 1.5 equivalents) 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 equivalent) and Pd(OAc)2 (CAS[3375-31-3], 26 mg, 0.116 mmol, 0.05 equivalents) were added, and the reaction mixture was stirred at 150°C for 4 hours. The mixture was cooled to room temperature, diluted with SiO2, and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (25g column, 0 / 100 to 100 / 0 siRNA / heptane gradient) to obtain intermediate 5 (428mg, yield: 39%) as a yellow solid.

[0161] Intermediate 6: (2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methaneamine.

[0162] [ka]

[0163] 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 equivalents) and 1,4-dioxane (40 mL), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum, and the residue was ground in Et2O to obtain intermediate 6 (HCl salt, 406 mg, quantitative) as an orange solid.

[0164] Intermediate 7: 3-Chloro-5-((difluoromethyl)sulfonyl)benzoic acid.

[0165] [ka]

[0166] 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 minutes, the reaction mixture was slowly warmed to room temperature over 1 hour. The mixture was cooled to 0°C and saturated NaHCO3 aqueous solution was added. The mixture was diluted with siRNA and washed twice with brine. The organic layer was dried (MgSO4), filtered, concentrated, and dried under high vacuum to obtain the title compound, which was used without further purification.

[0167] 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 in one go with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) (CAS[140681-55-6], 24.223 g, 68.376 mmol). The reaction mixture was stirred at 60°C for 40 minutes. After cooling, the mixture was concentrated, the crude substance was suspended in ELISA (100 mL), sonicated to break up all particles, filtered through Celite®, concentrated to obtain the title compound, which was used directly in the next step without further purification.

[0168] 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 stirred at room temperature for 1.5 hours. The reaction mixture was diluted with RINKAN and washed twice with brine. The organic layer was dried over (MgSO4), filtered, and concentrated to obtain the title compound as a pale yellow solid (6.85 g, yield: 88% in 3 steps), which was used without further purification.

[0169] 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 hour, the reaction was stopped by adding HCl (30 mL, 30 mmol, 1 M in H2O). The reaction mixture was diluted with HCl (300 mL) and washed twice with brine. The organic layer was dried over (MgSO4), filtered, and concentrated to obtain intermediate 7 (6.08 g, yield: 93%) as a pale yellow solid, which was used without further purification.

[0170] Compound 1: N-((2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyridine-2-yl)-1,6-naphthyridine-7-yl)methyl)-3-(1,1,2,2-tetrafluoroethoxy)benzamide.

[0171] [ka]

[0172] A solution of 1-propanephosphonic acid anhydride (CAS [68957-94-8], 50% solution in siRNA, 177 μL, 0.297 mmol, 1.3 equivalents) was added at room temperature to a suspension of intermediate 6 (107 mg, 0.228 mmol) and intermediate 7 (74 mg, 0.274 mmol, 1.2 equivalents) in dry DCM (5 mL). Then, triethylamine (159 μL, 1.142 mmol, 5 equivalents) was added dropwise to the suspension. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with DCM and saturated NaHCO3 aqueous solution. The layers were separated, and the aqueous layer was extracted again with DCM. The combined organic layers were dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10g; eluate: AcOEt / EtOH 3 / 1:n-heptane, 0:100~80:20) to obtain compound 1 (93mg, yield: 66%) as a yellow solid, which was dried under vacuum at 45°C.

[0173] Example B: Analytical characterization method for intermediates and compounds NMR Some NMR experiments were performed using a Bruker Avance 500 spectrometer equipped with a Bruker 5mm BBFO probe head with a z-gradient, operating at 500 MHz for protons and 125 MHz for carbon. Some NMR experiments were performed using a Bruker Avance III 400 spectrometer with internal deuterium locking and inverse double resonance with a z-gradient. 1 H, 13 The experiment was conducted using a C,SEI) probe head, operating at 400 MHz for protons. Unless otherwise specified, the experiment was performed at ambient temperature (298.6 K). 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.

[0174] [Table 2]

[0175] LC-MS LCMS general procedure High-performance liquid chromatography (HPLC) measurements were performed using the LC pump, diode array (DAD), or UV detector and column specified for each method. Additional detectors were included as needed (see the table of methods below). The flow from the column was delivered to a mass spectrometer (MS) configured with an atmospheric pressure ion source. Setting adjustment parameters (e.g., scanning range, residence time, etc.) to obtain ions that enable the identification of the nominal monoisotopic molecular weight (MW) of the compounds is within the knowledge of those skilled in the art. Data acquisition was performed with appropriate software. The compounds were analyzed based on their experimental retention time (R t ) and ions are described. Unless otherwise specified in the data table, the reported molecular ions are [M+H] +(protonated molecules) and / or [MH] - This corresponds to a (deprotonated molecule). If a compound cannot be directly ionized, its adduct form is identified (i.e., [M+NH4]). + [M+HCOO] - (etc.). For molecules with multiple isotopic patterns (Br, Cl), the reported values ​​are those obtained with respect to the lowest isotopic mass. All results are obtained with experimental uncertainty generally associated with the methods used.

[0176] In the following, "SQD" means single quadrupole detector, "MSD" means mass sorting detector, "RT" means room temperature, "BEH" means cross-linked ethylsiloxane / silica hybrid, "DAD" means diode array detector, and "HSS" means high-intensity silica.

[0177] LCMS method code (flow rate expressed in mL / min; column temperature expressed in °C (T); runtime expressed in minutes).

[0178] [Table 3]

[0179] [Table 4]

[0180] Example C: Pharmacological assay The enzyme assays described below measured the DNA or nucleosome-dependent ATPase activity of various SMARCA2 and SMARCA4 protein constructs by monitoring ADP production using the ADP Glo® kinase assay kit (Promega, V9101). The assays were performed in two steps after the enzymatic reaction was complete. In the first step, the ATPase reaction was stopped, and the remaining ATP was depleted. In the second step, ADP was converted to ATP, and the newly synthesized ATP was measured using a luciferase / luciferin reaction. The generated light was measured using an Envision Luminescence reader.

[0181] SMARCA2 or 4 / SMARCC1 / SMARCC2 / SMARCB1 ADP-Glo ​​assay: The following assay buffers were newly prepared and used as described below: 20 mM Tris·HCl pH 7.5 in molecular biology grade water (Invitrogen, catalog no. 15567-027), 20 mM NaCl (VWR, catalog no. E529), 0.25 mM MgCl2 (Sigma, catalog no. M1028), 1 mM DTT (Sigma, catalog no. 646563), 1 mM EGTA (Alfa Caesar, catalog no. J60767), 0.005% Pluronic F-127 (Sigma, catalog no. 540025), and 0.2 mg / mL BSA (Sigma, catalog no. B8667). Enzyme mixes and ATP / nucleosome mixtures were prepared by diluting each stock solution in assay buffer to the indicated concentrations: (a) 0.664 nM for SMARCA2 or SMARCA4 core complexes, and (b) 250 μM ATP and 2.5 nM biotin-GatC2 nucleosomes (Epicypher, catalog no. 16-4112).

[0182] Compounds dissolved in DMSO or vehicle control and 3 μL of assay buffer or enzyme mix were dispensed into individual wells of a white 384-well PerkinElmer Proxiplate plate (PerkinElmer, catalog no. 6008289). The plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 30 minutes. Then, 2 μL of ATP / nucleosome mix was added, followed by centrifuging at 1000 rpm for 1 minute and incubation at room temperature for 180 minutes. Next, 3 μL of ADP-Glo® reagent supplemented with 14.5 mM MgCl2 and 0.1% CHAPS (G Biosciences, catalog no. DG097) was added. The plate was then centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 60 minutes. Finally, 6 μL of kinase detection reagent supplemented with 0.1% CHAPS was dispensed, the plate was centrifuged at 1000 rpm for 1 minute, sealed, and incubated at room temperature for at least 30 minutes.

[0183] The results obtained from testing the compounds disclosed herein in the above assay (IC 50 The values ​​(expressed in μM) are shown in Table 5 below.

[0184] [Table 5]

[0185] Example D: Predictive Formulation The “active ingredient” (ai) used throughout these examples relates to the compounds of the present invention, comprising any tautomer or stereoisomer form, or a pharmaceutically acceptable addition salt thereof.

[0186] A typical example of the formulation of the present invention is as follows: 1. Tablets Active ingredient 5-50mg Dicalcium phosphate 20mg Lactose 30mg Talcum 10mg Magnesium stearate 5mg Potato starch (plus 200mg)

[0187] 2. Suspension The aqueous suspension for oral administration is prepared to contain 1 to 5 mg of the active ingredient, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol, and water (plus 1 mL) per milliliter.

[0188] 3. Injectable The parenteral composition is prepared by stirring 1.5% (by weight / volume) of the active ingredient in a 0.9% NaCl solution or a 10% by volume aqueous solution of propylene glycol.

[0189] 4. Ointment Active ingredient: 5-1000 mg Stearyl alcohol 3g Lanolin 5g Vaseline 15g Water (add 100g)

Claims

1. formula: 【Chemistry 1】 Compounds thereof, and pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in claim 1 and at least one pharmaceutically acceptable additive.

3. A compound according to any one of claims 1 to 2, for use in therapeutic purposes.

4. A compound according to any one of claims 1 to 2, for use in the treatment of SMARCA4-deficient cancer.

5. The compound for use according to 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 treating a disease condition or symptom mediated by the SMARCA2 protein.

7. The compound for use according to claim 6, wherein the disease state or state mediated by the SMARCA2 protein is cancer or non-small cell lung cancer (NSCLC).

8. Use of the compound according to any one of claims 1 to 2 for manufacturing a pharmacopoeia for the treatment of cancer or NSCLC.

9. An in vitro method for modulating SMARCA2 activity, comprising contacting the SMARCA2 protein or a portion thereof with a compound described in any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof.

10. A method for treating SMARCA4-deficient cancer, the method comprising administering a compound according to any one of claims 1 to 2 to a subject in need thereof.

11. The method according to claim 10, wherein the SMARCA4-deficient cancer is a SMARCA4-deficient NSCLC.

12. A method for treating a disease state or condition mediated by the SMARCA2 protein, wherein the method comprises administering a compound according to any one of claims 1 to 2 to a subject in need thereof.

13. The method according to claim 12, wherein the disease or condition is selected from cancer or NSCLC.

14. The method according to any one of claims 10 to 13, wherein the subject is a mammal.

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