Smarca2 inhibitors useful for the treatment of smarca4 deficient cancers

Abstract

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

Description

SMARCA2 INHIBITORS USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS CROSS-REFERENCEThis application claims benefit of US Application No. 63 / 585,680, filed on September 27, 2023, which is herein incorporated by reference in its entirety.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 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] The present invention relates to a compound having the structure of Formula (I):or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R1is selected from:R2is selected from:R3is hydrogen or hydroxy.

[0010] The present invention further relates to the compounds disclosed in the claims.

[0011] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention; and at least one pharmaceutically acceptable excipient.

[0012] The present invention further relates to the compounds presented herein for use in therapy, in particular for use in the treatment of a SMARCA4 deficient cancer.

[0013] The SMARCA4 deficient cancer may be a SMARCA4 deficient non-small cell lung cancer (NSCLC).

[0014] The present invention further relates to the compounds presented herein for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.

[0015] In one embodiment, the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

[0016] The present invention further relates to the use of a compound as defined herein for the manufacture of a medicament for the treatment of cancer or NSCLC.

[0017] The present invention further relates to an in vitro method of modulating SMARCA2 activity comprising contacting the SMARCA2 protein, or portion thereof, with a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0018] The present invention further relates to a method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined herein.

[0019] In one embodiment, the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

[0020] The present invention further relates to 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 herein.

[0021] In one embodiment, the disease or condition is selected from a cancer or NSCLC.

[0022] In one embodiment, the subject is a mammal.

[0023] The present invention further relates to the probe compound,

[0024] which is useful as a probe compound for testing the enzymatic activities of the compounds of the present invention.INCORPORATION BY REFERENCE

[0025] All publications, patents, patent applications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, patent application, or published nucleotide and amino acid sequence, was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.”

[0030] 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.

[0031] 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.

[0032] Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0033] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0034] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York.

[0035] 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 variousgeneral and more specific references that are cited and discussed throughout the present specification.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0049] 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.

[0050] 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.

[0051] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites.Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.

[0052] As used herein, the term “cancer” refers to a malignant neoplasm.

[0053] 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).

[0054] 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

[0055] Hereinbefore and hereinafter, the terms compounds, compound of formula (I), compound of the present disclosure or invention, compound presented herein, or similar terms or expressions, is meant to include the addition salts, and the stereoisomers thereof.

[0056] 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.

[0057] In some situations, the compound may exist as tautomers. All tautomers are included within the scope of the compound presented herein.

[0058] Examples of tautomers are compounds of formula Ila and lib:

[0059] 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.

[0060] 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.

[0061] Disubstituted cycloalkyl and heterocycloalkyl stereoisomers may be designated by nomenclature prefixes such as cis and trans. Cis and trans isomers are also called "geometric isomers". When a compound described herein is for instance specified as “cis”, this means that the two groups point in the same direction relative to the plane of the ring. In the “trans” isomer, they point in the opposite direction. Exemplified below are “cis” 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.

[0062] The present disclosure includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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, (+)-( 1 S -camphor- 1 ((-sulphonate. calcium edetate, camsylate, caprate, caproate, caprylate, carbonate, chloride, cinnamate, citrate, cyclamate, dihydrochloride, dodecylsulphate, edetate, estolate, esylate, ethane- 1,2-disulphonate, ethanesulphonate, formate, fumarate, galactarate, gentisate, glucoheptonate, gluceptate, gluconate, D-gluconate, glucuronate (e.g. D-glucuronate), glutamate (e.g. L-glutamate), a-oxoglutarate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydrabamine, hydrobromide, hydrochloride, hydriodate, 2-hydroxyethane-sulphonate, 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), naphthal ene- 1,5-disulphonate, 1 -hydroxy -2 -naphthoate, napsylate, nicotinate, nitrate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pantothenate, phosphate / di phosphate, propionate, polygalacturonate, L-pyroglutamate, pyruvate, salicylate, 4-amino-salicylate, sebacate, stearate, subacetate, succinate, sulfate, tannate, tartrate, (+)-L-tartrate, teoclate, thiocyanate, toluenesulphonate (e.g. p-toluenesulphonate), tosylate, triethiodide, undecylenate, valeric acids, as well as acylated amino acids and cation exchange resins. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

[0070] 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(CH3)4+, and substituted ammonium ions (e.g., NH3R+, NH2R2+, NHR3+, NR4+); 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.

[0071] Conversely said salt forms can be converted by treatment with an appropriate acid into the free form.

[0072] 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.

[0073] 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 scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. In another embodiment, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may also be useful in a diagnostic context. Radiolabeled compounds described herein may comprise a radioactive isotope selected from the group of2H,3H,11C,18F,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the radioactive isotope is selected from the group of2H,3H,11C and18F. More preferably, the radioactive isotope is2H. In particular, deuteratedcompounds 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

[0074] The synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions presented herein may vary. Techniques and materials recognized in the field are described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of 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.

[0075] 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.

[0076] In the reactions described herein, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0077] 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.

[0078] 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-butoxy carbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxy carbonyl (Fmoc). Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0079] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°- catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from:

[0081] 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.

[0082] General synthetic pathways

[0083] Compounds of Formula (I), wherein1and R2are defined as in the general scope can be prepared according to Scheme 1,Scheme 1By reacting an intermediate of Formula (II) with a suitable carboxylic acid R1CO2H, in the presence of a suitable coupling agent such as, for example, HATU, HBTU, or 1- propanephosphonic anhydride, in the presence of a suitable base such as, for example, Et3N, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, room temperature.Alternatively, compounds of Formula (I) can be prepared by reacting an intermediate of Formula (II) with a suitable activated form of a carboxylic acid, such as, for example, an acyl chloride or its corresponding anhydride, in the presence of a suitable base such as, for example, DIPEA or EtsN, in a suitable solvent such as, for example, DCM or DMF, at a suitable temperature such as, for example, 0 °C or room temperature.Intermediates of Formula (II) can be prepared by reacting an intermediate of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, with a suitable deprotecting agent such as, for example, TFA, MSA, or HC1, in a suitable solvent such as, for example, DCM or 1,4-di oxane, at a suitable at a suitable temperature such as, for example, room temperature.

[0084] Intermediates of Formula (V), wherein R2 is defined as, can be prepared according to Scheme 2,Scheme 2By reacting an intermediate of Formula (IV), wherein P is a suitable protecting group such as, for example, Boc, and X is a suitable leaving group such as, for example, fluoride, with a suitable amine such as, for example, cis-2,6-dimethylmorpholine, in a suitable solvent such as, for example, DMSO, at a suitable temperature such as, for example, 130 °C.Intermediates of Formula (IV) can be prepared by reacting an intermediate of Formula (V), wherein Y is a suitable leaving group such as, for example, trifluoromethanesulfonate, with a suitable heteroaryl-boronate or -boronic acid such as, for example, 6-fluoropyridine-2-boronic acid, in the presence of a suitable base such as, for example, potassium phosphate, in the presence of a suitable catalyst such as, for example, XantPhos Pd G4 (CAS [1621274-19-8]) or tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3]), in a suitable solvent such as, for example, 1,4-dioxane, at a suitable temperature such as, for example, 90-100 °C.

[0085] Alternatively, Intermediates of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, and R2 is defined as C-linked heteroaryl, such as, for example, pyridyl, pyrazinyl, or pyrazolyl, can be prepared according to Scheme 3,Scheme 3

[0086] By reacting an intermediate of Formula (V), wherein Y is a suitable leaving group such as, for example, triflate, with a suitable heteroaryl-boronate or -boronic acid such as, for example, l-(3-oxetanyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (CAS [1339890-99-1]), in the presence of a suitable base such as, for example, potassium phosphate or Na2CO3, in the presence of a suitable catalyst such as, for example, tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3]), or [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4]), in a suitable solvent such as, for example, 1,4-dioxane or a mixture of 1,4- dioxane and water, at a suitable temperature such as, for example, 100-110 °C.

[0087] Alternatively, Intermediates of Formula (III), wherein P is a suitable protecting group such as, for example, Boc, and R2is defined as C-linked heteroaryl, further functionalization of the heteroaryl group such as, for example, pyrazolyl, can be performed, for example by alkylating an unsubstituted nitrogen in the presence of a suitable source of alkyl group such as, for example, oxetan-3-ol (CAS [7748-36-9]) in the presence of a suitablecatalyst such as, for example, cyanomethylenetributylphosphorane (CAS [157141-27-0]), in a suitable solvent such as, for example, toluene, at a suitable temperature such as, for example, 100 °C.

[0088] Intermediates of Formula (V) can be prepared according to Scheme 4,Scheme 4By reacting an intermediate of Formula (VI) with a suitable trifluorosulfonylating agent such as, for example, trifluoromethanesulfonic anhydride, in the presence of a suitable base such as, for example, Et3N, in a suitable solvent such as, for example, DCE, at a suitable temperature such as, for example, room temperature.Intermediates of Formula (VI) can be prepared by reacting an intermediate of Formula (VII) with a suitable source of ammonia such as, for example, ammonia in EtOH, in a suitable solvent such as, for example, EtOH, at a suitable temperature such as, for example, 50 °C.Intermediates of Formula (VII) can be prepared by reacting an intermediate of Formula (VIII) with a suitable source of hydroxy group such as, for example, N-hydroxyacetamide (CAS [546-88-3]), in the presence of a suitable base such as, for example, K2CO3, in a suitable solvent such as, for example, DMSO, at a suitable temperature such as, for example, 80 °C.Intermediates of Formula (VIII) can be prepared by reacting 2-bromo-3,4- difluorobenzaldehyde (CAS [1578156-21-4]) with a suitably protected aminomethylalkyne such as, for example, tert-butyl N-(prop-2-yn-l-yl)carbamate (CAS [92136-39-5]), in the presence of a suitable phosphine such as, for example, triphenylphosphine, in the presence of a suitable base such as, for example, Et3N, in the presence of a suitable Pd catalyst such as, for example, Pd(PPh3)2Cl2 (CAS [13965-03- 2]), in the presence of a suitable copper catalyst such as, for example, Cui, in a suitable solvent such as, for example, THF, at a suitable temperature such as, for example, 70 °C

[0089] Wherein a compound of Formula (I) has a protecting group such as, for example, Boc, the protecting group can be removed employing conditions known to one skilled in theart. For example, reaction with a reagent such as, for example, pTsOH (p-toluenesulfonic acid), MSA, TFA, or HC1, in a suitable solvent such as, for example, DCM, or 1,4-di oxane, at a suitable temperature such as, for example, room temperature or 40 °C.

[0090] Wherein a compound of Formula (I) has a protecting group on the R1group such as, for example, Boc or THP, the protecting group can be removed by reaction with a suitable reagent such as, for example, HC1, pTsOH, or pyridinium p-toluenesulfonate, in a suitable solvent such as, for example, 1,4-di oxane, or EtOH, at a suitable temperature such as, for example, room temperature. Wherein when the protecting group is an ester, a compound of Formula (I) can be reacted with a suitable hydrolyzing agent such as, for example, LiOH or NaOH, in a suitable solvent such as, for example, THF, MeOH, water, or a mixture thereof, at a suitable temperature such as, for example, room temperature.

[0091] The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I).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.

[0092] The compounds of Formula (I) may also be converted into each other via art- known reactions or functional group transformations. For instance, substituents like -C(=O)- O-C1-6alkyl can be converted into a carboxylic acid in the presence of lithium hydroxide, and in the presence of a suitable solvent, such as for example tetrahydrofuran or an alcohol, e.g. methanol.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] The compounds of the invention as prepared in the processes described herein may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures. Racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternativemanner of separating the enantiomeric forms of the compounds of Formula (I), and the pharmaceutically acceptable addition salts thereof, involves liquid chromatography using a chiral stationary phase e.g., by supercritical fluid chromatography. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereo specifically. Preferably if a specific stereoisomer is desired, said compound would be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

[0097] 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.

[0098] In all these preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration, and chromatography. The purity of the reaction products may be determined according to methodologies generally known in the art such as for example LC-MS, TLC, HPLC.Methods of Treatment and Medical Uses, Pharmaceutical compositions, and combinations

[0099] 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.

[0100] 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.

[0101] The proliferative disease to be treated or prevented using the compounds described 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. Thecompounds 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.

[0102] A proliferative disease may also be associated with inhibition of apoptosis of a cell in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. Inhibition of the activity of SMARCA2 is expected to cause cytotoxicity via induction of apoptosis. The compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may induce apoptosis, and therefore, be useful in treating and / or preventing proliferative diseases.

[0103] In certain embodiments, the proliferative disease to be treated or prevented using the compounds of the present disclosure is cancer.

[0104] 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.

[0105] In another aspect, the present invention provides methods of downregulating the expression of SMARCA2 in a biological sample or subject.

[0106] In yet another aspect, the present invention provides the compounds of the present disclosure, and pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of a proliferative disease in a subject. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting cell growth. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inducing apoptosis in a cell. The compounds described herein, and pharmaceutically acceptable salts and compositions thereof, may be used in inhibiting transcription.

[0107] One skilled in the art will recognize that a therapeutically effective amount of the compounds of the present invention is the amount sufficient to have therapeutic activity and that this amount varies inter alias, depending on the type of disease, the concentration of the compounds in the therapeutic formulation, and the condition of the patient. Generally, the amount of the compounds 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.

[0108] 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 ofthe 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.

[0109] While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

[0110] The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18thed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous or parenteral administration; or topical administration such as via inhalation, or a nose spray. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration tothe 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 compounds 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.

[0115] Therefore, an embodiment of the present invention relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agent, as a combined preparation for simultaneous, separate, or sequential use in the treatment of patients suffering from cancer.

[0116] The one or more other medicinal agents and a 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.

[0117] The weight ratio of a 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

[0118] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0119] When a stereocenter is indicated with ‘RS ’ this means that a racemic mixture was obtained.

[0120] 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.

[0121] Hereinafter, DCM and CH2Cl2 means dichloromethane; r.t. means room temperature; Boc means tert-butoxycarbonyl; CH3CNand 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; POCl3means phosphorus oxychloride; RuPhos Pd G3 means (2- Dicyclohexylphosphino-2',6'-diisopropoxy-1,1’-biphenyl)(2-(2’-amino-1,1’- biphenyl))palladium(II) methanesulfonate; Na2CO3means sodium carbonate; KHSO4means 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. Example 1: Preparation of the Intermediates and the final Compounds, and characterization thereof

[0122] 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 MeaningAbbreviation MeaningAs understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities.

[0123] 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.

[0124] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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 (^) 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 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. Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye). Compounds designated as *R or *S are enantiopure compounds where the absolute configuration was not determined.Intermediate 1A mixture of 2-bromo-3,4-difluorobenzaldehyde (CAS [1578156-21-4], 24.6 g, 111.31 mmol), tert-butyl N-(prop-2-yn-l-yl)carbamate (CAS [92136-39-5], 17.28 g, 111.31 mmol, 1 eq.), Pd(PPh3)2C12 (CAS [13965-03-2], 1.56 g, 2.22 mmol, 0.02 eq.), PPh3(0.88 g, 3.33 mmol, 0.03 eq.), and Et3N (326.66 g, 3228.04 mmol, 29 eq.) in dry THF (500 mL) was stirred under nitrogen atmosphere for 20 min at room temperature. Cui (1.06 g, 5.56 mmol, 0.05 eq.) was then added and the reaction mixture was stirred at 70 °C overnight under nitrogen atmosphere. After cooling, the reaction mixture was poured into NH4CI and ice (500 mL). The resulting mixture was extracted with EtOAc (3 x 600 mL). The combined organic layer was washed with water (3 x 1 L), brine (2 x 1 L), and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc 85 / 15) to afford Intermediate 1 (22 g, yield: 67 %) as a light yellow solid.Intermediate 2K2CO3 (51.48 g, 372.52 mmol, 5 eq.) was added to a mixture of Intermediate 1 (22 g, 74.50 mmol) and N-hydroxyacetamide (CAS [546-88-3], 16.78 g, 223.51 mmol, 3 eq.) in DMSO (330 mL) at room temperature. The resulting mixture was stirred for 3 h at 80 °C. After cooling, the reaction mixture was poured into NH4CI and ice (500 mL) and acidified to pH 4 with HC1 (2 M in water). The resulting mixture was extracted with EtOAc (3 x 400 mL). The combined organic layer was washed with NaHCO3(1 x 300 mL), water (2 x 400 mL), brine (2 x 400 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc 85 / 15) to afford Intermediate 2 (19 g, yield: 87 %) as a light yellow solid.Intermediate 3A mixture of Intermediate 2 (19 g, 64.78 mmol) and ammonia (2 M in EtOH, 287 mL, 8.84 eq.) in EtOH (100 mL) was stirred at 50 °C under nitrogen atmosphere for 1 h. After cooling, the mixture was concentrated under reduced pressure. The residue was triturated with MTBE (80 mL) and filtered to give Intermediate 3 (17 g, yield: 90 %) as a light yellow solid.Intermediate 4Trifluoromethanesulfonic anhydride (34.17 g, 121.10 mmol, 2 eq.) was added to a mixture of Intermediate 3 (17.7 g, 60.55 mmol) and triethylamine (24.51 g, 242.20 mmol, 4 eq.) in DCE (600 mL) at -20 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at - 20 °C. The reaction mixture was allowed to warm to 0 °C and was further stirred for 2 h at this temperature. The reaction mixture was poured into NaHCO3 / ice (1 L). The resulting mixture was extracted with DCM (3 x 600 mL). The combined organic layer was washed with brine (500 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether 25 / 75) followed by trituration with hexane:MTBE 9:1 to afford Intermediate 4 (10 g, yield: 39 %) as an off white solid.Intermediate 5XantPhos Pd G4 (CAS [1621274-19-8], 1196 mg, 1.243 mmol, 0.1 eq.) was added to a suspension of Intermediate 4 (5274 mg, 12.428 mmol), 6-fluoropyridine-2-boronic acid (CAS [916176-61-9], 2627 mg, 18.642 mmol, 1.5 eq.), and potassium phosphate (5276 mg, 24.855 mmol, 2 eq.) in dry 1,4-di oxane (45 mL). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 90 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 350 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 20:80) to give Intermediate 5 (2548 mg, yield: 55 %) as an off-white solid.Intermediate 6A suspension of Intermediate 5 (237 mg, 0.638 mmol), cis-2,6-dimethylmorpholine (CAS [6485-55-8], 237 μL, 1.914 mmol, 3 eq.), and DIPEA (550 μL, 3.191 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a thick wall vial. The vial was sealed, and the reaction mixture was stirred at 130 °C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4. filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: AcOEt / EtOH 3 / l:heptane from 0: 100 to 80:20) to give Intermediate 6 (256 mg, yield: 86 %) as a light brown solid.Intermediate 7HC1 (37 % in water, 458 μL, 5.487 mmol, 10 eq.) was added dropwise to a solution of Intermediate 6 (256 mg, 0.549 mmol) in 1,4-di oxane (5 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was co-evaporated with toluene to give Intermediate 7 (HC1 salt, 241 mg, quantitative) as a yellow solid, dried under vacuum at 45 °C and used without further purification.Intermediate 8A solution of Intermediate 5 (314 mg, 0.845 mmol), (2R,6S)-tert-butyl 2,6- dimethylpiperazine-1 -carboxylate (CAS [180975-66-0], 362 mg, 1.691 mmol, 2 eq.), and DIPEA (728 μL, 4.227 mmol, 5 eq.) in dry DMSO (3 mL) was introduced into a thick-wall vial. The vial was sealed, and the reaction mixture was stirred at 130 °C overnight. More (2R,6S)-tert-butyl 2,6-dimethylpiperazine-l -carboxylate (181 mg, 0.845 mmol, 1 eq.) was added and the vial was sealed again. The reaction mixture was then stirred at 130 °C for 3 days. After cooling, the reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: AcOEt / EtOH 3 / l:heptane from 0:100 to 50:50) to give Intermediate 8 (388 mg, yield: 70 %) as a brown solid.Intermediate 9Intermediate 9 was prepared following the same procedure as Intermediate 7, using Intermediate 8 instead of Intermediate 6.Intermediate 10Tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 63 mg, 0.0542 mmol, 0.1 eq.) was added to a mixture of Intermediate 4 (230 mg, 0.542 mmol), 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (CAS [269410-08-4], 158 mg, 0.813 mmol, 1.5 eq.), and potassium phosphate (230 mg, 1.084 mmol, 2 eq.) in dry 1,4-di oxane (5 mL). The vial was sealed, and the reaction mixture was stirred at 100 °C overnight. After cooling, the reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 0:100) to give Intermediate 10 (52 mg, yield: 28 %) as a white solid.Intermediate 11Cyanomethylenetributylphosphorane (CAS [157141-27-0], 60 μL, 0.228 mmol, 1.5 eq.) was added dropwise to a solution of Intermediate 10 (52 mg, 0.152 mmol) and oxetan-3-ol (CAS [7748-36-9], 19 μL, 0.304 mmol, 2 eq.) in dry toluene (5 mL) at room temperature. The reaction mixture was stirred at 100 °C for 15 h. The solvent was evaporated and the residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 0: 100) to give Intermediate 11 (39 mg, yield: 64 %) as a brown solid.Intermediate 12TFA (37 μL, 0.489 mmol, 5 eq.) was added to a solution of Intermediate 11 (39 mg, 0.098 mmol) in dry DCM (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated to give Intermediate 12 (TFA salt, 51 mg, 75 % pure, contaminated with the corresponding diol instead of oxetane, quantitative) as a brown solid, used without further purification.Intermediate 13A mixture of Intermediate 4 (400 mg, 0.943 mmol), 6-chloropyridine-2-boronic acid pinacol ester (CAS [652148-92-0], 248 mg, 1.037 mmol, 1.1 eq.), Na2CO3(200 mg, 1.885 mmol, 2 eq.), and Xantphos Pd G4 (CAS [1621274-19-8], 91 mg, 0.094 mmol, 0.1 eq.) in water (4 mL) and 1,4-di oxane (12 mL) was degassed with nitrogen for 5 min. The vial was sealed and the mixture was stirred at 80 °C for 7 h. The mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 80:20) to give Intermediate 13 (299 mg, yield: 78 %) as a white solid.Intermediate 14A mixture of Intermediate 13 (76 mg, 0.165 mmol), l-(3-oxetanyl)-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (CAS [1339890-99-1], 45 mg, 0.181 mmol, 1.1 eq.), Na2CO3(35 mg, 0.329 mmol, 2 eq.), and [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 13 mg, 0.016 mmol, 0.1 eq.) in 1,4- dioxane (3 mL) and water (1 mL) was degassed with nitrogen for 5 min. The vial was then sealed, and the reaction mixture was stirred at 110 °C for 2 h in a microwave oven. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 80:20) to give Intermediate 14 (50 mg, 67 % pure, yield: 43 %) as a white solid.Intermediate 15TFA (27 μL, 0.352 mmol, 5 eq.) was added to a solution of Intermediate 14 (67 % pure, 50 mg, 0.070 mmol) in dry DCM (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h. The solvent was evaporated to give Intermediate 15 (53 mg, 79 % pure, quantitative) as a brown solid, used without further purification.Intermediate 16A mixture of Intermediate 13 (299 mg, 0.732 mmol), bdboeck_3438_l (289 mg, 0.879 mmol, 1.2 eq.), Na2CO3(155 mg, 1.465 mmol, 2 eq.), and [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 60 mg, 0.073 mmol, 0.1 eq.) in 1,4-dioxane (12 mL) and water (3 mL) was degassed with nitrogen for 5 min. The vial was then sealed, and the reaction mixture was stirred at 110 °C for 2 h in a microwave oven. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on Na2SC>4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 80:20) to give Intermediate 16 (257 mg, yield: 74 %) as a brown solid.Intermediate 17Intermediate 17 (contaminated with the corresponding diol instead of oxetane) was prepared following the same procedure as Intermediate 15, using Intermediate 16 instead of Intermediate 14.Intermediate 18[l,l'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride di chloromethane complex (CAS [95464-05-4], 0.079 g, 0.097 mmol, 0.1 eq.) was added to a suspension of chloro-6- (2,6-dimethyl-4-pyridinyl)pyrazine (CAS [2283748-94-5], 213 mg, 0.97 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 0.295 g, 1.164 mmol, 1.2 eq.), and KOAc (0.285 g, 2.909 mmol, 3 eq.) in dry 1,4-dioxane (10 mL). The mixture was degassed with nitrogen for 5 min then the vial was sealed. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated to give Intermediate 18 (433 mg, impure, assumed quantitative) as a black solid, used directly in the next step.Intermediate 19XantPhos Pd G4 (CAS [1621274-19-8], 31 mg, 0.032 mmol, 0.1 eq.) was added to a mixture of Intermediate 4 (136 mg, 0.321 mmol), Intermediate 18 (300 mg, 0.964 mmol, 3 eq.), and potassium phosphate (136 mg, 0.643 mmol, 2 eq.) in dry 1,4-dioxane (15 mL). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed, and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane:EtOH / EtOAc 1 / 3 from 100:0 to 20:80) to give Intermediate 19 (147 mg; yield: 96 %) as an off-white solid.Intermediate 20Intermediate 20 was prepared following the same procedure as Intermediate 7, using Intermediate 19 instead of Intermediate 6.Intermediate 21A suspension of Intermediate 5 (169 mg, 0.455 mmol), 2-azaspiro[3.3]heptan-6-ol, 6-methyl-, hydrochloride (CAS [1638765-02-2], 223 mg, 1.365 mmol, 3 eq.), and DIPEA (392 μL, 2.275 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a thick glass vial. The vial was sealed, and the reaction mixture was stirred at 130 °C for 6 h. The reaction mixture was diluted with water and DCM / MeOH 9 / 1. The layers were separated, and the aqueous layer was extracted again with DCM / MeOH 9 / 1. 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 :heptane from 0: 100 to 80:20) to give Intermediate 21 (98 mg, yield: 43 %) as a yellow solid.Intermediate 22Methanesulfonic acid (0.129 mL, 1.986 mmol, 10 eq.) was added dropwise to a solution of Intermediate 21 (98 mg, 0.199 mmol) in dry DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated to give Intermediate 22 (266 mg, 78 % pure, assumed quantitative) as a thick brown oil, used without further purification.Intermediate 23(3-a, 4-β, 5-α)A suspension of Intermediate 5 (101 mg, 0.272 mmol), (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4], 135 mg, 0.816 mmol, 3 eq.), and DIPEA (234 μL, 1.360 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a thick glass vial. The vial was sealed, and the reaction mixture was stirred at 110 °C for 24 h. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: AcOEt / EtOH 3 / l:heptane from 0:100 to 80:20) to give Intermediate 23 (69 mg, yield: 52 %) as a yellow solid.Intermediate 24(3-a, 4-β, 5-α)Intermediate 24 was prepared following the same procedure as Intermediate 7, using Intermediate 23 instead of Intermediate 6.Intermediate 25[l,l'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride di chloromethane complex (CAS [95464-05-4], 153 mg, 0.187 mmol, 0.1 eq.) was added to a suspension of rel-(2R,6S)- 4-(6-bromo-2-pyrazinyl)-2,6-dimethylmorpholine (CAS [2850376-50-8], 598 mg, 1.868 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 569 mg, 2.241 mmol, 1.2 eq.), and KO Ac (550 mg, 5.603 mmol, 3 eq.) in dry 1,4-dioxane (10 mL). The mixture was degassed with nitrogen for 5 min then the vial was sealed. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organiclayer was dried on Na2SO4, filtered, and evaporated to give Intermediate 25 (1096 mg, 42 % pure, quantitative) as a black solid, used without further purification.Intermediate 26XantPhos Pd G4 (CAS [1621274-19-8], 28 mg, 0.029 mmol, 0.1 eq.) was added to a mixture of Intermediate 4 (123 mg, 0.290 mmol), Intermediate 25 (42 % pure, 327 mg, 0.579 mmol, 2 eq.), and potassium phosphate (123 mg, 0.579 mmol, 2 eq.) in dry 1,4-dioxane (15 mL). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed, and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on Na2SO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 20:80) to give Intermediate 26 (67 mg, yield: 46 %) as a yellow solid.Intermediate 27Intermediate 27 was prepared following the same procedure as Intermediate 7, using Intermediate 26 instead of Intermediate 6.Intermediate 28A suspension of Intermediate 5 (122 mg, 0.329 mmol), 2-thia-6-azaspiro[3.3]heptane 2,2- dioxide hemioxalate (CAS [1263182-09-7], 253 mg, 0.658 mmol, 2 eq.), and DIPEA (284 μL, 1.645 mmol, 5 eq.) in dry DMSO (2 mL) was introduced into a thick glass vial. The vial was sealed, and the reaction mixture was stirred at 110 °C for 24 h. The reaction mixture was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: AcOEt / EtOH 3 / 1 :heptane from 0: 100 to 80:20) to give Intermediate 28 (63 mg, yield: 38 %) as an off-white solid.Intermediate 29Intermediate 29 was prepared following the same procedure as Intermediate 22, using Intermediate 28 instead of Intermediate 21.Intermediate 30, Intermediate 31, and Intermediate 32Step A: methyl 3-chloro-5-((difluoromethyl)thio)benzoate. Sodium 2-chloro-2,2- difluoroacetate (CAS [1895-39-2], 129.6 g, 849.8 mmol, 1.5 eq.) was added to a solution of methyl 3-chloro-5-mercaptobenzoate (CAS [1566273-16-2], 115 g, 566.5 mmol), DMF (1150 mL), and K2CO3 (156 g, 1130.0 mmol, 2 eq.) at room temperature. The resulting mixture was stirred for 0.5 h at 90 °C. After cooling, the reaction mixture was diluted with water (3000 mL). The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with water (3 x 1500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc 2 / 3) to afford methyl 3-chloro-5-((difluoromethyl)thio)benzoate (80 g, yield: 56 %) as a white solid.Step B: methyl 3-chloro-5-[(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate. A mixture of methyl 3-chloro-5-[(difluoromethyl)sulfanyl]benzoate (80 g, 316.63 mmol), 2,2,2- trifluoroethanol (800 mL), PIDA (CAS [3240-34-4], 316.16 g, 981.55 mmol, 3.1 eq.), and ammonium carbamate (61.80 g, 791.57 mmol, 2.5 eq.) was stirred for 2 h at room temperature. The mixture was concentrated under vacuum. The residue was quenched by the addition of water (400 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layer was washed with brine (800 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / THF 12 / 1) to afford methyl 3-chloro-5- [(difluoromethyl)(imino)oxo-X6-sulfanyl]benzoate (61 g, yield: 66 %) as a yellow oil.Step C: 3-chloro-5-|(difluoromethyl)(imino)oxo-X6-sulfanyl |benzoic acid (Intermediate 30). A mixture of methyl 3-chloro-5-|(difluoromethyl)(imino)oxo-X6-sulfanyl |benzoate (63 g, 222.089 mmol), THF (315 mL), water (157 mL), and LiOH.H2O (18.64 g, 444.178 mmol, 2 eq.) was stirred for 1 h at 0 °C. The resulting mixture was concentrated under vacuum. The residue was acidified to pH 1 with 1 M aqueous HC1. The resulting mixture was extracted with EtOAc (3 x 630 mL). The combined organic layer was washed with brine (630 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford Intermediate 30 (3-chloro-5-[(difhioromethyl)(imino)oxo-X6-sulfanyl]benzoic acid, 47 g, yield: 76 %) as an off-white solid. A sample of Intermediate 30 was purified by chiral SFC (Column: CHIRALPAK IG 5 * 30 cm, 10 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Gradient: isocratic 30 % B) to afford Intermediate 31 and Intermediate 32, both as light yellow solids.Intermediate 33Difluoromethanesulfonyl chloride (CAS [1512-30-7], 225 μL, 2.41 mmol, 1.5 eq.) was added to a solution of ethyl lH-pyrrolo[3,2-b]pyridine-6-carboxylate (CAS [1261885-66-8], 300 mg, 1.58 mmol) and 1 -methylimidazole (CAS [616-47-7], 200 μL, 2.48 mmol, 1.6 eq.) in dry DCM (8 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with aqueous Na2CO3(1 M, 1 mL) and extracted with DCM (3 x 15 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (12 g SiO2; EtOAc / heptane from 0 / 100 to 15 / 85) to yield Intermediate 33 (330 mg, yield: 67 %) as a white solid.Intermediate 34Palladium hydroxide (400 mg, 0.57 mmol, 0.4 eq.) was added to solution of Intermediate 33 (430 mg, 1.41 mmol) in MeOH (14 mL) under nitrogen atmosphere at 0 °C. The reaction mixture was evacuated and placed under hydrogen atmosphere, then was stirred under hydrogen atmosphere (1 atm) for 18 h at room temperature. The mixture was filtered through a pad of celite that was further washed with MeOH (3 x 50 mL). The filtrate was evaporated to afford Intermediate 34 (155 mg, yield: 35 %) as a white solid.Intermediate 35NaOH (1 M in water, 1 mL, 1 mmol, 2 eq.) was added to a solution of Intermediate 34 (150 mg, 0.49 mmol) in MeOH (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the residue was dissolved in water (10 mL). KHSO4 (1 M in water) was added until pH 3-4, and the mixture was extracted with DCM (10 mL x 3). The combined organic layer was dried over MgSO4, filtered, and concentrated to give Intermediate 35 (80 mg, yield: 58 %) as a white solid.Intermediate 36To a solution of methyl 3-bromo-5-(methylsulfonyl)benzoate (CAS [154117-77-8], 100 g, 340 mmol) and ethyl trifluoroacetate (242 g, 1.70 mol, 234 mL, 5 eq.) in THF (1 L) was added LiHMDS (1 M in THF, 511 mL, 1.5 eq.) at -65 °C. The mixture was stirred at -65 °C for 1 h. The reaction mixture was quenched by addition of saturated aqueous NaHCO? (500 mL) at 0-5 °C. The mixture was diluted with EtOAc (1 L). The layers were separated, and the aqueous layer was extracted again with EtOAc (600 mL x 3). The combined organic layer was washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate 36 (140 g, yield: 82 %), used without further purification.Intermediate 37To a solution of Intermediate 36 (120 g, 240 mmol) in ACN (1200 mL) was added Selectfluor (CAS [140681-55-6], 340 g, 960 mmol, 4 eq.) at 0-5 °C. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (1000 mL), then the mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give Intermediate 37 (140 g, quantitative) as a yellow oil, used without further purification.Intermediate 38To a solution of Intermediate 37 (130 g, 190 mmol, 1 eq.) in water (400 mL) and THF (800 mL) was added DIPEA (89.3 mL, 513 mmol, 2.7 eq.) at 20 °C. The reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with EtOAc (1000 mL), washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica Flash Column; EtOAc / petroleum ether from 0 / 100 to 20 / 80). The combined desired fractions were evaporated and the residue was triturated with MBTE (200 mL) at 20 °C for 12 h. The solid was filtered and dried to give Intermediate 38 (47.0 g, yield: 35 %) as a white solid.Intermediate 39A mixture of Intermediate 38 (494 mg, 1.494 mmol, 1.46 eq.), l,3-dihydro-l,3-dioxo-2H- isoindol-2-yl 2-(difluoromethoxy)acetate (CAS [2248358-15-6], 278 mg, 1.025 mmol), Nickel(II) chloride hexahydrate (CAS [7791-20-0], 49 mg, 0.205 mmol, 0.2 eq.), and 2,2'-bipyridine (CAS [366-18-7], 32 mg, 0.205 mmol, 0.2 eq.) in dry NMP (8 mL) was stirred until full dissolution. Then, silver nitrate (CAS [7761-88-8], 87 mg, 0.513 mmol, 0.5 eq.) was added. The vial was closed with an ElectraSyn 2.0 vial cap with a magnesium sacrificial anode and a 100 ppi RVC (carbon) cathode (3 mm x 7 mm x 51 mm). The vial was then placed on an IKA ElectraSyn 2.0 stirring plate and electrolysis was performed (12 mA, 1 mmol, 3 F / mol), in the presence of air for 6.5 h. The reaction mixture was poured into water (50 mL) and EtOAc was added. The emulsion was filtered on a pad of dicalite and the layers of the filtrate were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was purified by silica gel chromatography (heptane / EtOAc 100 / 0 to 60 / 40) followed by preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, ACN) to yield Intermediate 39 (58 mg, yield: 17 %) as a white solid.Intermediate 40LiOH (21 mg, 0.878 mmol, 5 eq.) was added to a solution of Intermediate 39 (58 mg, 0.176 mmol) in THF:MeOH: Water (1:1:1, 3 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and was acidified to pH=l with HC1 (1 M in water). The mixture was extracted 3 times with EtOAc. The combined organic layer was dried over MgSO4, filtered, and evaporated, yielding Intermediate 40 (52 mg, yield: 94 %) as a white solid, used without further purification.Intermediate 41To a mixture of methyl 3 -(hydroxymethyl)-5 -iodobenzoate (CAS [177734-81-5], 200 g, 685 mmol) in DCM (200 mL) and H2O (1 L) was added KHF2 (214 g, 2.74 mol, 4 eq.). Then, (bromodifluoromethyl)trimethylsilane (CAS [115262-01-6], 278 g, 1.37 mol, 2 eq.) was added at 25 °C. The reaction mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The mixture was poured into water (1 L) and DCM (1 L). The organic layer was separated,the aqueous layer was extracted with DCM (1 L x 2), the combined organic layer was washed with brine (1 L), dried over Na2SO4. filtered, and concentrated. The residue was purified by flash silica gel chromatography (400 g SepaFlash®Silica, petroleum ether / EtOAc from 100 / 0 to 80 / 20) to give Intermediate 41 (176 g, yield: 71 %) as a white solid and starting material (39.0 g, yield: 18 %).Intermediate 42To a solution of Intermediate 41 (176 g, 515 mmol) in toluene (1.26 L) and acetone (500 mL) was added potassium thioacetate (CAS [10387-40-3], 64.6 g, 566 mmol, 1.1 eq.) and Xantphos (CAS [161265-03-8], 35.7 g, 61.7 mmol, 0.12 eq.), Pd2(dba)3(CAS [51364-51-3], 28.3 g, 30.9 mmol, 0.06 eq.) at 25 °C. The mixture was stirred at 70 °C for 12 h. After cooling, the mixture was poured into water (1.5 L) and EtOAc (1.5 L). The layers were separated, and the aqueous layer was extracted with EtOAc (2 L x 2). The combined organic layer was washed with brine (2 L), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (400 g SepaFlash® Silica, petroleum ether / EtOAc from 100 / 0 to 70 / 30) to afford Intermediate 42 (115 g, yield: 69 %) as a yellow oil.Intermediate 43To a solution of Intermediate 42 (110 g, 379 mmol) in MeOH (2.2 L) was added K2CO3(105 g, 758 mmol, 2 eq.) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (1 L) and DCM (2 L), then KHSO4 (1 M in water) was added dropwise over 10 min with vigorous stirring until the pH reached the value of 2-3. The layers were separated, and the aqueous layer was extracted with DCM (2 x 2 L). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica, petroleum ether / EtOAc from 100 / 0 to 80 / 20) to give Intermediate 43 (55.8 g, yield: 56 %) as a colourless oil.Intermediate 44This reaction was carried out in 29 batches that were combined for the work-up and purification. To a solution of Intermediate 43 (2 g, 8.06 mmol) in DMF (20 mL) was added sodium 2-chloro-2,2-difluoro-acetate (CAS [1895-39-2], 2.46 g, 16.1 mmol, 2 eq.) at 25 °C, then the mixture was warmed to 95 °C, and K2CO3 (2.24 g, 16.2 mmol, 2.01 eq.) was added. The mixture was stirred at 95 °C for 30 min. The crude reaction mixture was combined with other batches for workup. After cooling, the mixture was poured into water (500 mL) and EtOAc (1 L), the organic layer was separated, the aqueous layer was extracted with EtOAc (500 mL x 2). The combined organic layer was washed with brine (1 L), dried over Na2SCO4, filtered, and concentrated to dryness under reduce pressure. The residue was purified by flash silica gel chromatography (330 g SepaFlash®Silica, petroleum ether / EtOAc from 100 / 0 to 80 / 20) to afford Intermediate 44 (26.0 g, yield: 37 %) as a colourless oil.Intermediate 45 and Intermediate 46Intermediate 45 (*S) Intermediate 46 (*R)To a solution of Intermediate 44 (26.0 g, 87.2 mmol) in MeOH (156 mL) was added ammonium carbamate (CAS [1111-78-0], 23.8 g, 305 mmol, 3.5 eq.) and (diacetoxyiodo)benzene (CAS [3240-34-4], 70.2 g, 218 mmol, 2.5 eq.) at 25 °C. The mixture was stirred at 40 °C for 2 h. After cooling, the mixture was poured into water (500 mL) and EtOAc (500 mL), the organic layer was separated, the aqueous layer was extracted with EtOAc (300 mL x 2), the combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (120 g SepaFlash®Silica, petroleum ether / EtOAc from 100 / 0 to 70 / 30) followed by SFC (DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 um), [CO2-EtOH (0.1% NH3H2O)]) to afford Intermediate 45 (8.90 g, yield: 29 %) and Intermediate 46 (9.70 g, yield: 32 %), both as yellow oils. Intermediate 47 ) To a solution of Intermediate 45 eOH (50 mL), THF 2 50 mL) was added LiOHH(50 mL), and HO (.2O (2.27 g, 54.1 mmol, 2 eq.) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and DCM (200 mL x 2). The aqueous phase was acidified with KHSO4 (1 N in water) to pH = 2. The aqueous layer was extracted with DCM (300 mL x 2), the combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated. The crude product was triturated with petroleum ether (50 mL) at 25 °C for 1 h. The solid was filtered to give Intermediate 47 (7.70 g, yield: 89 %) as an off-white solid. Intermediate 48 R) Intermediate 48 was prepared fole as Intermediate 47, starting from Intermediate 46 instead of Intermediate 45. Intermediate 49 In a thick glass vial, potassiu6 eq.) and (2- dicyclohexylphosphino-2',4',6-triisopropyl-1,1-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(II) methanesulfonate (CAS [1445085-55-1], 23 mg, 0.027 mmol, 0.05eq.) were added to a solution of Intermediate 4 (229 mg, 0.540 mmol) and bis(pinacolato)diboron (CAS [73183-34-3], 274 mg, 1.079 mmol, 2 eq.) in dry 1,4-dioxane (8 mL) and the mixture was degassed with nitrogen for 5 min. The vial was sealed, and the reaction mixture was stirred at 90 °C for 5 h. The reaction mixture containing Intermediate 49 was used as such in the next step.Intermediate 50N,N-Diisopropylethylamine (1922 μL, 11.035 mmol, 3 eq.) was added to a solution of 2- bromo-6-fluoropyrazine (CAS [1209458-12-7], 651 mg, 3.678 mmol) and 6-methyl-2- azaspiro[3.3]heptan-6-ol (CAS [1638920-25-8], methanesulfonate salt, 821 mg, 3.678 mmol, 1 eq.) in dry DMSO (10 mL) and the reaction mixture was stirred at 50 °C for 1.5 h. The reaction mixture was diluted with DCM / MeOH 9 / 1 and water. The layers were separated, and the aqueous layer was extracted again with DCM / MeOH 9 / 1. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: AcOEt / EtOH 3 / l:heptane from 0:100 to 20:80) to give Intermediate 50 (487 mg, 68 % pure, yield: 32 %) as a yellow solid.Intermediate 51XantPhos Pd G4 (CAS [1621274-19-8], 32 mg, 0.034 mmol, 0.1 eq.) was added to a mixture of Intermediate 49 (220 mg, 49 % pure, 0.337 mmol), Intermediate 50 (141 mg, 68 % pure, 0.337 mmol, 1 eq.), and potassium phosphate (CAS [7778-53-2], 143 mg, 0.673 mmol, 2 eq.) in dry 1,4-dioxane (15 mL). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed, and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on MgSO4,filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 0:100) to give Intermediate 51 (44 mg, 82 % pure, yield: 22 %) as a yellow solid.Intermediate 52Intermediate 52 was prepared following the same procedure as Intermediate 22, starting from Intermediate 51 instead of Intermediate 21.Intermediate 53A solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 10.04 g, 35.62 mmol), cis- 2,6-dimethylmorpholine (CAS [6485-55-8], 4.83 mL, 39.182 mmol, 1.1 eq.), and EtsN (14.85 mL, 106.86 mmol, 3 eq.) in dry toluene (50 mL) was stirred at reflux for 2 h. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane:EtOH / EtOAc 1 / 3 from 100:0 to 50:50) to give Intermediate 53 (10.18 g, yield: 90 %) as a bright orange solid.Intermediate 54Tetramethylammonium fluoride (CAS [373-68-2], 2210 mg, 23.722 mmol, 1.5 eq.) was added to a solution of Intermediate 53 (5 g, 15.815 mmol) in dry DMF (80 mL) in a thick-walled tube. The tube was sealed, and the reaction mixture was stirred at 65 ° C for 3.5 h. The reaction mixture was poured into brine and the mixture was extracted several times with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane :EtOH / EtO Ac 1 / 3 from 100:0 to 100:0) to give Intermediate 54 (4.49 g, yield: 92 %) as a white solid.Intermediate 55In a sealed thick glass vial, a mixture of Intermediate 4 (500 mg, 1.178 mmol), bis(pinacolato)diboron (CAS [73183-34-3], 359 mg, 1.414 mmol, 1.2 eq.), potassium acetate (173 mg, 1.767 mmol, 1.5 eq.), and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (CAS [95464-05-4], 96 mg, 0.118 mmol, 0.1 eq.) in 1,4-dioxane (6 mL) degassed with nitrogen was stirred at 90 °C overnight. After cooling to room temperature, Intermediate 54 (435 mg, 1.414 mmol, 1.2 eq.) was added, followed by K2CO3 (651 mg, 4.713 mmol, 4 eq.), EtOH (3 mL), and water (3 mL). The reaction mixture was degassed with nitrogen then stirred at 90 °C for 4 h. After cooling, the reaction mixture was diluted with water. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layer was dried on MgSCU, filtered, and evaporated. The residue was purified by column chromatography on silica gel (heptane / EtOAc) to give Intermediate 55 (590 mg, 77 % pure, yield: 80 %).Intermediate 56Intermediate 56 was prepared following the same procedure as Intermediate 22, starting from Intermediate 55 instead of Intermediate 21.Intermediate 57Methanesulfonyl chloride (2.1 mL, 27.281 mmol, 1.2 eq.) was added to a solution of methyl 3-(hydroxymethyl)-5-iodobenzoate (CAS [177734-81-5], 6.64 g, 22.734 mmol) and triethylamine (6.3 mL, 45.200 mmol, 2 eq.) in DCM (100 mL) at 0 °C. The solution was then stirred at room temperature for 3 h. The mixture was diluted with water (600 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with brine (2 x 40 mL), dried over MgSO4. filtered, and concentrated. The residue was purified by flash column chromatography (80 g SiO2: EtOAc / heptane from 0 / 100 to 30 / 70) to afford Intermediate 57 (4.98 g, yield: 59 %) as a colourless sticky solid.Intermediate 58Cyclopropanol (1.04 mL, 16.128 mmol, 1.2 eq.) was added dropwise to a suspension of sodium hydride (60 % in mineral oil, 618 mg, 16.137 mmol, 1.2 eq.) in dry DMF (30 mL) at 0 °C. The resulting white suspension was stirred for 30 min at 0 °C. A solution of Intermediate 57 (4.98 g, 13.454 mmol) in DMF (50 mL) was added dropwise to the stirring suspension, giving a yellow homogeneous mixture which was stirred for 2 h at 60 °C. The mixture was diluted with saturated aqueous NaHCO3(50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g SiO2; EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 58 (535 mg, yield: 12 %) as a colorless oil.Intermediate 59 A mixture of Intermediate 58 (1.4 g ssium thioacetate (0.530 g, 4.636 mmol, 1.1 eq.) in acetone (4 mL) anouene ( m ) was sparged with nitrogen for 5 min before adding Pd2dba3(CAS [51364-51-3], 0.233 g, 0.254 mmol, 0.06 eq.) and Xantphos (CAS [161265-03-8], 0.297 g, 0.512 mmol, 0.1 eq.). The vial was sealed, and the reaction mixture was stirred at 70 ºC for 16 h. After cooling, the mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was dried (MgSO4), filtered, and the solvents evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 0 / 100 to 20 / 80) to yield Intermediate 59 (786 mg, yield: 66 %) as an oil. Intermediate 60 Potassium carbonate (0.776 g, 5.6 dded to a solution of Intermediate 59 (0.786 g, 1.34 mmol) in MeOH (1m ) at room temperature. The solution was stirred at room temperature for 2h. The reaction mixture was diluted with water (15 mL) and DCM (10 mL), then KHSO4 (1 M in water) was added dropwise over 10 min with vigorous stirring until the pH reached the value of 2-3. The mixture was extracted with DCM (3 x 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (12 g SiO2; EtOAc / heptane from 0 / 100 to 100 / 0) to give Intermediate 60 (446 mg, yield: 66 %) as a colourless oil.In termediate 61A solution of Intermediate 60 (0.446 g, 1.872 mmol) in anhydrous DMF (6 mL) was treated with potassium carbonate (0.516 g, 3.735 mmol, 2 eq.) and sodium 2-chloro-2,2- difluoroacetate (CAS [1895-39-2], 0.558 g, 3.657 mmol, 2 eq.). The reaction mixture was stirred at 95 °C for 50 min. After cooling, the mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with brine, dried over MgSO4. filtered, and evaporated in vacuo. The residue was purified by flash column chromatography (12 g silica; EtOAc / heptane from 0 / 100 to 60 / 40) to yield Intermediate 61 (300 mg, yield: 55 %) as a colourless oil.Intermediate 62Ruthenium(III) chloride hydrate (4.24 mg, 0.016 mmol, 0.076 eq.) was added to a solution of Intermediate 61 (68 mg, 0.212 mmol) and sodium periodate (181 mg, 0.847 mmol, 4 eq.) in DCM (6 mL), ACN (6 mL), and water (12 mL). The mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (20 mL) and extracted with EtOAc (3 x 20mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g SiO2; EtOAc / heptane from 0 / 100 to 50 / 50) to afford Intermediate 62 (43 mg, yield: 63 %) as a yellow solid.Intermediate 63A mixture of Intermediate 62 (125 mg, 0.35 mmol) and NaOH (2.5 M aqueous solution, 0.84 mL, 2.1 mmol, 6 eq.) in MeOH (3 mL) was stirred for 16 h at room temperature. The reaction mixture was diluted with EtOAc (20 mL) and water (10 mL) and the layers were separated. The aqueous layer was acidified to pH 4 using HC1 (1 M in water) and extracted with EtOAc (5 x 20 mL). The combined extract was dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate 63 (118 mg, yield: 99 %) as a colourless oil.Intermediate 64Di-tert-butyl dicarbonate (CAS [24424-99-5], 2 M in THF, 29.45 mL, 58.91 mmol, 2 eq.) was added to a solution of 6-chloro-3,4-dihydro-2H -pyrido[3,2-b][l,4]oxazine (CAS [1260665- 94-8], 5.025 g, 29.455 mmol) and DMAP (CAS [1122-58-3], 5.398 g, 44.183 mmol, 1.5 eq.) in THF (120 mL). The reaction mixture was stirred at reflux for 4 h. The solvent was evaporated and the residue was dissolved in EtOAc. The mixture was washed with HC1 (0.5 M in water) followed by water. The organic layer was dried on MgSO-i. filtered, and evaporated to give Intermediate 64 (6.545 g, yield: 82 %) as a white solid, used without further purification.Intermediate 65A mixture of Intermediate 64 (1.155 g, 4.267 mmol), azetidin-3-ol hydrochloride (CAS [18621-18-6], 748 mg, 6.826 mmol, 1.6 eq.), cesium carbonate (2.78 g, 8.533 mmol, 2 eq.), and Xphos (CAS [564483-18-7], 407 mg, 0.853 mmol, 0.2 eq.) in dry 1,4-dioxane (15 mL) was degassed with nitrogen for 5 min. Pd2(dba)s (CAS [51364-51-3], 391 mg, 0.427 mmol, 0.1 eq.) was added and the vial was sealed. The reaction mixture was stirred at 100 °C for 24 h. The solvent was evaporated and the residue was purified by column chromatography (Biotage Sfar 100 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 50:50) to give Intermediate 65 (753 mg, 83 % pure, yield: 48 %) as a light brown solid.Intermediate 66Intermediate 65 (600 mg, 1.386 mmol), imidazole (CAS [288-32-4], 133 mg, 1.940 mmol, 1.4 eq.), and DMAP (CAS [1122-58-3], 9 mg, 0.069 mmol, 0.05 eq.) were dissolved in dry DMF (10 mL). Tert-butylchlorodiphenylsilane (CAS [58479-61-1], 396 μL, 1.525 mmol, 1.1 eq.) was then added dropwise to the reaction mixture at room temperature. After the addition, the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 50:50) to give Intermediate 66 (868 mg, quantitative) as a yellow sticky solid.Intermediate 67TFA (1.22 mL, 15.905 mmol, 10 eq.) was added dropwise to a solution of Intermediate 66 (868 mg, 1.590 mmol) in dry DCM (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h. To push the reaction to completion, more TFA (609 μL, 7.952 mmol, 5 eq.) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with DCM and saturated aqueous Na2CO3. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layer was dried on MgSO4. filtered, and evaporated to give Intermediate 67 (700 mg, 93 % pure, yield: 92 %) as a sticky yellow solid.Intermediate 68Tris(dibenzylideneacetone)dipalladium (CAS [51364-51-3], 20 mg, 0.022 mmol, 0.1 eq.) was added to a mixture of Intermediate 4 (93 mg, 0.219 mmol), Intermediate 67 (77 % pure, 190 mg, 0.328 mmol, 1.5 eq.), CS2CO3 (143 mg, 0.438 mmol, 2 eq.), and X-Phos (CAS [564483- 18-7], 22 mg, 0.044 mmol, 0.2 eq.) in dry 1,4-dioxane (5 mL). The mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 110 °C overnight. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 20:80) to give Intermediate 68 (155 mg, 59 % pure, yield: 58 %) as a thick brown oil, still impure but used without further purification.Intermediate 69TFA (0.1 mL, 1.270 mmol, 10 eq.) was added dropwise to a solution of Intermediate 68 (155 mg, 59 % pure, 0.127 mmol) in dry DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent and excess TFA were evaporated under reduced pressure to give Intermediate 69 (TFA salt, 78 mg, quantitative) as a brown solid, used without further purification.Intermediate 701-Propanephosphonic anhydride solution (50 % solution in EtOAc, CAS [68957-94-8], 56 μL, 0.189 mmol, 1.5 eq.) followed by triethylamine (105 μL, 0.755 mmol, 6 eq.) were added dropwise to a solution of Intermediate 69 (78 mg, 0.126 mmol) and Intermediate 63 (42 mg, 0.138 mmol, 1.1 eq.) in dry DCM (2 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM and saturated aqueous NaHCO3. The aqueous layer was extracted again with DCM. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated to give Intermediate 70 (114 mg, 53 % pure, yield: 53 %), used without further purification in the next step.Intermediate 71A solution of 2,6-dibromo-4-nitropyridine (CAS [175422-04-5], 1671 mg, 5.927 mmol), 6- methyl-2-azaspiro[3.3]heptan-6-ol hydrochloride (CAS [1638765-02-2], 1067 mg, 6.52 mmol, 1.1 eq.), and DIPEA (3.1 mL, 17.782 mmol, 3 eq.) in dry toluene (20 mL) was stirred at reflux for 24 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 50 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 50:50) to give Intermediate 71 (297 mg, yield: 14 %) as a sticky orange solid.Intermediate 72A mixture of Intermediate 71 (458 mg, 1.326 mmol) and tetramethylammonium fluoride (CAS [373-68-2], 136 mg, 1.458 mmol, 1.1 eq.) in dry DMF (5 mL) was stirred at 65 °C for 4 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 0:100) to give Intermediate 72 (358 mg, 81 % pure, yield: 73 %) as an orange thick oil.Intermediate 73Na2CO3(124 mg, 1.173 mmol,bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 48 mg, 0.059 mmol, 0.1 eq.) were added to a mixture of Intermediate 49 (432 mg, 87 % pure, 1.173 mmol, 2 eq.) and Intermediate 72 (242 mg, 73 % pure, 0.587 mmol, 1 eq.) in 1,4-dioxane (15 mL) and water (3 mL). The mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 0:100) to give Intermediate 73 (186 mg, yield: 63 %) as a white solid.Intermediate 74 Methanesulfonic acid (120 µL,ed dropwise to a suspension of Intermediate 73 (186 mg, 0.371 mmol) in dry DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture containing Intermediate 74 was used directly in the next step. Intermediate 75 A solution of Intermediate 64 (sodium carbonate (3.132 g, 29.551 mmol, 4 eq.) in 1,4-dioxane (50 mL) was bubbled for 20 min with a nitrogen flow. Then, ethyl acrylate (CAS [140-88-5], 2.412 mL, 22.163 mmol, 3 eq.) and mesylate[(di(1- adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS [1651823-59- 4], 538 mg, 0.739 mmol, 0.1 eq.) were added and the suspension was bubbled with nitrogen for 5 min. Finally, the reaction mixture was heated at 110 °C for 12 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / AcOEt 100 / 0 to 0 / 100), yielding Intermediate 75 (2.15 g, 67 % pure, yield: 58 %) containing 33 % of the corresponding deprotected morpholinopyridine. Intermediate 76 A solution of impure Intermedia 4.3 mmol), Et3N (1.7 mL, 12 mmol, 2.8 eq.), and platinum(IV) oxide (98 mg, 0.43 mmol, 0.1 eq.) in MeOH (30 mL) underwent three cycles of vacuum-H2purges and the reaction mixture was stirred for 16 h under H2atmosphere. Then, the reaction mixture was filtered through celite and the filtrate wasconcentrated under vacuum. The residue was dissolved in DCM (8 mL) and TFA (4.32 mL, 56.4 mmol, 20 eq.) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM and water. Then saturated aqueous NaHCO3was added at 0 °C until pH-5-6. The layers were separated and the aqueous layer was extracted three times with DCM. The combined organic layer was dried over MgSO4. filtered, and evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography (n-heptane / AcOEt:EtOH (3:1) 100 / 00 to 50 / 50) to yield Intermediate 76 (1.1 g, yield: 60 %).In termediate 77A solution of Intermediate 76 (117 mg, 0.471 mmol), Intermediate 4 (200 mg, 0.47 mmol, 1 eq.) and CS2CO3 (384 mg, 1.18 mmol, 2.5 eq.) in 1,4-dioxane (3 mL) were bubbled with nitrogen for 10 min. Then, XantPhos Pd G4 (CAS [1621274-19-8], 27 mg, 0.03 mmol, 0.06 eq.) was added and the reaction mixture was stirred at 110 °C for 1 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / AcOEt 100 / 0 to 20 / 80) to yield Intermediate 77 (214 mg, yield: 85 %) as a yellow oil.Intermediate 78TFA (305 μL, 3.98 mmol, 10 eq.) was added to a solution of Intermediate 77 (214 mg, 0.398 mmol) in DCM (0.8 mL). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the crude product was charged on a filter containing di-amino-silica, and was washed with methanol. The filtrate was concentrated under vacuum to yield Intermediate 78 (173 mg, yield: 93 %) as a yellow oil, used without further purification.Intermediate 79 A suspension of Intermediatemmol), 2-chloro-4-iodopyridine (CAS [153034-86-7], 185 mg, 0.773 mmol, 0.9 eq.), sodium carbonate (182 mg, 1.718 mmol, 2 eq.), and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (CAS [1621274-19-8], 83 mg, 0.086 mmol, 0.1 eq.) in 1,4-dioxane (4 mL) and water (1 mL) was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 100 °C for 2 h in a microwave oven. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again with EtOAc / MeOH 9 / 1. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane:EtOH / EtOAc 1 / 3100:0 to 0:100) to give Intermediate 79 (77 mg, yield: 23 %) as a thick yellow oil. Intermediate 80 A mixture of Intermediate 79 thyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (CAS [325142-95-8], 69 mg, 0.298 mmol, 1.5 eq.), Na2CO3 (42 mg, 0.397 mmol, 2 eq.), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 16 mg, 0.020 mmol, 0.1 eq.) in 1,4-dioxane (3 mL) and water (1 mL) was degassed with nitrogen for 5 min. The vial was then sealed and the reaction mixture was stirred at 110 °C for 2 h in a microwave oven. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3100:0 to 80:20) to give Intermediate 80 (78 mg, yield: 84 %) as a brown solid.Intermediate 81HC1 (37 % in H2O, 142 μL, 1.701 mmol, 10 eq.) was added dropwise to a solution of Intermediate 80 (78 mg, 0.170 mmol) in 1,4-dioxane (2 mL) at room temperature. After the addition, the reaction mixture was stirred at room temperature for 1.5 h. The solvent was evaporated and the residue was co-evaporated with toluene to give Intermediate 81 (85 mg, yield: 93 %) as an off-white solid, used without further purification.Intermediate 82(3-α, 4-β, 5-α)Intermediate 82 was prepared following the same procedure as Intermediate 53, using (3a,4p,5a)-3,5-dimethyl-4-piperidinol (CAS [374067-78-4]) instead of cis-2,6- dimethylmorpholine.Intermediate 83(3-α, 4-β, 5-α)Intermediate 83 was prepared following the same procedure as Intermediate 54, using Intermediate 82 instead of Intermediate 53.Intermediate 84(3-α, 4-β, 5-α)Na2CO3(192 mg, 1.81 mmol, 2 eq.), water (3 mL), and [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (CAS [95464-05-4], 74 mg, 0.0905 mmol, 0.1 eq.) were added to a mixture of Intermediate 83 (319 mg, 0.905 mmol) and Intermediate 49 (724 mg, 2.262 mmol, 2.5 eq.). The reaction mixture was degassed with nitrogen for 5 min. The vial was sealed and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (CombiFlash 40 g; heptane:EtOAc 100:0 to 0:70) to give Intermediate 84 (340 mg, yield: 70 %) as an off-white solid.Intermediate 85(3-α, 4-β, 5-α)Intermediate 85 was prepared following the same procedure as Intermediate 81, using Intermediate 84 instead of Intermediate 80.Intermediate 86A suspension of methyl 3 -chloro-5 -mercaptobenzoate (CAS [1566273-16-2], 440 mg, 2.019 mmol), sodium chlorodifluoroacetate (CAS [1895-39-2], 924 mg, 6.057 mmol, 3 eq.), and cesium carbonate (1974 mg, 6.057 mmol, 3 eq.) in dry DMF (8 mL) was stirred at 110 °C for 2 h. The reaction mixture was diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 20:80) to give Intermediate 86 (359 mg, 90 % pure, yield: 63 %) as a brown oil.Intermediate 873-Chloroperoxybenzoic acid (CAS [937-14-4], 287 mg, 1.279 mmol, 1 eq.) was added in one portion to a solution of Intermediate 86 (90 % pure, 359 mg, 1.279 mmol, 1 eq.) in dry DCM (13 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, then at room temperature overnight. The reaction mixture was poured into aqueous NaOH (1 M) and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layer was dried on MgSO4and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane :EtOH / EtO Ac 1 / 3 100:0 to 20:80) to give Intermediate 87 (256 mg, 93 % pure, yield: 69 %) as a thick yellow oil.Intermediate 88A suspension of Intermediate 87 (420 mg, 1.407 mmol) and LiOH (168 mg, 7.035 mmol, 5 eq.) in MeOH (4 mL), THF (4 mL), and water (4 mL) was stirred at room temperature for 4.5 h. The reaction mixture was concentrated under vacuum to the aqueous layer. The aqueous layer was diluted with water and HC1 (1 M in water) was added until acidic pH. The aqueous layer was extracted twice with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated to give Intermediate 88 (376 mg, quantitative) as a white solid, used without further purification.Intermediate 89A solution of 5-mercapto-3-pyridinecarboxylic acid, methyl ester (CAS [74470-37-4], 1.01 g, 5.96 mmol) in anhydrous DMF (12 mL) was treated with sodium 2-chloro-2,2-difluoroacetate (CAS [1895-39-2], 1.63 g, 10.6 mmol, 1.8 eq.) and sodium carbonate (4.89 g, 46.13 mmol, 7.7 eq.). The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature and treated with saturated aqueous NaHCO3(50 mL). The mixture was extracted with DCM (2 x 50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2, 80 g; gradient of DCM:MeOH 9:1 in DCM from 0 % to 100 %) to yield Intermediate 89 (325 mg, yield: 24 %) as a white solid.Intermediate 90Lithium hydroxide monohydrate (CAS [1310-66-3], 70 mg, 1.63 mmol, 1.5 eq.) was added to a solution of Intermediate 89 (226 mg, 1.03 mmol) in THF (2 mL) and water (0.5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solvents were concentrated to dryness. The crude product was acidified with HC1 (1 N in water, 1.1 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated to dryness to yield Intermediate 90 (157 mg, yield: 74 %) as a white solid.Intermediate 91Ruthenium (III) chloride hydrate (CAS [14898-67-0], 20 mg, 0.015 mmol, 0.06 eq.) was added to a stirred solution of Intermediate 90 (247 mg, 1.2 mmol) and sodium periodate (CAS [7790-28-5], 1 g, 4.67 mmol, 3.8 eq.) in DCM (22 mL), ACN (22 mL), and water (44 mL). The mixture was stirred at room temperature for 16 h. Volatiles were removed under reduced pressure. The aqueous residue (pH<7) was extracted with DCM (3 x 15 mL). The combined organic layer was dried over MgSO4. filtered, and concentrated to dryness to yield Intermediate 91 (249 mg, yield: 86 %) as a white solid.Intermediate 92lodoethane (762 μL. 9.5 mmol, 1.1 eq) was added to a suspension of methyl 5-bromo-6- hydroxypyridine-2-carboxylate (CAS [178876-86-3], 2.0 g, 8.6 mmol, 1 eq.) and K2CO3 (2.4 g, 17 mmol, 1.2 eq.) in DMF (21 mL). The reaction mixture was stirred at room temperature for 16 h. Water was added to the reaction mixture and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO-i. filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / AcOEt 100 / 0 to 50 / 50) to give Intermediate 92 (1.2 g, yield: 53 %) as a white solid and the corresponding N-ethyl isomer (720 mg, yield: 32 %) as a white solid.Intermediate 93Lithium borohydride (2 M in THF, 2.3 mL, 4.6 mmol, 1 eq.) was added to a solution of Intermediate 92 (1.2 g, 4.6 mmol, 1 eq.) in THF (4.6 mL). Then, a few drops of MeOH were added and the resulting mixture was stirred for 1.5 h at room temperature. The reaction mixture was quenched with a saturated aqueous solution of NH4CI and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield Intermediate 93 (1 g, yield: 89 %) as a colourless oil, used without further purification.Intermediate 94To a stirred solution of Intermediate 93 (1 g, 4 mmol, 1 eq.) in anhydrous ACN (20 mL) were added, at room temperature, in this order: tetrakis(acetonitrile)copper(I) tetrafluoroborate (CAS [15418-29-8], 64 mg, 0.20 mmol, 0.05 eq.), 2,2'-bipyridine (CAS [366-18-7], 32 mg, 0.20 mmol, 0.05 eq.), TEMPO (CAS [2564-83-2], 32 mg, 0.20 mmol, 0.05 eq.), and 1- methylimidazole (CAS [616-47-7], 33 μL, 0.41 mmol, 0.1 eq.). After stirring at room temperature for 2 h, the solvent was removed under reduced pressure and the crude productwas purified by silica gel chromatography (n-heptane / AcOEt 100 / 0 to 80 / 20) to giveIntermediate 94 (920 mg, yield: 98 %) as a pale yellow oil.Intermediate 95Diethylaminosulfur trifluoride (CAS [38078-09-0], 1.6 mL, 12 mmol, 3 eq.) was added to a solution of Intermediate 94 (930 mg, 4.042 mmol, 1 eq.) in anhydrous DCM (10 mL). The reaction mixture was stirred at room temperature for 2 h and then slowly quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM and the organic layer was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash chromatography (n-heptane / AcOEt 100 / 00 to 70 / 30) to yield Intermediate 95 (550 mg, yield: 52 %) as a yellow oil.Intermediate 96A solution of Intermediate 95 (550 mg, 2.12 mmol, 1 eq.), bis(pinacolato)diboron (CAS [73183-34-3], 645 mg, 2.54 mmol, 1.2 eq.) and AcOK (623 mg, 6.35 mmol, 3 eq.) in 1,4- di oxane (7.5 mL) was bubbled for 10 min with nitrogen. Then, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (CAS [72287-26-4], 77 mg, 0.11 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was concentrated under vacuum to give Intermediate 96 (0.9 g, 68 % pure, yield: 97 %), used directly in the next step.Intermediate 97A solution of Intermediate 4 (338 mg, 0.796 mmol, 1 eq.), Intermediate 96 (350 mg, 0.796 mmol, 1.5 eq.), and K3PO4 (338 mg, 1.59 mmol, 2 eq.) in 1,4-dioxane (3 mL) was degassedwith nitrogen for 10 min. Then, tetrakis(triphenylphosphine)palladium(0) (CAS [14221-01-3], 46 mg, 0.04 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (n-heptane / AcOEt 100 / 00 to 0 / 100) to yield Intermediate 97 (252 mg, yield: 52 %) as a pale yellow oil.Intermediate 98HC1 (4 M in 1,4-dioxane, 1.034 mL, 4.134 mmol, 10 eq.) was added to a solution of Intermediate 97 (253 mg, 0.413 mmol, 1 eq.) in 1,4-dioxane at room temperature. The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to give Intermediate 98 (130 mg, yield: 61 %), used without further purification.Intermediate 99A solution of methyl 3-fluoro-5-(methylsulfonyl)benzoate (CAS [2113829-39-1], 791 mg, 3.406 mmol) and 2,2,2-trifluoroethyl trifluoroacetate (CAS [407-38-5], 0.988 mL, 7.375 mmol, 2.2 eq.) in dry THF (30 mL) was cooled to -78 °C under nitrogen atmosphere and treated dropwise with LiHMDS (CAS [4039-32-1], 1 M in THF, 5.1 mL, 5.079 mmol, 1.5 eq.). After 5 min, the reaction mixture was allowed to warm to room temperature and was stirred for 30 min. The reaction was quenched with saturated aqueous NaHCO3and the mixture was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to afford Intermediate 99 (1118 mg, quantitative), used without further purification.Intermediate 100A solution of Intermediate 99 (1118 mg, 3.406 mmol) in dry ACN (21 mL) was cooled to 0 °C. Then, the mixture was treated with l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (CAS [140681-55-6], 3.62 g, 10.219 mmol, 3 eq.) in 3 portions, over the course of 5 min. Upon complete addition, the reaction mixture was stirred at 60 °C for 30 min. The solvent was evaporated and the residue was taken up in EtOAc, and sonicated to obtain a suspension. The solid was filtered and rinsed with EtOAc. The filtrate was concentrated and dried to yield Intermediate 100 (1240 mg, quantitative), used without further purification.Intermediate 101DIPEA (1.17 mL, 6.809 mmol, 2 eq.) was added to a solution of Intermediate 100 (1240 mg, 3.405 mmol) in THF (21 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture w as diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The crude product was purified via flash column chromatography (25 g SiO2, EtOAc / heptane 0 / 100 to 30 / 70) to afford Intermediate 101 (729 mg, yield: 80 %) as a white solid.Intermediate 102LiOH (98 mg, 4.077 mmol, 1.5 eq.) was added to a solution of Intermediate 101 (729 mg, 2.718 mmol) in THF (10 mL), MeOH (3 mL), and water (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated under reduced pressure.The residue was dissolved in water and this solution was acidified to pH=2-3 using HC1 (1 M in water). The formed precipitate was filtered and dried under vacuum to afford Intermediate 102 (558 mg, yield: 81 %) as a white solid.Intermediate 103A mixture of Intermediate 5 (131 mg, 0.353 mmol), 4-methoxybenzylamine (CAS [2393-23- 9], 184 μL, 1.411 mmol, 4 eq.), and DIPEA (182 μL, 1.058 mmol, 3 eq.) in dry DMSO (2 mL) was introduced into a thick-wall pressure vial. The vial was closed and the reaction mixture was stirred at 130 °C for 22 h. The reaction mixture was diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layer was dried on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: from AcOEt / EtOH 3 / l :heptanes 0: 100 to 80:20) followed by preparative HPLC (RP XBridge Prep C18 OBD-10 pm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, CH3CN) to afford Intermediate 103 (51 mg, 93 % pure, yield: 28 %) as a yellow solid.Intermediate 104TFA (74 μL, 0.971 mmol, 10 eq.) was added dropwise to a solution of Intermediate 103 (51 mg, 93 % pure, 0.097 mmol) in dry DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM / MeOH 8 / 2 and saturated aqueous Na2CO3. The layers were separated and the aqueous layer was extracted again with DCM / MeOH 8 / 2. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated to give Intermediate 104 (48 mg, 92 % pure, quantitative) as a yellow solid, used without further purification.Intermediate 1051-Propanephosphonic anhydride solution (50 % solution in EtOAc, CAS [68957-94-8], 102 μL, 0.171 mmol, 1.5 eq.) followed by triethylamine (79 μL, 0.568 mmol, 5 eq.) were added dropwise to a solution of Intermediate 104 (48 mg, 92 % pure, 0. 114 mmol) and 3-chloro-5- (difluoromethylsulfonyl)benzoic acid (CAS [2592405-50-8], 37 mg, 0.136 mmol, 1.2 eq.) in dry DCM (4 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and was w ashed with saturated aqueous NaHCO3. The organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue w as purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3 100:0 to 20:80) to give Intermediate 105 (44 mg, yield: 59 %) as a white solid.Intermediate 106To a stirred solution of chlorosulfonic acid (1642 g, 14092 mmol, 20 eq.) was added 3-fluoro- 4-hydroxy benzoic acid (CAS [350-29-8], 110 g, 705 mmol, 1 eq.) in portions at 0 °C. The resulting mixture was stirred at 30 °C for 16 h, then at 80 °C for 2 h. After cooling, the reaction mixture was poured into water / ice (7 L) at 0 °C. The precipitated solids were collected by filtration and washed with water (3 x 1 L). The resulting solid was dried to give Intermediate 106 (146 g, yield: 81 %) as an off-white solid, used without further purification.Intermediate 107To a stirred solution of Intermediate 106 (146 g, 573.4 mmol, 1 eq.) in toluene (3 L) was added PPh3 (526.4 g, 2007.0 mmol, 3.5 eq.) in portions at 30 °C. The resulting mixture was stirred at 90 °C for 16 h. After cooling, the reaction mixture was quenched with saturated aqueous NaHCO3(1 L) and extracted with MTBE (3 x 1 L). The aqueous layer was acidified to pH=3 with aqueous HC1 (3 M) and extracted with EtOAc (3 x 1 L). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate 107 (90 g) as a light yellow solid, used in the next step directly without further purification.Intermediate 108To a stirred solution of Intermediate 107 (90 g, 478.3 mmol, 1 eq.) in MeOH (900 mL) was added H2SO4 (46.9 g, 478.3 mmol, 1 eq.) at 20 °C. The resulting mixture was stirred at 70 °C for 16 h. After cooling, the mixture was diluted with water (3 L) and was extracted with EtOAc (3 x 1 L). The combined organic layer was washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate 108 (86 g) as a light yellow solid, used in the next step directly without further purification.Intermediate 109 To a stirred solution of Intermediate 10mmol, 1 eq.) and 1,3-dibromopropane (86 g, 425 mmol, 1 eq.) in DMF (860 mL) was added Cs2CO3(485 g, 1489 mmol, 3.5 eq.) in portions at 20 °C. The resulting mixture was stirred at 25 °C for 12 h. The reaction was quenched by the addition of water / ice (3 L) at 10 °C. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layer was washed with water (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc 5:1) to afford Intermediate 109 (65 g, yield: 63 %) as an off-white solid. Intermediate 110 To a stirred solution of Intermediate 13 mmol, 1 eq.) in MeOH (1300 mL) and water (650 mL) was added oxone (CAS [37222-66-5], 90 g, 147 mmol, 0.55 eq.) in portions at 0 °C. The resulting mixture was stirred at 30 °C for 12 h under nitrogen atmosphere. The reaction mixture was diluted with water (3000 mL). The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layer was washed with saturated aqueous Na2SO3 (400 mL) and brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / THF 40 / 1) to afford Intermediate 110 (60 g, yield: 87 %) as a light yellow solid. Intermediate 111 To a stirred solution of Intermediate 113 mmol, 1 eq.) in CHCl3 (600 mL) was added DAST (CAS [38078-09-0], 748.9 g, 4646.5 mmol, 20 eq.) at 20 °C. The resulting mixture was stirred at 50 °C for 6 days under nitrogen atmosphere. The reaction wasquenched by the addition of saturated aqueous NaHCO3 (10 L) at 0 °C. The resulting mixture was extracted with DCM (3 x 2 L). The combined organic layer was washed with water (2 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(Petroleum ether / EtOAc 10 / 1) to afford Intermediate 111 (29 g, yield: 48 %) as a white solid. Intermediate 112 To a stirred solution of Intermediate 14 mmol, 1 eq.) in THF (150 mL), MeOH (75 mL), and water (75 mL) was added NaOH (13.37 g, 334.3 mmol, 3 eq.) in portions at 10 °C. The resulting mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction mixture was diluted with water (150 mL). The mixture was acidified to pH=3 with aqueous HCl (2 M). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate 112 (27 g, yield: 98 %) as an off- white solid. Intermediate 113 and Intermediate 114 Interm114 (*S) To a solution of Intermediate 112 (27 g, 110 mmol, 1 eq.) in MeOH (540 mL) and water (270 mL) was added oxone (CAS [37222-66-5], 203 g, 330 mmol, 3 eq.) in portions at 0 °C. The resulting mixture was stirred at 30 °C for 12 h. The reaction mixture was diluted with water (1350 mL) and was extracted with CH2Cl2(3 x 500 mL). The combined organic layer was washed with saturated aqueous Na2SO3(200 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a white solid. This solid was dissolved in EtOH (400 mL) and the solution was separated by SFC (Column: XA- CHIRALPAK IH, 3*25 cm 5 um; Mobile Phase A: CO2, Mobile Phase B: iPrOH (0.1 % TFA), isocratic 20 % B). The first fraction from SFC was concentrated to remove most of the iPrOH, then the residue was diluted with EtOAc (300 mL), the organic layer was washed with brine (5 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by slurry with Et2O:hexane 1:4 (120 mL) at roomtemperature for 2 h. Filtration afforded Intermediate 113 (10.12 g, yield: 37 %) as a white solid. Following the same procedure, the second fraction from SFC afforded Intermediate 114 (10.13 g, yield: 37 %) as a white solid. Intermediate 115 HCl in 1,4-dioxane (4 M, 0.24s added dropwise to a solution of Intermediate 4 (50 mg, 0.097 mmol) in 1,4 dioxane (5 mL). The reaction mixture was stirred at room temperature for 16 h. To push the reaction to completion, more HCl in 1,4-dioxane (4 M, 0.70 mL, 2.79 mmol, 29 eq.) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated in vacuo to give Intermediate 115 (52 mg) as a beige solid, used in the next step without further purification. Intermediate 116 Propylphosphonic anhydriin EtOAc, 59 µL, 0.098 mmol, 1.1 eq.) was added to a solution of Intermediate 115 (52 mg, 0.089 mmol), 3-chloro-5- (difluoromethyl sulfonyl) benzoic acid (CAS [2592405-50-8], 27 mg, 0.098 mmol, 1.1 eq.), and DIPEA (94 µL, 0.54 mmol, 6 eq.) in DCM (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was dried on MgSO4, filtered, and the solvent was evaporated. The residue was purified by silica gel chromatography (4 g, heptane / EtOAc from 100 / 0 to 32 / 68) to afford Intermediate 116 (66 mg, quantitative) as a brown oil. Intermediate 117 To a solution of 3-bromo-2-(cyclopifluoromethyl)-pyridine (CAS [3008582-91-7], 237 mg, 0.853 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (CAS [73183-34-3], 260 mg, 1.024 mmol, 1.2 eq.), Pd(dppf)Cl2.DCM(CAS [95464-05-4], 70 mg, 0.085 mmol, 0.1 eq.), and KOAc (251 mg, 2.559 mmol, 3 eq.). The mixture was degassed and purged with nitrogen 3 times, then was stirred at 110 ºC for 2 h under nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with EtOAc (30 mL x 3). The combined filtrate was concentrated under reduced pressure to give Intermediate 117 (593 mg, quantitative) as a brown oil, used without further purification. Intermediate 118 Difluoromethanesulfonyl chloride (C, 621 µL, 6.996 mmol, 1.8 eq.) was added dropwise, over 5 min, at 0 °C, to a solution of 5-methyl-3-piperidinecarboxylic acid, methyl ester (CAS [1044591-98-1], 611 mg, 3.886 mmol) and 1-methylimidazole (CAS [616- 47-7], 620 µL, 7.773 mmol, 2 eq.) in dry DCM (33 mL). The reaction mixture was stirred at room temperature for 2 days. Saturated aqueous NaHCO3 was added and the biphasic mixture was stirred vigorously for 5 min. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layer was washed with HCl (1 M in water), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in THF / water (3 / 1, 50 mL) and LiOH.H2O (326 mg, 7.770 mmol, 2 eq.) was added. The reaction mixture was stirred at room temperature for 2 days. HCl (1 M in water) was added to reach pH 3-4. The mixture was extracted with EtOAc. The organic layer was dried on MgSO4, filtered, and the solvent was evaporated to give Intermediate 118 (quantitative, 63 % pure), used without further purification. Intermediate 119 Cis-2,6-dimethylmorpholine (CAS [648, 0 mL, 53.3 mmol, 1.05 eq.) was added to a solution of 2,6-dibromopyridine (CAS [626-05-1], 12.0 g, 50.7 mmol) and potassium carbonate (15.0 g, 109 mmol, 2.14 eq.) in DMF (150 mL). The reaction mixture was stirred at 120 º C for 18 h. After cooling, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL x 3). The combined extracts were dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (120 g silica; EtOAc / heptane from 0 / 100 to 50 / 50) to yield Intermediate 119 (12.33 g, yield: 88 %) as a white solid.Intermediate 120 A mixture of (4-bromo-3-fluorpropanoate (CAS [1938129-47- 5], 640 mg, 2.01 mmol), N-Boc propargylamine (CAS [92136-39-5], 469 mg, 3.02 mmol, 1.5 eq.), [Cp*RhCl2]2 (CAS [12354-85-7], 31 mg, 0.05 mmol, 0.025 eq.), and cesium pivalate (CAS [20442-70-0], 942 mg, 4.02 mmol, 2 eq.) in 2,2,2-trifluoroethanol (10 mL) was stirred at room temperature for 1 h. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica 80 g, EtOAc / heptane from 0 / 100 to 100 / 0) to afford Intermediate 120 (710 mg, yield: 90 %) as a beige solid. Intermediate 121 Pd(dppf)Cl2.CH2Cl2 (CA25 eq.) was added to a mixture of Intermediate 120 (148 mg, 0.399 mmol), bis(pinacolato)diboron (CAS [73183-34- 3], 121 mg, 0.478 mmol, 1.2 eq.), and potassium acetate (117 mg, 1.196 mmol, 3 eq.) in 1,4- dioxane (4 mL) in a sealed tube at room temperature under nitrogen atmosphere. The reaction mixture was stirred at 90 ºC for 16 h. The mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined extracts were dried over MgSO4, filtered, and concentrated to dryness in vacuo to afford Intermediate 121 (194 mg, quantitative) as a brown oil, used directly in the next step. Intermediate 122 S) PdCl2(dppf).CH2Cl2 (CAS.05 eq.) was added to a solution of Intermediate 121 (184 mg, 0.375 mmol, 1.2 eq.), Intermediate 119 (85 mg, 0.313mmol), and sodium bicarbonate (53 mg, 0.625 mmol, 2 eq.) in 1,4-dioxane (4 mL) and water (1 mL) in a sealed tube under nitrogen atmosphere. The reaction mixture was stirred at 90 ºC for 16 h. After cooling, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (25 g; EtOAc / heptane from 0 / 100 to 100 / 0) to afford Intermediate 122 (141 mg, yield: 92 %) as a white solid. Intermediate 123 oric acid (4 M in 1,HN O OS) Hydrochl 2 HN eq.) was added dropwise to a solution of Intermediate 122 (18 mg, 0.04 mmol) in 1,4-dioxane (5 mL).The reaction mixture was stirred at 50 ºC for 36 h. The solvent was evaporated in vacuo to give Intermediate 123 (17 mg, yield: 85 %) as a white solid, used in the next step without further purification. Preparation of final compounds Compound 2 Method A S) 1-Propanephosphonic AS [68957-94-8], 197 µL, 0.331 mmol, 1.5 eq.) followed by triethylamine (153 µL, 1.104 mmol, 5 eq.) were added dropwise to a suspension of Intermediate 7 (97 mg, 0.221 mmol) and 3-chloro-5- (difluoromethylsulfonyl)benzoic acid (CAS [2592405-50-8], 72 mg, 0.265 mmol, 1.2 eq.) in dry DCM (5 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM and was washed with saturated aqueous NaHCO3. The organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3from 100:0 to 20:80) to give Compound 2 (136 mg, yield: 99 %) as a yellow solid, dried under vacuum at 45 °C. Compound 8 Method B 1-Propanephosphonic a CAS [68957-94-8], 43 µL, 0.145 mmol, 1.5 eq.) followed by triethylamine (67 µL, 0.484 mmol, 5 eq.) were added dropwise to a suspension of Intermediate 12 (75 % pure, 51 mg, 0.097 mmol) and 3-chloro-5- (difluoromethylsulfonyl)benzoic acid (CAS [2592405-50-8], 29 mg, 0.107 mmol, 1.1 eq.) in dry DCM (3 mL). The reaction mixture was stirred at room temperature for 3.5 h. The reaction mixture was diluted with DCM and was washed with saturated aqueous NaHCO3. The organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3 from 100:0 to 20:80), followed by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3 solution in water, CH3CN) to give Compound 8 (17 mg, yield: 32 %) The following compounds were prepared using the intermediates, reagents, and methods shown in Table 2: Table 2 Cpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCpd Acid Amine Product structure MethodCompound 37 Tetrabutylammonium flHF, 0.080 mmol, 1.2 eq.) was added to a solution of Intermediate 70 (114 mg, 0.066 mmol) in dry THF (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted again twice with EtOAc. The combined organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3100:0 to 20:80), followed by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 30 x 150 mm; 0.25 % NH4HCO3solution in water, CH3CN) to give Compound 37 (18 mg, yield: 40 %) as a yellow solid. Compound 39 Compound 39 was isol 150 mm; CO2, MeOH + 20 mM NH4OH) of an impure batch of Compound 38, due to contamination of a batch of Intermediate 74 with its corresponding nitropyridine analogue. Compound 41 LiOH (2 mg, 0.084 mund 40 (30 mg, 0.042 mmol) in THF / MeOH / water (0.5 mL each). The reaction mixture was stirred at roomtemperature for 16 h. It was then diluted with water and acidified with aqueous HCl (1 M) till pH=4-5. Then, the aqueous layer was extracted with EtOAc and the combined organic layer was concentrated under vacuum. The crude product was purified by silica gel flash chromatography (n-heptane / AcOEt:EtOH (3:1) 100 / 00 to 20 / 80) to yield Compound 41 (14 mg, yield: 50 %) as a pale yellow solid. Compound 441-Propanephosphonic anhydride (112 µL, 0.188 mmol, 1.5 eq.) was added to a solution of Intermediate 85 (50 mg, 0.12 mmol), Intermediate 63 (38 mg, 0.12 mmol, 1 eq.), and DIPEA (130 µL, 0.753 mmol, 6 eq.) in DCM (0.6 mL). The reaction mixture was stirred at room temperature for 1 h. Then, saturated aqueous NaHCO3 was added and the reaction mixture was stirred at room temperature overnight. The formed precipitate was filtered and dried under vacuum, yielding Compound 44 (28 mg, yield: 32 %) as a white solid. Compound 45Compound 45 was prepared following the same procedure as Compound 44, using 3-chloro- 5-(difluoromethyl sulfonyl) benzoic acid (CAS [2592405-50-8]) instead of Intermediate 63.Compound 46Compound 46 was prepared following the same procedure as Compound 44, using Intermediate 40 instead of Intermediate 63. Compound 50 S) 1-PropanephosphonicCAS [68957-94-8], 246 µL, 0.414 mmol, 1.3 eq.) followed by triethylamine (221 µL, 1.592 mmol, 5 eq.) were added dropwise to a suspension of Intermediate 7 (156 mg, 0.318 mmol) and 3-chloro-5- [(difluoromethyl)sulfanyl]benzoic acid (CAS [2592405-49-5], 95 mg, 0.35 mmol, 1.1 eq.) in dry DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and was washed with saturated aqueous NaHCO3. The organic layer was dried by filtration on Extrelut NT3 and evaporated. The residue was purified by column chromatography (Biotage Sfar 10 g; eluent: heptane:EtOH / EtOAc 1 / 3100:0 to 50:50). The obtained off-white solid was triturated in CH3CN (10 mL) and a few drops of DMSO. The suspension was filtered to give Compound 50 (60 mg) as a white solid. The filtrate was concentrated and a few drops of water were added. The solid was filtered and washed with a small amount of CH3CN to give another crop of Compound 50 (45 mg, total yield: 56 %) as a white solid.Compound 52 and Compound 53Compound 53 (*S), (CIS) 1-Propanephosphonic anhydride solution (50 % solution in EtOAc, CAS [68957-94-8], 639 µL, 1.073 mmol, 1.3 eq.) followed by triethylamine (574 µL, 4.128 mmol, 5 eq.) were added dropwise to a suspension of Intermediate 7 (405 mg, 0.826 mmol) and Intermediate 88 (231 mg, 0.908 mmol, 1.1 eq.) in dry DCM (15 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. 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 on MgSO4, filtered, and evaporated. The residue was purified by column chromatography (Biotage Sfar 25 g; eluent: heptane:EtOH / EtOAc 1 / 3100:0 to 20:80), followed by preparative SFC (Chiralpak Daicel ID 20 x 250 mm; CO2, MeOH + 0.4 % iPrNH2), to give Compound 52 (97 mg, yield: 19 %) and Compound 53 (114 mg, yield: 23 %), both as yellow solids. Compound 59 A mixture of Intermediat mL, 16.816 mmol, 250 eq.) was stirred at 60 °C for 2h. The TFA was evaporated and the residue was taken up 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: heptane:EtOH / EtOAc 1 / 3100:0 to 20:80) followed by preparative HPLC (RP XBridge Prep C18 OBD-10 µm, 50 x 150 mm; 0.25 % NH4HCO3 solution in water, CH3CN) to give Compound 59 (26 mg, yield: 74 %) as a white solid.Compound 62 A mixture of Intermeediate 116 (66 mg, 0.092 mmol), and K3PO4 (58 mg, 0.275 mmol, 3 eq.) in 1,4-dioxane (4 mL) and water (0.3 mL) was sparged with nitrogen for 5 min. Pd(dppf)Cl2.DCM (CAS [95464-05-4], 11 mg, 0.009 mmol, 0.1 eq.) was then added and the mixture was stirred at 90 ºC for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography (40 g; heptane / AcOEt from 100 / 0 to 18 / 82) to afford Compound 62 (12 mg, yield: 21 %) as a white solid. Compound 63, Compound 64, Compound 65, and Compound 66Compound 63, Compound 64, Compound 65, and Compound 66 were obtained starting from Intermediate 7 and Intermediate 118, according to Method A, followed by separation of the stereoisomers by preparative SFC (Chiralpak Daicel ID 20 x 250 mm; CO2, EtOH + 0.4 % iPrNH2,followed by Chiralpak Daicel IC 20 x 250 mm, CO2, EtOH + 0.4 % iPrNH2, and finally Chiralcel Diacel IH 20 x 250 mm, CO2, EtOH + 0.4 % iPrNH2). Example 2: Analytical characterization methods of Intermediates and Compound NMR 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 (^) are reported in parts per million (ppm). J values are expressed in Hz. Table 3:1H NMR Results. Cmpd ID NMR peaks listCmpd ID NMR peaks listCmpd ID NMR peaks listCmpd ID NMR peaks listCmpd ID NMR peaks listCmpd ID NMR peaks listCmpd ID NMR peaks list ,LCMS General procedureThe High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time... ) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. Hereinafter, SQD means Single Quadrupole Detector, MSD Mass Selective Detector, RT room temperature, BEH bridged ethylsiloxane / silica hybrid, DAD Diode Array Detector, HSS High Strength silica.LCMS Method Codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes):Table 4: LC-MS Methods.Table 5: LCMS Results (RT means retention time, in min)SFC measurements and resultsThe SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time... ) in order to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Analytical SFC-MS Methods (Flow expressed in mL / min; column temperature (Col T) in °C; Run time in minutes, Backpressure (BPR) in bars. iPrNH2means isopropylamine, iPrOH means 2-propanol, EtOH means ethanol, min mean minutes, DEA means diethylamine.Table 6: SFC Methods.Analytical SFC data - Rt means retention time (in minutes), [M+H]+means the protonated mass of the compound, method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds.Table 7: SFC Results.High Resolution Mass SpectrometryTable 8: HRMS methods.Table 9: HRMS results.Melting pointsFor melting points, values are peak values and are obtained with experimental uncertainties that are commonly associated with this analytical method. Melting points were determined with a Mettler-Toledo MP50 or FP62 apparatus. Melting points were measured with a temperature gradient of 10 °C / min. Maximum temperature was 300°C.Table 10: Melting Point Results. Cmpd # Melting PointExample 3: Pharmacological Assays SMARCA2 or 4 / SMARCC1 / SMARCC2 / SMARCB1 ADP-Glo Assays: These enzymatic assays measured the DNA or nucleosome-dependent ATPase activities of various SMARCA2 and SMARCA4 protein constructs by monitoring ADP production using the ADP GloTMKinase 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. The 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 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). Compound(s) 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-GloTMreagent, supplemented with 14.5 mM MgCl2and 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.SMARCA2 HTRF Assay Protocol. Compounds were prepared as 3-fold serial dilutions in 100 % DMSO with 11 total concentrations. A LabCyte ECHO was used to dispense each compound into the assay plate (Corning 4570). Assay buffer was prepared containing 20 mM Tris pH 7.4 (Teknova), 20 mM NaCl (Sigma), 1.25 mM MgCl2 (Sigma), 1 mM dithiothreitol (Invitrogen), 0.5 mg / mL bovine serum albumin (Sigma), and 0.005 % Tween-20 (BioVision). A 1X SMARCA2 solution of 25 pM Streptavidin-Terbium Cryptate (CisBio), 100 pM biotinylated SMARCA2 (495-1590, in- house), and 20 nM of the Probe compound was prepared in assay buffer. 1X SMARCA2 solution was added to all wells of the assay plate using a Multidrop Combi (Thermo). The assay plate was centrifuged at 1000 rpm for one minute, covered to protect from light, and incubated for four hours at room temperature. After the incubation, the assay plate was read using a BMG Labtech PHERAstar FSX using λex = 337 nm and λem = 620, 665 nm (dual emission). Data was normalized to DMSO and 2.5 µM of the Control compound to represent 0 % (bottom) and 100 % (top) probe displacement, respectively. Normalized data was fitted to the following 4-parameter logistic equation to gener ^= ^^^^^^^^^^^^ + ^^^ate IC50 values: ^^^^ − ^^^^^^^^^^^^1 + 10(^^^ூ^ହ^ି )∗ு^^^ ௌ^^^^SMARCA4 HTRF A Compounds were prepared as 3-fold serial dilutions in 100 % DMSO with 11 total concentrations. A LabCyte ECHO was used to dispense each compound into the assay plate (Corning 4570). Assay buffer was prepared containing 20 mM Tris pH 7.4 (Teknova), 20 mM NaCl (Sigma), 1.25 mM MgCl2(Sigma), 1 mM dithiothreitol (Invitrogen), 0.5 mg / mL bovine serum albumin (Sigma), and 0.005 % Tween-20 (BioVision). A 1X SMARCA4 solution of 25 pM Streptavidin-Terbium Cryptate (CisBio), 100 pM biotinylated SMARCA4 (519-1647, in- house), and 300 nM of the Probe compound was prepared in assay buffer. 1X SMARCA4 solution was added to all wells of the assay plate using a Multidrop Combi (Thermo). The assay plate was centrifuged at 1000 rpm for one minute, covered to protect from light, and incubated for four hours at room temperature. After the incubation, the assay plate was read using a BMG Labtech PHERAstar FSX using λex = 337 nm and λem = 620, 665 nm (dual emission). Data was normalized to DMSO and 2.5 µM of the Control compound to represent 0 % (bottom) and 100 % (top) probe displacement, respectively. Normalized data was fitted to the following 4-parameter logistic equation to generate IC va ^^^^^^^ + ^^^^^^ − ^^^50 lues: ^^ = ^^^^^ ^^^^^^^^^1 + 10(^^^ூ^ହ^ି^)∗ு^^^ ௌ^^^^Preparation of the Control compound The Control compoundwas prepared according to the method described in patent application nr. PCT / EP2023 / 068560. Preparation of the Probe compound A solution of N-((2-(6-((2- S,6- R)-2-(5-aminopentyl)-6-methylmorpholino)pyridin-2-yl)- 1,6-naphthyridin-7-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide (30 mg, 0.049 mmol, prepared according to the method described in patent application nr. PCT / EP2023 / 068560), AfDYE 647 NHS Ester (CAS [2490495-36-6], 48 mg, 0.049 mmol), and NaHCO3(180 mg, 2.143 mmol) in THF / H2O (1 / 1, 1 mL) was stirred for 16 h at room temperature under a nitrogen atmosphere. The crude reaction mixture was purified by preparative HPLC (Phenomenex C1880 * 40 mm * 3 um; water (NH4HCO3) / ACN from 92 / 8 to 62 / 38) to give the Probe compound as an ammonium salt (48 mg, yield: 97 %) as a blue solid.LC-MS: confirms the MW (RT: 1.06, [M+H]+1472.3, Method: 6) 1H NMR (400MHz, DMSO-d6) δ (ppm) 9.56 (s, 1H), 9.40 (s, 1H), 8.72 - 8.65 (m, 1H), 8.64 - 8.58 (m, 1H), 8.52 (s, 1H), 8.37 (br t, J=12.3 Hz, 2H), 8.23 (br d, J=8.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.83 - 7.69 (m, 5H), 7.66 - 7.60 (m, 3H), 7.37 (br d, J=8.5 Hz, 1H), 7.33 - 7.02 (m, 12H), 6.60 - 6.42 (m, 2H), 6.30 (br d, J=13.6 Hz, 1H), 4.81 (br d, J=5.5 Hz, 2H), 4.29 (br d, J=8.0 Hz, 4H), 4.07 (br s, 2H), 3.64 (br s, 1H), 3.50 (br s, 1H), 3.38 - 3.36 (m, 2H), 3.29 (s, 3H), 3.03 (br d, J=5.8 Hz, 2H), 2.73 (s, 3H), 2.58 (br s, 4H), 2.30 - 2.11 (m, 3H), 2.05 (br t, J=7.0 Hz, 2H), 1.97 (br s, 2H), 1.74 - 1.61 (m, 11H), 1.61 - 1.22 (m, 16H), 1.20 (d, J=6.3 Hz, 3H), 0.86 - 0.69 (m, 1H), 0.48 (br s, 1H) Results (indicated as IC50, in nM) obtained from testing the compounds of the present disclosure in the above-described assays are indicated in the Table 11 below. Table 11: Biochemical and Biophysical Assay Results. Compound ID SMARCA2 SMARCA4 SMARCA2 SMARCA4Compound ID SMARCA2 SMARCA4 SMARCA2 SMARCA4Compound ID SMARCA2 SMARCA4 SMARCA2 SMARCA4

[0129] “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 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

CLAIMS 1. A compound having the structure of Formula (I): I) or a pharmaceutically acceptab er thereof, wherein R1is selected from:R2is selected from:

52. A compound of claim 1 selected fromJAB7120 F F F FO O( S SR)O NHCl O O NH -124- NH N NF F N NN N H N H N-Z£l-and pharmaceutically acceptable salts, tautomers, or stereoisomers thereof.

3. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1; and at least one pharmaceutically acceptable excipient.

4. A compound according to any one of claims 1 to 2 for use in therapy.

5. A compound according to any one of claims 1 to 2 for use in the treatment of a SMARCA4 deficient cancer.

6. The compound for the use of claim 5, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).

7. 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.

8. The compound for the use of claim 7, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).

9. 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.

10. 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.

11. 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.

12. The method of claim 11, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.

13. 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.

14. The method of claim 13, wherein the disease or condition is selected from a cancer or NSCLC.

15. The method of any one of claims 11 to 14, wherein the subject is a mammal.

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