Methyl 2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate compounds as CAV1.2 activators

Abstract

The present disclosure provides a compound according to formula (I) or a pharmaceutically acceptable salt thereof as a Cav1.2 activator for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, and early repolarization syndrome. [Formula 1] JPEG2023531399000116.jpg45170

Description

[Technical field]

[0001] The present disclosure relates to methyl 2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate compounds, pharmaceutical compositions containing them, and Ca2+-dependent inhibitors for the treatment of calcium signaling defects and / or synaptic dysfunction in psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome. V 1.2 Concerning the use of such compounds as activators. [Background technology]

[0002] Advances in human genomics have shed light on the genetic basis of psychiatric disorders. Genome-wide association studies (GWAS) of schizophrenia have revealed that Ca V Over 100 disease-associated loci have been identified, including genes involved in calcium signaling in neurons, including schizophrenia, bipolar disorder, major depressive disorder, ADHD, and autism spectrum disorder. V 1.2 and its channel-forming beta subunit (CACNB2) have been identified. In addition to evidence from GWAS, exome sequencing in patients with schizophrenia has demonstrated that Ca V We showed an enrichment of disruptive mutations in 1.2 and other gene members of the neuronal calcium signaling pathway, including CACNA2D, CACNB, and CAMK2 genes. V Ca 1.2 has been shown to be important for neuronal differentiation and migration, neurite outgrowth, synaptic signaling, gene expression and brain plasticity. V1.2 has been shown to play a role in the brain's emotion, learning and memory, executive functions, and reward responses.

[0003] Ca V 1.2 is widely expressed throughout the body and plays critical roles in multiple organ systems, including the cardiovascular system; however, Ca regulation in the cardiovascular system is poorly understood. V The physiological function of Ca 1.2 is different from its function in the brain. V Studies have shown that Ca 1.2 is an important contributor to action potential generation in the heart, while it is an important driver of intracellular signaling and gene expression in neurons, with a minimal role in action potential generation. V 1.2 The mutation p.G406R results in a distinct cellular phenotype between cardiomyocytes and neurons. Ca2+, which leads to cardiovascular specific disorders (Brugada syndrome and long QT syndrome type 8) V 1.2 mutation reduces Ca in the heart and brain V Further evidence of 1.2's versatility.

[0004] Although calcium channel activators have been reported previously, further investigation into their use for neuropsychiatric disorders has been limited by their effects on the cardiovascular system. In fact, many of these molecules were initially investigated and developed for their potential therapeutic use in heart failure. V The majority of 1.2 SNPs reside in the introns of genes, and these risk SNPs have been shown to be associated with reduced mRNA expression that often results in an overall reduction in calcium current amplitude. Therefore, small molecules that can increase the overall current amplitude may be most beneficial to patients. Summary of the Invention

[0005] The present disclosure relates to a compound according to formula (I) [ka] (In the formula: R 1 is H or halo; R 2 is ethyl, isopropyl, isopropenyl, cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 3 halo; or a pharma- ceutically acceptable salt thereof.

[0006] In a second aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0007] In a third aspect, the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in therapy, in particular in the treatment of psychiatric disorders including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; neurodegenerative disorders such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions such as Brugada syndrome, short QT syndrome, and early repolarization syndrome.

[0008] In a fourth aspect, the disclosure provides a method for the treatment of psychiatric disorders including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; neurodegenerative disorders such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions such as Brugada syndrome, short QT syndrome, and early repolarization syndrome, comprising the administration of an effective amount of a compound according to Formula (I) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment.

[0009] In a fifth aspect, the disclosure provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of psychiatric disorders including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; neurodegenerative disorders such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions such as Brugada syndrome, short QT syndrome, and early repolarization syndrome.

[0010] In a sixth aspect, the disclosure provides a method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome comprising administering a compound of formula (I) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment. [Brief description of the drawings]

[0011] [Figure 1] 1 illustrates simulated myocardial action potentials from an epicardial environment showing the effect of shifting the voltage of CaV1.2 activation towards more negative membrane potentials in potential (mV) versus time (ms). [Diagram 2] Illustrates a single X-ray crystal of methyl 2-methyl-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of Example 14, confirming that the active enantiomer is the S-enantiomer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] 5.1.Definition Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0013] As used herein, "administering" refers to the manner in which the compounds described herein are presented to a subject.

[0014] As used herein, "optionally substituted" means that the referenced group can be substituted in one or more positions with any one or any combination of the groups listed thereafter.

[0015] As used herein, "halo" as used herein may be fluorine, chlorine, bromine or iodine.

[0016] As used herein, "subject" or "patient" refers to a living organism suffering from one or more of the diseases or disorders described herein that can be treated by administration of the pharmaceutical compositions described herein (e.g., psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorder; neurodevelopmental disorders, such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome). Examples of subjects include mammals (e.g., humans and animals, such as dogs, cows, horses, monkeys, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals). In certain embodiments, the subject is a human, e.g., a human who suffers from, is at risk of suffering from, or may potentially suffer from, a disease described herein (e.g., psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; neurodegenerative disorders, e.g., multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, e.g., Brugada syndrome, short QT syndrome, and early repolarization syndrome).

[0017] Throughout this specification and in the claims that follow, unless the context requires otherwise, the word "comprises" or variations such as "included" or "comprising" should be understood to mean the inclusion of a stated integer or step, or group of integers or steps, but not the exclusion of any other integer or step, or group of integers or steps.

[0018] In the event of a discrepancy between a depicted structure and a chemical name given to that structure, the depicted structure shall be given weight. Furthermore, if the configuration of a structure or portion of a structure is not shown, for example, with bold or dashed lines, the structure or portion of the structure shall be interpreted as encompassing all stereoisomers of the structure or portion of the structure.

[0019] 5.2. Compounds Compounds according to formula (I) [ka] (In the formula: R 1 is H or halo; R 2 is ethyl, isopropyl, isopropenyl, cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 3 halo); or a pharma- ceutically acceptable salt thereof.

[0020] One embodiment is a compound of formula (Ia): [ka]

[0021] Another embodiment is a compound of formula (Ib). [ka]

[0022] In another embodiment, R 1 is H or F.

[0023] In another embodiment, R 1 is H.

[0024] In another embodiment, R 1 is F.

[0025] In another embodiment, R 2 is ethyl, isopropyl, isopropenyl, cyclopropyl, or cyclobutyl, each of which is optionally substituted with 1 to 3 F.

[0026] In another embodiment, R 2 is cyclopropyl optionally substituted with 1-3 F.

[0027] In another embodiment, R 2 is ethyl optionally substituted with 1 to 3 F.

[0028] In another embodiment, R 2 is isopropyl optionally substituted with 1 to 3 F.

[0029] The specific compound is Methyl (S)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-cyclobutyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-cyclopropyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-ethyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-ethyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(3-fluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(3-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(3,5-difluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; and Methyl (S)-4-(3-fluoro-2-(3-fluorocyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Includes.

[0030] Depending on the selection of starting materials and procedures, the compounds can exist in one of the possible stereoisomers depending on the number of asymmetric carbon atoms, or as mixtures thereof, for example as pure optical isomers, or as stereoisomeric mixtures, for example as racemates and diastereoisomeric mixtures. The present disclosure is meant to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R) and (S) stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds contain double bonds, the substituents can be in the E or Z configuration. When the compounds contain disubstituted cycloalkyl, the cycloalkyl substituents can have cis or trans configuration. All tautomeric forms are also intended to be included.

[0031] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the disclosed compound. "Salt" specifically includes "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the disclosed compound and is typically not biologically or otherwise undesirable. In many cases, the disclosed compound can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0032] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0033] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0034] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0035] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0036] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

[0037] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0038] In another aspect, the present disclosure provides an acid salt, such as acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, lauric acid salt ... In one embodiment, the compounds of the present disclosure are provided in the form of a salt of the arylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, trifenatate, trifluoroacetate, or xinafoate salt.

[0039] Compounds of the present disclosure, i.e., compounds of formula (I), containing groups capable of acting as donors and / or acceptors for hydrogen bonds, may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting compounds of formula (I) and co-crystal formers in solution under crystallization conditions and isolating the co-crystals formed thereby. Suitable co-crystal formers include those described in WO 2004 / 078163. Thus, the present disclosure further provides co-crystals comprising compounds of formula (I).

[0040] Furthermore, the compounds of the present disclosure, including their salts, can also be obtained in the form of their hydrates, or contain other solvents used for their crystallization. The compounds of the present disclosure can inherently or intentionally form solvates with pharma-ceutically acceptable solvents, including water; therefore, the present disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of the compounds of the present disclosure, including their pharma-ceutically acceptable salts, with one or more solvent molecules. Such solvent molecules are those commonly used in pharmaceutical technology, known to be harmless to recipients, such as water, ethanol, etc. The term "hydrate" refers to a complex where the solvent molecule is water.

[0041] The present disclosure includes unlabeled and isotopically labeled forms of the compound of formula (I).Isotopically labeled compounds have the structure shown by the formula shown herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number.The isotopes that can be incorporated in the compounds of the present disclosure include, for example, isotopes of hydrogen.

[0042] Additionally, certain isotopes, particularly deuterium (i.e. 2Incorporation of H or D) may provide certain therapeutic benefits due to greater metabolic stability, for example, increased half-life in vivo or reduced dosage requirements, or improved therapeutic index or tolerability. It is understood that deuterium is considered in this context as a substituent of the compounds of the present disclosure. The concentration of deuterium may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present disclosure is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0043] For example, formula (I) is deuterated as shown in formula (II): [ka] or a pharma- ceutically acceptable salt thereof, 1 and R 2 is as defined in formula (I); R D1 ~R D9 are each independently H or D.

[0044] Other examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as: 3 H,11 C. 13 C. 14 C. 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I. Thus, the present disclosure includes, for example, radioisotopes, e.g., 3 H and 14 Compounds incorporating one or more of any of the above isotopes, including C, or non-radioactive isotopes therein, e.g. 2 H and 13 It should be understood that this includes compounds in which C is present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radioactive treatment of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying examples and preparations, substituting the appropriate isotopically labeled reagent for the unlabeled reagent previously used.

[0045] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present disclosure can be present in racemic or enantiomerically enriched configuration, for example, (R), (S) or (R,S) configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) or (S) configuration. Substituents at atoms with unsaturated double bonds can be present in cis-(Z)- or trans-(E)-forms, where possible.

[0046] Thus, as used herein, the compounds of the present disclosure may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0047] Any resulting mixtures of stereoisomers can be separated on the basis of the physical chemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0048] Any resulting racemates of the compounds or intermediates of the present disclosure can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases, and liberating the optically active acidic or basic compounds. In particular, basic moieties can be used in this way to resolve the compounds of the present disclosure into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemates or racemic intermediates of the present disclosure can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC), using chiral adsorbents.

[0049] 5.3. Method of Use The compounds of the present disclosure, either in free form or in the form of a pharma- ceutically acceptable salt, have valuable pharmacological properties, e.g., Ca V 1.2 exhibits activating properties and is therefore indicated for use as a tool compound, for example for therapy or as a research chemical.

[0050] The compounds of the present disclosure may be useful in the treatment of an indication selected from the list below: psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; Neurodevelopmental disorders, such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders; and Neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia and Alzheimer's disease, and Cardiac conditions, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome. In one embodiment, the indication is a psychiatric disorder, such as schizophrenia, bipolar disorder, major depressive disorder, and substance use disorder. In another embodiment, the indication is schizophrenia or bipolar disorder.

[0051] Thus, as a further aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, in therapy. In a further embodiment, the therapy is V In another embodiment, the disease is selected from the above list of indications.

[0052] Thus, as a further aspect, the present disclosure provides a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, for use in therapy. In a further embodiment, the therapy comprises administering to a patient a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, V In another embodiment, the disease is selected from the above list of indications.

[0053] In another aspect, the present disclosure provides a method for treating Ca deficiency comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutical acceptable salt thereof. V In a further embodiment, the disease is selected from the above list of indications.

[0054] In another aspect, the present disclosure provides a method for treating Ca deficiency comprising administering a compound of the present disclosure or a pharma- ceutical acceptable salt thereof. V In a further embodiment, the disease is selected from the above list of indications.

[0055] Thus, as a further aspect, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament. V 1.2 is for the treatment of a disease treatable by activation of 1.2. In another embodiment, the disease is selected from the above list of indications.

[0056] In another aspect, the present disclosure provides a method for treating Ca deficiency comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutical acceptable salt thereof. VThe present invention provides a method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome, which are treated by activation of .1.2.

[0057] In another aspect, the disclosure provides a method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome comprising administration of a compound of the disclosure or a pharma- ceutically acceptable salt thereof.

[0058] Thus, as a further aspect, the present disclosure provides the use of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, for treating a disease selected from schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome.

[0059] Thus, as a further aspect, the disclosure provides a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for use in treating a disease selected from schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome.

[0060] In another aspect, the disclosure provides a method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome comprising administration of a therapeutically effective amount of a compound of the disclosure or a pharma- ceutically acceptable salt thereof.

[0061] In another aspect, the disclosure provides a method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome comprising administration of a compound of the disclosure or a pharma- ceutically acceptable salt thereof.

[0062] Thus, as a further aspect, the disclosure provides the use of a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome.

[0063] Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharma- ceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for a particular route of administration, for example, oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical composition of the present disclosure can be made in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be film-coated or enteric-coated by methods known in the art. Typically, the pharmaceutical composition comprises: a) excipients, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) for tablets also lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) optionally binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colouring agents, flavouring agents and sweetening agents The active ingredient is preferably a tablet or gelatin capsule containing one or more of the following:

[0064] The pharmaceutical compositions or combinations of the present disclosure may be in unit dosages of about 1-1000 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of active ingredient for a subject of about 50-70 kg. The therapeutically effective dosage of the compounds, pharmaceutical compositions, or combinations thereof depends on the species, weight, age, and individual condition of the subject, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of the disorder or disease.

[0065] The above-mentioned dosage properties are demonstrable in in vitro and in vivo tests, preferably using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues and preparations thereof. The compounds of the present disclosure can be applied in vitro in the form of solutions, e.g. aqueous solutions, and in vivo enterally, parenterally, advantageously intravenously, e.g. as a suspension or in aqueous solution. The dosage in vitro is about 10 -3 Molar concentration ~ 10 -9 The therapeutically effective amount in vivo may range from about 0.1 to 500 mg / kg, or from about 1 to 100 mg / kg, depending on the route of administration. EXAMPLES

[0066] 6. Intermediates and Examples The following examples are intended to illustrate the present disclosure and are not to be construed as limitations thereon.

[0067] All examples were separated into their single enantiomers and tested in the Sophion QPatch assay described in the Biological Data section below. However, the configuration of each enantiomer was not determined. The configuration of methyl 2-methyl-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate in Example 14 was determined by single crystal X-ray crystallography, which confirmed that the active enantiomer was the S-enantiomer (Figure 2). Therefore, it is assumed that the S-enantiomer of methyl 2-methyl-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate shown below is the active enantiomer in all examples. [ka]

[0068] Example numbers (Examples 1, 2, 3, etc.) are given for the active enantiomers which are all assumed to have the S configuration. All other isomers isolated from the synthesis have been given example numbers with letters (Examples 1b, 2b, 3b, etc.). Although there is strong evidence suggesting that the S configuration is the preferred configuration, it remains possible that in some of the examples the R-enantiomer may be the active enantiomer.

[0069] Temperatures are given in degrees Celsius. Unless otherwise noted, all evaporations are carried out under reduced pressure, typically at about 15 mm Hg to 100 mm Hg (=20 to 133 mbar). The structure of final products, intermediates, and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR.

[0070] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present disclosure are either commercially available or can be prepared by organic synthesis methods known to those of skill in the art. Additionally, the compounds of the present disclosure can be prepared by organic synthesis methods known to those of skill in the art, such as those illustrated in the Examples below. Abbreviations used are those conventional in the art or are as follows: 1 H NMR Proton Nuclear Magnetic Resonance AUX Ca V 1.2 channel auxiliary subunit C Celsius CD3OD methanol-d4 CDCl3 Chloroform-d CHO Chinese hamster ovary cells Ct Threshold cycle in quantitative polymerase chain reaction assay d double line DAST Diethylaminosulfur trifluoride DCM Dichloromethane dd Double line double line DME 1,4-dimethoxyethane DMEM Dulbecco's Modified Eagle's Medium DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Dimethylsulfoxide-d6 D-PBS Dulbecco's Phosphate Buffered Saline EC50 50% effective concentration EDTA Ethylenediaminetetraacetic acid EGTA Ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid Eq equivalent EtOAc Ethyl acetate FAM 6-Carboxyfluorescein FCS furin cleavage site FRT flippase recognition target site g grams h time H2O Water HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HOBt 1-Hydroxy-7-azabenzotriazole HPLC High Pressure Liquid Chromatography HRMS high-resolution mass spectrometry Hrs time Hz Hertz IACUC Animal Care and Use Committee IPA Isopropyl Alcohol kg Kilogram L Liter LCMS Liquid Chromatography Mass Spectrometry M mole m multiplet m / z mass-to-charge ratio mg milligram MHz Megahertz min mL Milliliters ml milliliter mL / min Milliliters per minute mm millimeters mM millimolar mmol mRNA Messenger Ribonucleic Acid MS mass spectrometry mV millivolt microliter N Normal n-BuLi n-Butyl lithium NMR nuclear magnetic resonance NOESY Nuclear Overhauser Effect Spectroscopy pCMV cytomegalovirus promoter P2A Peptide self-cleavage sequence derived from porcine teschovirus-1 PdCl2(dppf) Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) PD Pharmacodynamics PK Pharmacokinetics ppm parts per million PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate QT: The time interval between the Q and T waves on an electrocardiogram rac Racemic rpm Revolutions per minute RNA Ribonucleic acid RT room temperature Rt retention time RT-PCR Reverse transcription polymerase chain reaction s single line SFC Supercritical Fluid Chromatography SFM Serum-free medium SNP Single nucleotide polymorphism t triple line TFA Trifluoroacetic acid THF Tetrahydrofuran THF Tetrahydrofuran uL microliter Um micrometer UPLC Ultra-Performance Liquid Chromatography UV ultraviolet light VIC 2'-chloro-7'phenyl-1,4-dichloro-6-carboxy-fluorescein v / v volume / volume percent

[0071] Small molecule X-ray crystal structure analysis Data collection Intensity data were collected at 100 K on a Bruker AXS three-axis diffractometer with monochromator-mounted Cu(Kα) radiation, a microfocus rotating anode source, and a Smart6000 CCD detector using SMART software (Bruker AXS (2003)). Sixteen ω-scans at different Φ positions were performed to ensure adequate data overlap. Data processing and global cell refinement were performed in Saint (Bruker AXS (2012)). Semiempirical absorption corrections were applied based on the intensities of symmetric reflections measured at different angle settings using SADABS version 2016 / 2 (Krause L (2015)). The extinction coefficient was refined to 0.00048 (11). The crystallographic data, data collection parameters, and convergence results are listed.

[0072] Structure analysis and refinement The structure was solved by a dual space recycling method followed by DF synthesis and refined based on full matrix least squares fitting for F2 using the SHELXTL program suite (Sheldrick GM (2001)) with SHELXL-2013 / 4.

[0073] References: Allen FH, Kennard O, Watson D et al (1987)Tables of Bond Lengths determined by X-Ray and Neutron Diffraction.Part 1,Bond Lengths in Organic Compounds.J.Chem.Soc.Perkin Trans II;S1-S19. Bruker AXS(2005)SMART V5.632.Bruker AXS Inc.,Madison,WI,USA. Bruker AXS(2012)SAINT V7.36A.Bruker AXS Inc.,Madison,WI,USA. Krause L, Herbst-Irmer R, Sheldrick GM et al (2015) Comparison of silver and molybdenum microfocus X-ray sources for single-crystal structure determination.J.Appl.Cryst.;48:3-10. Spek AL(2003)Single-crystal structure validation with the program PLATON.J.Appl. Cryst.;36:7-13. Sheldrick GM(2001)SHELXTL V6.12.Bruker AXS Inc..Madison,WI,USA.

[0074] LCMS method 1: Instrument: Waters Acquity UPLC, photodiode array detector; Column: Acquity UPLC BEH C 18 , 1.7 μm, 21 × 30 mm; run time 2 min, 2% solvent B, 0–0.1 min, 2 → 98% solvent B: solvent A, 0.1–1.8 min, 98% solvent B, 0.2 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v); injection volume 2–5 μL; UV detection array 210–400, mass detection 120–1250 (electrospray ionization); column at 50 °C; flow rate 1.0 mL / min.

[0075] LCMS method 2: Instrument: Waters Acquity UPLC, photodiode array detector; Column: Acquity UPLC BEH C 18, 1.7 μm, 21 × 50 mm; 2 min run time, 2% solvent B, 0–0.1 min, 2 → 98% solvent B: solvent A, 0.1–1.8 min, 98% solvent B, 0.2 min. Solvents: solvent A = 5 mM ammonium hydroxide in water, solvent B = 5 mM ammonium hydroxide in acetonitrile. Injection volume 2–5 μL; UV detection array 210–400, mass detection 120–1250 (electrospray ionization); column at 50 °C; flow rate 1.0 mL / min.

[0076] LCMS method 3: Instrument: Waters Acquity UPLC, photodiode array detector; column: Acquity UPLC BEH C 18 , 1.7 μm, 21 × 30 mm; run time 5.2 min, 2 → 98% solvent B: solvent A, 0–5.15 min, 98% solvent B, 5.15–5.20 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v). Injection volume 2–5 μL; UV detection array 210–400, mass detection 120–1600; column at 50 °C, flow rate 1.0 mL / min.

[0077] LCMS method 4: Instrument: Waters Acquity UPLC, photodiode array detector; column: Acquity UPLC BEH C 18 , 1.7 μm, 21 × 30 mm; run time of 5.2 min, 2 → 98% solvent B: solvent A, 0–5.15 min, 98% solvent B, 5.15–5.20 min. Solvents: solvent A = 5 mM ammonium hydroxide in water, solvent B = 5 mM ammonium hydroxide in acetonitrile). Injection volume 2–5 μL; UV detection array 210–400, mass detection 120–1600; column at 50 °C, flow rate 1.0 mL / min.

[0078] LCMS method 5: Instrument: Agilent 1200LC / G1956A, Diode Array Detector; Column: Chromolith Flash C 18, 1.6 micron, 2 × 25 mm; 1.5 min run time, 5 → 95% solvent B:solvent A, 0 → 1.2 min, then 95% solvent B, 1.21 → 1.5 min. Solvents: solvent A = 0.0375% TFA in water (v / v), solvent B = 0.01875% TFA in acetonitrile (v / v). Injection volume 2-5 μL; UV detection 220 and 254 nM, mass detection 100-1000 (electrospray ionization); column at 50 °C; flow rate 1.5 mL / min.

[0079] LCMS method 6: Instrument: SHIMADZU LCMS-2020, photodiode array detector; Column: Kinetex EVO C 18 , 5 uM, 1 × 30 mm; 1.55 min run time, 5 → 95% solvent B:solvent A, 0 → 1.20 min, then 95% solvent B, 1.21 min to 1.55 min. Solvents: solvent A = 0.025% NH4OH in water (v / v), solvent B = acetonitrile. Injection volume 2-5 μL; UV detection 220 and 254 nM, mass detection 100-1000 (electrospray ionization); column at 40 °C; flow rate 1.5 mL / min.

[0080] LCMS method 7: Instrument: API2000, Column: Mercury MS Synergi, 2 μm, 20 × 4.0 mm, C12; Gradient: A- 0.1% formic acid in water / B- acetonitrile: time / %B: 0.0 / 30, 0.5 / 30, 1.5 / 95, 2.0 / 95, 2.5 / 30, 3.0 / 30, flow rate 2.0 mL / min; UV detection array 190-400, mass detection 100-1000 (electrospray ionization); Column temperature 30 °C.

[0081] LCMS method 8: Instrument: API3000, Column: Synergi, 2.5 μm, MAX-RP, 20 × 4.0 mm, 100A Mercury; Gradient: B: 0.1% formic acid in water, B: acetonitrile: Time %B 0 / 10, 0.5 / 20, 1.5 / 95, 2.0 / 95, 2.5 / 10, 3 / 10, Flow rate 2.0 mL / min; UV detection array 190-400 (total wavelength chromatogram), Mass detection 100-1000 (electrospray ionization); Column temperature 30 °C.

[0082] LCMS method 9: Instrument: API3000, Column: Synergi, 2.5 μm, 50 × 4.6 mm, MAX-RP100A; Gradient: A: 0.1% formic acid in water, B: acetonitrile: Time 0.0 / 10, 0.2 / 50, 1.0 / 95, 1.5 / 100, 2.5 / 95, 2.9 / 50, 3.2 / 10, 4 / 10, Flow rate 1.2 mL / min; UV detection array 190-400 (total wavelength chromatogram), Mass detection 100-1000 (electrospray ionization); Column temperature 30 °C.

[0083] LCMS method 10: Shimadzu, Column: Mercury MS Synergi, 2.5 μm, 20 × 4.0 mm, C12; Gradient: A- 0.1% formic acid in water / B- acetonitrile: time / %B: 0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5, flow rate 2.0 mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ionization); Column temperature 40 °C.

[0084] LCMS method 11: Shimadzu, Column: Kinetex, 5 μm, EVO C18 100A, (100 × 2.1 mm); Gradient: A- 0.1% formic acid in water / B- acetonitrile: time / %B: 0 / 5, 1 / 30, 3 / 95, 4 / 95, 4.1 / 5, 6 / 5, flow rate 1.4 mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ionization); Column temperature 40 °C.

[0085] LCMS method 12: Shimadzu, Column: Synergi, 2.5 μm, MAX-RP100A, (20 × 4.0 mm) Mercury; Gradient: A- 0.1% formic acid in water / B- acetonitrile: time / %B: 0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5, flow rate 2.0 mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ionization); Column temperature 40 °C.

[0086] LCMS method 13: Acquity, Column: UPLC BEH C18, 1.7 μm, 2.1 × 50 mm; Gradient: A-0.1% formic acid in water / B-acetonitrile: 2.2 min run time, 2 → 98% solvent B: solvent A, 0 → 1.76 min, then 95% solvent B, 1.76 min to 2.0 min; Flow rate 1.0 mL / min; UV detection array 210-400 nm; Mass range 100-2050 Da; HRMS_2 min; Column temperature 50 °C

[0087] Preparative HPLC method for purification: Method 1: HPLC column: XBRIDGE-C18 (19.0 x 150 mm, 5 micron), Mobile phase-A: 0.1% TFA in HO, B: CH3CN, Gradient (time / %B): 0 / 20, 2 / 20, 8 / 50) Flow rate: [19 mL / min].

[0088] Method 2: HPLC column: ZORBAXECLIPSE XDB C18 (21.2×150 mm, 5 micron), mobile phase-A: 0.1% TFA in H2O, B: CH3CN, gradient (time / %B): 0 / 10, 2 / 20, 10 / 40 and flow rate: [20 mL / min].

[0089] Method 3: HPLC column: XBRIDGE C18 (21.2×150 mm, 5 micron), mobile phase-A: 10 mM NH4HCO3 in water, B: CH3CN, gradient (time / % B): 0 / 10, 2 / 20, 8 / 50 and flow rate: [18 mL / min].

[0090] Method 4: HPLC column: Gemini NX C18 (21.2 x 150.00 mm, 5 microns); Mobile phase - (A): 0.1% TFA in water (B): acetonitrile / methanol; Flow rate: 15 mL / min; (time / %B, 0 / 20, 2 / 20, 8 / 20)

[0091] Method 5: HPLC column: KINETEX EVO, 5μ, C18 (21.2×150 mm), mobile phase: water (A) CH3CN (B), gradient (time / % B): 0 / 20, 2 / 30, 7 / 70 and flow rate: [18 mL / min].

[0092] Method 6: HPLC column: KINETEX C18, (21.2 x 150 mm), mobile phase: A: water, B: CH3CN:MeOH, gradient (time / %B): 0 / 20, 2 / 30, 7 / 70, flow rate: 18 mL / min].

[0093] Method 7: HPLC column: KINETEX (21.2 x 150 mm, 5 micron), mobile phase: A = 0.05% TFA in water, B = CH3CN, gradient (time / %B): 0 / 20, 2 / 30, 10 / 60, flow rate: 20 mL / min].

[0094] Chiral preparative HPLC method for separation of isomers: Method 1: Column: CHIRALPAK IC (10 x 250 mm, 5 micron); Mobile phase: Hexane (A) IPA:MeOH, 1:1 (B); Flow rate: 8 mL / min; Isocratic: 96:04 (A:B).

[0095] Method 2: Column: REGIS WELKO (250 x 10 mm, 5 micron); Mobile phase: Hexane (A):EtOH, 1:1 (B); Flow rate: 9 mL / min; Isocratic: 85:15 (A:B).

[0096] Method 3: Column: CHIRALPAC IG (250 x 10 mm, 5 micron); Mobile phase: IPA (A):MeOH, 1:1 (B); Flow rate: 6 mL / min; Isocratic: 98:2 (A:B).

[0097] Method 4: Column: LUX CELLULOSE-4 (10 x 250 mm, 5 micron); Mobile phase: Hexane (A) EtOH:IPA 1:1 (B); Flow rate: 8 mL / min; Isocratic: 90:10 (A:B).

[0098] Intermediates and general procedures: Intermediate A: Formation of ethyl 4-acetoxy-3-oxobutanoate [ka] To a solution of ethyl 4-chloro-3-oxobutanoate (200 g, 1215.1 mmol) in acetic acid (1500 mL) was added potassium acetate (357 g, 3645.4 mmol). The resulting solution was stirred at 90° C. for 18 h. The solvent was dissolved in water (2 L) and extracted into ethyl acetate (1 L×4 h). The combined organic phase was washed with saturated NaHCO3 solution (2 L) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→15%) afforded the title compound as a light brown liquid, ethyl 4-acetoxy-3-oxobutanoate (152 g). 1 H NMR(400MHz,CDCl3)δ 4.78(s,2H),4.20(q,J=14.1,7.2Hz,2H),3.49(s,2H),2.16(s,3H),1.28(t,J=7.2Hz,3H).

[0099] General Procedure I: Formation of 2-Methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Compounds [ka] To a solution of the aldehyde (1 equiv.) and methyl (Z)-3-aminobut-2-enoate (1 equiv.) in EtOH or MeOH (0.3 M) was added ethyl 4-chloro-3-oxobutanoate (1 equiv.). The resulting solution was stirred at 80° C. for 16-48 h. The solvent was removed under reduced pressure and the crude product was purified by silica column chromatography.

[0100] General Procedure II: Formation of 2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate compounds [ka] Step 1: To a solution of the aldehyde (1 eq.) and methyl (Z)-3-aminobut-2-enoate (1 eq.) in EtOH or MeOH (0.3 M) was added ethyl 4-acetoxy-3-oxobutanoate (Intermediate A, 1 eq.). The resulting solution was stirred at 80° C. for 14 h. The solvent was removed under reduced pressure to give the crude compound, which was generally taken on to step 2 without further purification.

[0101] Step 2: To the crude intermediate from step 2 in methanol (0.3 M) was added potassium carbonate (3 equiv.). The resulting solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, added to water (500 mL), extracted into ethyl acetate and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography to give the product.

[0102] Example 1. Methyl (S)-4-(2-((R or S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate and Example 2. Methyl (S)-4-(2-((S or R)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of commercially available 2-bromo-3-fluorobenzaldehyde (60 g, 295.56 mmol) and ethylene glycol (65.4 mL, 1182.2 mmol) in toluene (600 mL) was added p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol). The resulting solution was stirred at 120° C. for 24 h using a Dean-Stark apparatus. The solvent was dissolved in water (2 L) and extracted into ethyl acetate (3 L). This was washed with saturated NaHCO3 solution (1 L) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (60 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.42-7.37(m,1H),7.34-7.29(m,1H),7.16-7.10(m,1H),6.10(s,1H),4.19-4.09(m,4H).

[0103] Step 2: 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane [ka] To a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, 15 g, 60.72 mmol) and potassium vinyltrifluoroborate (16.26 g, 121.45 mmol) in isopropyl alcohol (200 mL) was added triethylamine (25.5 mL, 182.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (4.95 g, 6.07 mmol). The resulting solution was degassed with argon gas for 10 min and stirred at 80 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (100 mL). The filtrate was added to water (1 L), extracted into ethyl acetate (2 L), and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane (7.5 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.45-7.41(m,1H),7.27-7.20(m,1H),7.10-7.03(m,1H),6.82(dd,J=17.7,11. 7Hz,1H),5.82-5.78(m,1H),5.66-5.60(m,1H),5.95(s,1H),4.18-4.02(m,4H).

[0104] Step 3: 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane (from step 2, 6.5 g, 33.47 mmol) and trifluoromethyltrimethylsilane (50 mL, 334.7 mmol) in tetrahydrofuran (120 mL) was added sodium iodide (2.5 g, 16.73 mmol). The resulting solution was stirred at 65° C. for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM (100 mL). It was washed with water (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, which gave the title compound 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3-dioxolane (8 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.42(d,J=7.5Hz,1H),7.34-7.28(m,1H),7.16-7.03(m,1H),6.06(s,1H),4.20-4.01(m,4H),2.77-2.66(m,1H),2.02-1.72(m,2H).

[0105] Step 4: 2-(2,2-difluorocyclopropyl)-3-fluorobenzaldehyde [ka] To a solution of 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 8 g, 32.76 mmol) in diethyl ether (80 mL) was added 6N HCl (10 mL). The resulting solution was stirred at room temperature for 2 h. It was washed with water (50 mL) and saturated NaHCO3 solution (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→5%) afforded the title compound 2-(2,2-difluorocyclopropyl)-3-fluorobenzaldehyde (3.8 g) as a colorless liquid. 1H NMR(400MHz,CDCl3)δ 10.28(s,1H),7.70(d,J=6.9Hz,1H),7.50-7.43(m,1H),7.36-7.26(m,1H),2.92-2.81(m,1H),2.16-2.06(m,1H),1.67-1.53(m,1H).

[0106] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using general method II, step 1 (using the aldehyde from step 4, 3.8 g, 18.93 mmol) to give (9.3 g, crude). LCMS Rt=1.716 min;MS m / z, 468.3[M+H]+;[Method 7]

[0107] Step 6: Methyl-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using step 2 of general method II (using intermediate from step 5, 9.3 g, 19.89 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) to give the title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (2.3 g) as an off-white solid. LCMS Rt=1.489 min;MS m / z, 380.1[M+H]+;[Method 7]

[0108] The racemic sample was separated into its four stereoisomers by chiral SFC (mobile phase: 30% IPA / CO2, 80 g / min; column: (SS) Whelk-O1, 21 x 250 mm; instrument: Thar80_SN4739).

[0109] Example 1 290.6 mg of the second eluting stereoisomer (73.6%) as a white solid SFC Rt=2.94 min; ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.12 min;MS m / z, 380.3[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),7.29(td,J=7.9,5.6Hz,1H),7.11-6.91(m,2H),5.20(s,1H),4.88(q,J=16.3Hz,2H),3.49(s,3H),2 .85(td,J=12.5,8.5Hz,1H),2.60(dtd,J=11.9,7.9,3.5Hz,1H),2.27(s,3H),2.16(tq,J=12.9,7.3,6.7Hz,1H).

[0110] Example 2 261.0 mg of the first eluting stereoisomer (68.9%) as a white solid SFC Rt=2.86 min; ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.08 min;MS m / z, 380.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.86(s,1H),7.31(td,J=8.0,5.7Hz,1H),7.05-6.97(m,2H),5.23(s,1H),4.78(s,2H),3.43(s,3H),3.15( td,J=12.6,8.5Hz,1H),2.36(s,3H),2.23(tt,J=12.3,6.7Hz,1H),1.93(dtd,J=11.0,8.4,7.7,4.7Hz,1H).

[0111] Example 1b 275.0 mg of the third eluting stereoisomer (72.2%) as a white solid SFC Rt=3.16 min; ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.08 min;MS m / z, 380.1[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.89(s,1H),7.31(td,J=7.9,5.6Hz,1H),7.01(dd,J=9.7,8.2Hz,2H),5.23(s,1H),4.77(s,2H),3.43(s ,3H),3.15(td,J=12.7,8.7Hz,1H),2.36(s,3H),2.30-2.15(m,1H),1.94(dtd,J=14.1,8.0,3.3Hz,1H).

[0112] Example 2b 366.0 mg of the fourth eluting stereoisomer (93.0%) as a white solid. SFC Rt=3.39 min; ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.07 min;MS m / z, 380.1[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 10.01(s,1H),7.29(td,J=7.9,5.6Hz,1H),7.10-6.92(m,2H),5.19(s,1H),4.87(q,J=16.2Hz,2H),3.48(s,3H) ),2.85(td,J=12.5,8.5Hz,1H),2.61(dtd,J=11.8,8.0,3.4Hz,1H),2.27(s,3H),2.15(tt,J=12.1,7.0Hz,1H).

[0113] Example 3. Methyl (S)-4-(2-cyclobutyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-Fluoro-6-formylphenyl trifluoromethanesulfonate [ka] To a solution of 3-fluoro-2-hydroxybenzaldehyde (6 g, 42.82 mmol) and pyridine (10.35 mL, 128.47 mmol) in dichloromethane (35 mL) was added trifluoromethanesulfonic anhydride (8.45 mL, 51.38 mmol) at 0° C. The resulting solution was stirred at room temperature for 4 h. The reaction mixture was added to water (1 L), extracted into ethyl acetate (1 L), and the EtOAc was washed with saturated NH4Cl solution (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→20%) afforded the title compound 2-fluoro-6-formylphenyl trifluoromethanesulfonate (6 g) as a colorless liquid. 1H NMR(300MHz,CDCl3)δ 10.22(s,1H),7.80-7.76(m,1H),7.58-7.53(m,2H).

[0114] Step 2: 2-Cyclobutyl-3-fluorobenzaldehyde [ka] To a solution of 2-fluoro-6-formylphenyl trifluoromethanesulfonate (from step 1, 3 g, 11.03 mmol) and 2N cesium carbonate (8.82 mL, 17.64 mmol) in toluene (35 mL) was added cyclobutylboronic acid (1.32 g, 13.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (900 mg, 1.103 mmol). The resulting solution was degassed with argon gas for 10 min and stirred at 90 °C for 2.5 h. The reaction mixture was filtered and washed with ethyl acetate (100 mL). The filtrate was dissolved in water (1 L), extracted into ethyl acetate (2 L), and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→5%) afforded the title compound 2-cyclobutyl-3-fluorobenzaldehyde (200 mg) as a colorless liquid. 1 H NMR(600MHz,CDCl3)δ 10.26(s,1H),7.57(d,J=7.8Hz,1H),7.26-7.17(m,2H),4.27-4.22(m,1H),2.46-2.42(m,4H),2.14-2.05(m,1H),1.93-1.90(m,1H).

[0115] Step 3: 3-Ethyl-5-methyl-2-(acetoxymethyl)-4-(2-cyclobutyl-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl-5-methyl-2-(acetoxymethyl)-4-(2-cyclobutyl-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using general method II, step 1 (using the aldehyde from step 2, 200 mg, 1.12 mmol) to give (80 mg, crude). LCMS Rt=1.94 min;MS m / z, 446.4[M+H]+;[Method 8]

[0116] Step 4: Methyl-4-(2-cyclobutyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] To a stirred solution of 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclobutyl-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (intermediate from step 3, 80 mg, 19.89 mmol used) in methanol (5 mL) was added potassium hydroxide (1.2 g, 21.57 mmol). The resulting solution was stirred at 65° C. for 30 min. Water was added to the reaction mixture, a solid precipitated and filtered. The solid was washed with diethyl ether, and the solid was collected and dried under reduced pressure to give the crude title compound. The crude product was purified using preparative HPLC [Method 5], which gave the title compound, methyl-4-(2-cyclobutyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (34 mg) as an off-white solid. LCMS Rt=1.598 min;MS m / z, 358.2[M+H]+;[Method 7] The racemic mixture was separated into the two enantiomers using preparative chiral HPLC [Method 1].

[0117] Example 3 10 mg of the second eluting enantiomer as a white solid, 29% yield. Chiral HPLC Rt=6.306 min (Mobile phase: n-Hexane (A) IPA:MeOH, 1:1 (B); 1 mL / min; Isocratic: 70:30 (A:B); Column: Lux, 5 micron, Cellulose-4 (250×4.6 mm, 5 micron). LCMS Rt=1.6 min;MS m / z, 358.2[M+H]+;[Method 7] 1 H NMR(400MHz,MeOH-d4)δ 7.01-7.04(m,1H),6.94(d,J=11.2Hz,1H),6.84-6.79(m,1H),5.18(s,1H),4.76(s,2H),4.32-4 .23(m,1H),3.46(s,3H),2.74-2.50(m,2H),2.49-2.29(m,2H),2.35(s,3H),2.18-1.90(m,2H).

[0118] Example 3b 10 mg of the first eluting enantiomer as a white solid, 29% yield. Chiral HPLC Rt=5.796 min (Mobile phase: n-Hexane (A) IPA:MeOH, 1:1 (B); 1 mL / min; Isocratic: 70:30 (A:B); Column: Lux, 5 micron, Cellulose-4 (250×4.6 mm, 5 micron). LCMS Rt=1.602 min;MS m / z, 358.2[M+H]+;[Method 7] 1 H NMR(400MHz,MeOH-d4)δ 7.01-7.04(m,1H),6.94(d,J=11.2Hz,1H),6.84-6.79(m,1H),5.18(s,1H),4.76(s,2H),4.32-4 .23(m,1H),3.46(s,3H),2.74-2.50(m,2H),2.49-2.29(m,2H),2.35(s,3H),2.18-1.90(m,2H).

[0119] Example 4. Methyl (S)-4-(2-cyclopropyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3-fluorobenzaldehyde [ka] To a solution of commercially available 2-bromo-3-fluorobenzaldehyde (15 g, 73.88 mmol) and cyclopropylboronic acid (7.61 g, 88.66 mmol) in toluene (160 mL) was added 2N K2CO3 (25.5 mL, 182.16 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (6.03 g, 7.38 mmol). The resulting solution was degassed with argon gas for 10 min and stirred at 100 °C for 4 h. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The filtrate was added to water (500 mL) and the product was extracted into ethyl acetate (2 L) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→1%) afforded the title compound 2-cyclopropyl-3-fluorobenzaldehyde (11.2 g) as a colourless liquid. 1 H NMR(300MHz,CDCl3)δ 10.70(s,1H),7.63(dd,J=1.2,7.8Hz,1H),7.35-7.15(m,2H),2.14-2.02(m,1H),1.19-1.09(m,2H),0.85-0.75(m,2H).

[0120] Step 2: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using general method I (using intermediate from step 1, 24.5 g, 149.2 mmol). The crude product was purified using silica column chromatography to give the title compound, methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (5.15 g) as an off-white solid. LCMS Rt=1.598 min; MS m / z, 358.2 [M+H]+; [Method 7] The racemic sample was separated into its enantiomers by chiral SFC (mobile phase: 10% MeOH / CO2, 70 mL / min; column: OJ-H, 2 x 25 cm).

[0121] Example 4 2.27 g of the second eluting enantiomer (84%) as an off-white solid. SFC Rt=2.02 min (Chiralcel OJ-H, 4.6×100mm, 5μm, 5→55%MeOH / CO2). HRMS Rt=1.16 min;MS m / z, 344.1334[M+H]+;[Method 13] 1 H NMR(400MHz, methanol-d4)δ 7.11(td,J=7.9,5.2Hz,1H),6.98(dd,J=7.8,1.4Hz,1H),6.85-6.69(m,1H),5.57(s,1H),4.75(s,2H),3.52 (s,3H),2.34(s,3H),2.13(tt,J=8.7,5.8Hz,1H),1.26-1.14(m,1H),1.04-0.87(m,2H),0.87-0.69(m,1H).

[0122] Example 4b 2.38 g of the first eluting enantiomer (79%) as an off-white solid. SFC Rt=1.96 min (Chiralcel OJ-H, 4.6×100mm, 5μm, 5→55%MeOH / CO2). HRMS Rt=1.16;MS m / z, 344.1329[M+H]+;[Method 13] 1 H NMR(400MHz, methanol-d4)δ 7.11(td,J=8.0,5.3Hz,1H),6.98(dd,J=7.8,1.4Hz,1H),6.78(ddd,J=11.3,8.3,1.8Hz,1H),5.57(s,1H),4.78(s,2 H),3.52(s,3H),2.34(s,3H),2.14(tt,J=8.8,5.8Hz,1H),1.27-1.17(m,1H),1.01-0.90(m,2H),0.82-0.73(m,1H).

[0123] Example 5. Methyl (S)-4-(2-((R or S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate and Example 6. Methyl (S)-4-(2-((R or S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane [ka] A solution of 2-bromo-3,5-difluorobenzaldehyde (10 g, 45.24 mmol) and ethylene glycol (8.45 g, 135.7 mmol) (600 mL), p-toluenesulfonic acid monohydrate (6.88 g, 36.18 mmol) in toluene (100 mL) was stirred at 130 °C for 5 h using a Dean-Stark apparatus. The solvent was added to saturated NaHCO3 solution (100 mL), the organic layer was separated, the aqueous layer was extracted twice with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in hexanes, 0 → 10%) afforded the title compound 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane (11.5 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.201- 7.157(m,1H),6.49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H).

[0124] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane [ka] A solution of 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane (from step 1, 5 g, 18.94 mmol), potassium vinyltrifluoroborate (5.8 g, 37.89 mmol), and triethylamine (7.91 mL, 56.82 mmol) in isopropyl alcohol (50 mL) was degassed with argon gas for 10 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (1.55 g, 1.89 mmol) was added and the resulting solution was degassed again with argon gas for 10 min and stirred at 80 °C for 5 h. The reaction mixture was filtered and washed with ethyl acetate (100 mL). The filtrate was added to water (1 L), extracted into ethyl acetate (2 L), and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane 3.45 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.20-7.16(m,1H),6.94-6.83(m,1H),6.82(dd,J=17.7,11.7Hz,1H),5.60( dd,J=1.2,11.7Hz,1H),5.66-5.60(m,1H),5.95(s,1H),4.18-4.02(m,4H).

[0125] Step 3: 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-1,3-dioxolane [ka] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (from step 2, 2.4 g, 11.31 mmol) and trifluoromethyltrimethylsilane (16.1 g, 113.1 mmol) in tetrahydrofuran (15 mL) was added sodium iodide (850 mg, 5.65 mmol). The resulting solution was stirred at 65° C. for 24 hours. Re-cooled to room temperature, trifluoromethyltrimethylsilane (16.1 g, 113.1 mmol) and sodium iodide (850 mg, 5.65 mmol) were added to the reaction and the resulting solution was stirred at 65° C. for 24 hours. The reaction mixture was partitioned between EtOAc and water, the organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, which gave the title compound, 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-1,3-dioxolane (1.5 g) as a brown liquid. 1 H NMR(400MHz,CDCl3)δ 7.26-7.14(m,1H),6.90-6.77(m,1H),6.04(s,1H),4.17-4.03(m,4H),2.77-2.66(m,1H),1.98-1.70(m,2H).

[0126] Step 4: 2-(2,2-difluorocyclopropyl)-3,5-difluorobenzaldehyde [ka] To a solution of 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-1,3-dioxolane (from step 3, 1.5 g, 5.72 mmol) in diethyl ether (15 mL) was added 6N HCl (3 mL). The resulting solution was stirred at room temperature for 3 h. It was washed with water (50 mL) and saturated NaHCO3 solution (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in hexanes, 0→5%) afforded the title compound 2-(2,2-difluorocyclopropyl)-3,5-difluorobenzaldehyde (1.25 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.22(s,1H),7.50-7.39(m,1H),7.20-7.05(m,1H),2.80-2.60(m,1H),2.18-1.89(m,1H),1.65-1.53(m,1H).

[0127] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using general method II, step 1 (using the aldehyde from step 4, 1.25 g, 5.73 mmol) to give (1.45 g, crude). LCMS Rt=1.775 min;MS m / z, 486.3[M+H]+;[Method 12]

[0128] Step 6: Methyl 4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using step 2 of general method II (using intermediate from step 5, 945 mg, 1.948 mmol). Purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→50%) afforded the title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (520 mg) as an off-white solid. LCMS Rt=1.553 min;MS m / z, 398.2[M+H]+;[Method 12] 1 H NMR (300 MHz, CD3CN) δ 7.80 (s, 1H), 6.949-6.774 (m, 2H), 5.31 (s, 1H), 4.81, 4.79 and 4.70 (3 s, 2H), 3.54 and 3.49 (2 s, 3H), 2.79-2.66 (m, 1H), 2.39 and 2.30 (2 s, 3H), 2.14-2.05 (m, 2H), (peaks due to multiple diastereomeric mixtures).

[0129] The racemic sample was separated into its four stereoisomers by chiral SFC (mobile phase: 25% IPA / CO2, 80 g / min; column: (SS) Whelk-O1, 21 x 250 mm; instrument: Thar80_SN4740).

[0130] Example 5 120.2 mg of the second eluting stereoisomer (93.0%) as a white solid SFC Rt=2.70 points ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.19 minutes; MS m / z, 398.2[M+H]+; [Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.94(s,1H),7.07(ddd,J=11.1,8.8,2.8Hz,1H),6.96-6.68(m,1H),5.23(d,J=1.8Hz,1H),5.08-4.63(m,2H),3.50( s,3H),2.81(td,J=11.9,7.8Hz,1H),2.59(ddt,J=12.7,8.3,4.0Hz,1H),2.29(s,3H),2.18(tt,J=12.7,7.0Hz,1H).

[0131] Example 6 White solid として 61.8 mg, the first soluble stereoisotrope (47.8%) SFC Rt=2.64 points ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.20min;MS m / z, 398.3[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.92(s,1H),7.07(ddd,J=11.2,8.8,2.7Hz,1H),6.89-6.66(m,1H),5.25(d,J=1.8Hz,1H),4.86-4.72(m,2H),3 .45(s,3H),3.15-3.03(m,1H),2.38(s,3H),2.26(tq,J=12.2,7.1,6.3Hz,1H),1.92(qd,J=8.8,8.2,4.9Hz,1H).

[0132] Example 5b White solid として 76.7mg 3rd dissolution stereoisomer (59.4%) SFC Rt=2.86 points ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.19 min;MS m / z, 398.1[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.92(s,1H),7.07(ddd,J=10.1,8.6,2.7Hz,1H),6.92-6.64(m,1H),5.25(d,J=1.5Hz,1H),4.80(d,J=3.5Hz,2H ),3.45(s,3H),3.16-3.01(m,1H),2.38(s,3H),2.25(tt,J=12.2,6.6Hz,1H),1.92(qd,J=9.1,8.0,5.0Hz,1H).

[0133] Example 6b 133.6 mg of the fourth eluting stereoisomer (98.0%) as a white solid SFC Rt=3.08 min ((SS)Whelk-O1, 4.6×100mm, 5μm, 5→55%IPA / CO2). LCMS Rt=2.19 min;MS m / z, 398.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.92(s,1H),7.07(ddd,J=11.2,8.8,2.7Hz,1H),6.89-6.66(m,1H),5.25(d,J=1.8Hz,1H),4.86-4.72(m,2H),3 .45(s,3H),3.15-3.03(m,1H),2.38(s,3H),2.26(tq,J=12.2,7.1,6.3Hz,1H),1.92(qd,J=8.8,8.2,4.9Hz,1H).

[0134] Example 7. Methyl (S)-4-(3,5-difluoro-2-((S or R)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde [ka] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (step 2 from Example 5, 5 g, 23.58 mmol) and ruthenium chloride·XH2O (490 mg, 2.35 mmol) in dichloromethane (50 mL) and water (10 mL) was added diacetoxyiodobenzene (11.4 g, 35.37 mmol). The resulting solution was stirred at 30 °C for 2 h. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The filtrate was added to water (200 mL), extracted into ethyl acetate (500 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0 → 10%) afforded the title compound 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (3 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.41(s,1H),7.35(d,J=9.6Hz,1H),6.95-6.85(m,1H),6.53(s,1H),4.08(s,4H).

[0135] Step 2: 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethan-1-ol [ka] To a solution of 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (from step 1, 1.0 g, 4.67 mmol) in dry tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (2.33 mL, 3 M in ether, 4.67 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (10 mL) at 0° C. and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethan-1-ol (950 mg) as a colorless liquid. The crude compound was carried forward to the next step without further purification. 1 H NMR(300MHz,CDCl3)δ 7.17(dd,J=2.4,6.3Hz,1H),6.89-6.72(m,1H),6.17(s,1H),5.31(dd,J=6. 9,13.5Hz,1H),4.15-4.02(m,4H),2.64-2.59(m.1H),1.58(d,J=9.0Hz,3H).

[0136] Step 3: 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane [ka] To a solution of 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethan-1-ol (from step 2, 950 mg, 4.13 mmol) in dichloromethane (10 mL) at -78 °C was added diethylaminosulfur trifluoride (1.0 g, 6.13 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (10 mL) at 0 °C and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (600 mg) as a thick yellow liquid. The crude compound was carried forward to the next step without further purification. 1 H NMR(300MHz,CDCl3)δ 7.20(dd,J=2.4,6.3Hz,1H),6.87-6.75(m,1H),6.15-5.98(m,1H),6.11(s,1H),4.15-4.02(m,4H),1.70(dd,J=6.6,22.8Hz,3H).

[0137] Step 4: 3,5-Difluoro-2-(1-fluoroethyl)benzaldehyde [ka] To a solution of 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (from step 3, 600 mg, 2.58 mmol) in diethyl ether (10 mL) was added 4N HCl (2 mL) at room temperature. The resulting solution was stirred at room temperature for 3 h. It was washed with water (50 mL) and saturated NaHCO3 solution (100 mL), brine and dried over Na2SO4. The solvent was removed under reduced pressure, which gave the title compound 3,5-difluoro-2-(1-fluoroethyl)benzaldehyde (200 mg) as a colorless liquid. (Note: the resulting aldehyde is volatile in nature.) 1H NMR(300MHz,CDCl3)δ 10.44(d,J=3.0Hz,1H),7.20(d,J=9.3Hz,1H),7.10-6.98(m,1H),6.43-6.19(m,1H),1.78(dd,J=7.2,23.1Hz,3H).

[0138] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using step 1 of general method II (using the aldehyde from step 4, 200 mg, 1.06 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (800 mg, crude). LCMS Rt=1.738 min;MS m / z, 456.3[M+H]+;[Method 7]

[0139] Step 6: Methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using step 2 of general method II (using the crude intermediate from step 5, 800 mg, 1.75 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→80%) to give the title compound, methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (100 mg) as an off-white solid.

[0140] The diastereomeric mixture was separated into isomers using preparative HPLC [Method 4].

[0141] 39 mg of the first eluting diastereomer as a white solid and 35 mg of the second eluting diastereomer as a white solid. Peak 1: 39 mg and Peak 2: 35 mg were further separated into single enantiomers using preparative chiral HPLC [Method 1].

[0142] Example 7 9 mg of first eluting enantiomer as a white solid Chiral HPLC Rt=5.77 min (mobile phase: A=n-hexane, B=ethanol (1:1); 1 mL / min; isocratic: 70:30 (A:B); column: Regis, (S,S)Whelk-01-(250×4.6 mm, 5 microns). LCMS Rt=1.492 min;MS m / z, 366.0[MH]-;[Method 12] 1 H NMR (400 MHz, chloroform-d) δ 8.03 (s, 1H), 6.71-6.62 (m, 2H), 6.59-6.39 (m, 1H), 5.06 (s, 1H), 4.66 (d, J = 1.7 Hz, 2H), 3.55 (s, 3H), 2.40 (s, 3H), 1.90-1.67 (m, 3H).

[0143] Example 7b 9 mg of the second enantiomer as a white solid. Chiral HPLC Rt=7.806 min (Mobile phase: A=n-Hexane, B=Ethanol (1:1); 1 mL / min; Isocratic: 70:30 (A:B); Column: Regis, (S,S)Whelk-01-(250×4.6 mm, 5 microns). LCMS Rt=1.487 min;MS m / z, 366.0[MH]-;[Method 12] 1 H NMR (400 MHz, chloroform-d) δ 6.78-6.63 (m, 2H), 6.43-6.19 (m, 2H), 5.11 (s, 1H), 4.78-4.71 (m, 2H), 3.59 (s, 3H), 2.45 (d, J = 0.5 Hz, 3H), 1.92 (ddd, J = 23.2, 6.7, 1.5 Hz, 3H).

[0144] Example 7c 7 mg of the third enantiomer eluting as a white solid Chiral HPLC Rt=10.16 min (mobile phase: A=n-hexane, B=ethanol (1:1); 1 mL / min; isocratic: 70:30 (A:B); column: Regis, (S,S) Whelk-01-(250×4.6 mm, 5 microns). LCMS Rt=1.493 min;MS m / z, 366.0[MH]-;[Method 12] 1 H NMR (400 MHz, chloroform-d) δ 6.73-6.61 (m, 3H), 6.40-6.20 (m, 1H), 5.18-5.06 (m, 1H), 4.80-4.67 (m, 2H), 3.58 (s, 3H), 2.43 (s, 3H), 1.91 (ddd, J = 23.2, 6.6, 1.5 Hz, 3H).

[0145] Example 7d 7 mg of the fourth enantiomer eluted as a white solid Chiral HPLC Rt=11.83 min (mobile phase: A=n-hexane, B=ethanol (1:1); 1 mL / min; isocratic: 70:30 (A:B); column: Regis, (S,S) Whelk-01-(250×4.6 mm, 5 microns). LCMS Rt=1.510 min;MS m / z, 366.0[MH]-;[Method 12] 1 H NMR (400 MHz, chloroform-d) δ 7.81 (s, 1H), 6.67 (t, J = 9.0, 9.0 Hz, 2H), 6.50 (dq, J = 44.5, 6.7, 6.7, 6.7 Hz, 1H), 5.06 (s, 1H), 4.66 (s, 2H), 3.55 (s, 3H), 2.41 (s, 3H), 1.80 (dd, J = 22.8, 6.6 Hz, 3H).

[0146] Example 8. Methyl (S)-4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-6-fluorophenyl)propan-2-ol [ka] To a solution of commercially available 1-(2-bromo-6-fluorophenyl)ethan-1-one (11.0 g, 50.69 mmol) in dry tetrahydrofuran (100 mL) was added dropwise methylmagnesium bromide (33.8 mL, 3 M in ether, 101.3 mmol) at -15°C. The resulting solution was slowly warmed to room temperature and stirred for an additional hour. The reaction mixture was quenched with saturated ammonium chloride (30 mL) at 0°C and diluted with ethyl acetate (500 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(2-bromo-6-fluorophenyl)propan-2-ol (10 g) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.46-7.34 (m, 1H), 7.13-6.94 (m, 2H), 3.44 (bs, 1H), 1.77 (s, 3H), 1.76 (s, 3H).

[0147] Step 2: 1-Bromo-3-fluoro-2-(2-fluoropropan-2-yl)benzene [ka] To a solution of 2-(2-bromo-6-fluorophenyl)propan-2-ol (from step 1, 7.0 g, 30.02 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (8.06 mL, 60.06 mmol) at -78°C. The resulting solution was stirred at room temperature for 3 h. The reaction mixture was quenched with saturated ammonium bicarbonate solution (10 mL) at 0°C and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 1-bromo-3-fluoro-2-(2-fluoropropan-2-yl)benzene (4.0 g) as a colorless liquid. 1H NMR (300 MHz, chloroform-d) δ 7.45 (m, 1H), 7.17-6.87 (m, 2H), 1.89 (s, 3H), 1.82 (s, 3H).

[0148] Step 3: 1-Fluoro-2-(2-fluoropropan-2-yl)-3-vinylbenzene [ka] To a solution of 1-bromo-3-fluoro-2-(2-fluoropropan-2-yl)benzene (from step 2, 4.0 g, 17.02 mmol) and potassium vinyltrifluoroborate (4.55 g, 34.04 mmol) in isopropyl alcohol (40 mL) was added triethylamine (7.0 mL, 51.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (1.39 g, 1.702 mmol). The resulting solution was degassed with argon gas for 10 min and stirred at 80 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (100 mL). The filtrate was added to water (50 mL), extracted into ethyl acetate (200 mL), washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→5%) afforded the title compound 1-fluoro-2-(2-fluoropropan-2-yl)-3-vinylbenzene (2.0 g) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.44-7.30 (m, 1H), 7.25-7.10 (m, 2H), 7.03-6.76 (m, 1H), 5.45-5.16 (m, 2H), 1.84 (s, 3H), 1.76 (s, 3H).

[0149] Step 4: 3-Fluoro-2-(2-fluoropropan-2-yl)benzaldehyde [ka] To a solution of 1-fluoro-2-(2-fluoropropan-2-yl)-3-vinylbenzene (from step 3, 2.0 g, 10.97 mmol) and ruthenium chloride·XH2O (227 mg, 1.097 mmol) in dichloromethane (60 mL) and water (15 mL) was added diacetoxyiodobenzene (10.6 g, 32.93 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The filtrate was added to water (200 mL), extracted into ethyl acetate (500 mL), washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→5%) afforded the title compound 3-fluoro-2-(2-fluoropropan-2-yl)benzaldehyde (800 mg) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 10.57 (s, 1H), 7.61-7.46 (m, 1H), 7.48-7.30 (m, 1H), 7.23 (m, 1H), 1.91 (s, 3H), 1.85 (s, 3H).

[0150] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using general method II, step 1 (using the aldehyde from step 4, 600 mg, 3.25 mmol) to give (230 mg, crude). LCMS Rt=2.279 min;MS m / z, 452.4[M+H]+;[Method 9]

[0151] Step 6: Methyl 4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using step 2 of general method II (using intermediate from step 5, 200 mg, 0.509 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→60%) to give the title compound, methyl 4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (30 mg) as an off-white solid. LCMS Rt=1.477 min; MS m / z, 362.2 [MH]-; [Method 12] The racemic sample was separated into its enantiomers by chiral SFC (mobile phase: 15% MeOH / CO2, 80 mL / min; column: IC21 x 250 mm, 5 μm).

[0152] Example 8 6.0 mg of the first eluting enantiomer (23.8%) as a white solid. SFC Rt=1.98 min (Chiralpak IC, 4.6×100mm, 5μm, 5→55%MeOH / CO2) LCMS Rt=2.04 min;MS m / z, 362.2[MH]-;[Method 4] 1H NMR(400MHz,DMSO-d6)δ 9.67(s,1H),7.25(td,J=8.0,5.6Hz,1H),7.13(dd,J=8.0,1.5Hz,1H),7.05-6.89(m,1H),5.83 (d,J=15.2Hz,1H),4.75(s,2H),3.43(s,3H),2.28(s,3H),1.83(ddd,J=30.8,24.0,1.8Hz,6H).

[0153] Example 8b 6.0 mg of the second eluting enantiomer (23.8%) as a white solid. SFC Rt=2.35 min (Chiralpak IC, 4.6×100mm, 5μm, 5→55%MeOH / CO2) LCMS Rt=2.06 min;MS m / z, 362.4[MH]-;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.67(s,1H),7.25(td,J=7.9,5.5Hz,1H),7.13(dd,J=7.8,1.3Hz,1H),7.04-6.86(m,1H),5.83 (d,J=15.2Hz,1H),4.75(s,2H),3.43(s,3H),2.28(s,3H),1.83(ddd,J=30.9,23.9,1.8Hz,6H).

[0154] Example 9. Methyl (S)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of commercially available 2-bromo-3-fluorobenzaldehyde (60 g, 295.56 mmol) and ethylene glycol (65.4 mL, 1182.2 mmol) in toluene (600 mL) was added p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol). The resulting solution was stirred at 120° C. for 24 h using a Dean-Stark apparatus. The solvent was added to water (2 L) and extracted into ethyl acetate (3 L). The EtOAc was washed with saturated NaHCO3 solution (1 L), brine, and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (60 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.42- 7.37(m,1H),7.34- 7.29(m,1H),7.16- 7.10(m,1H),6.10(s,1H),4.19-4.09(m,4H).

[0155] Step 2: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde [ka] To a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, 7 g, 28.45 mmol) in THF (70 mL) was added n-butyllithium in n-hexane solution (13.66 mL, 2.5 M, 58.5 mmol) dropwise over 10 min at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 45 min and then DMF (2.5 g, 34.15 mmol) was added. The reaction was stirred at −78° C. for 1.15 h before being quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) followed by brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→50%) afforded the title compound 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5 g) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 10.52 (s, 1H), 7.67-7.53 (m, 2H), 7.22-7.12 (m, 1H), 6.50 (s, 1H), 4.27-3.99 (m, 4H).

[0156] Step 3: 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane [ka] A solution of acetonitrile (65 mL), triphenylphosphine (28.1 g, 107.1 mmol), potassium iodide (11.85 g, 71.4 mmol) and 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (from step 2, 7 g, 35.7 mmol) was stirred at 70° C. for 30 min under N2. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (12 g, 62.4 mmol) was added slowly over a period of 10 min (yellow in color upon addition) and the resulting mixture was stirred at 70° C. for an additional 3 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether and the precipitated solid was filtered and washed with diethyl ether (100 mL). The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→5%) afforded the title compound 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (6.9 g) as a pale yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.39 (dd, J = 7.8, 1.4 Hz, 1H), 7.31 (m, 1H), 7.11 (m, 1H), 5.87 (s, 1H), 5.39 (m, 1H), 4.21-3.95 (m, 4H).

[0157] Step 4: 2-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane [ka] To a solution of 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 2.7 g, 11.73 mmol) in MeCN was added tetrabutylammonium fluoride in THF (13.7 g, 1 M, 13.7 mmol). The reaction was heated to 70° C. in a closed system and the resulting solution was stirred for 2 h. The reaction mixture was cooled, diluted with diethyl ether, water (50 mL), washed with saturated NaHCO3 solution (100 mL), brine and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane (1.2 g) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.49-7.42 (m, 1H), 7.35 (m, 1H), 7.17-7.05 (m, 1H), 6.03 (s, 1H), 4.25-3.90 (m, 4H), 3.75 (m, 2H).

[0158] Step 5: 3-Fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde [ka] To a solution of 2-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane (from step 4, 2 g, 8.0 mmol) in diethyl ether (40 mL) was added 6N HCl (5 mL). The resulting solution was stirred at room temperature for 3 h. It was washed with water (50 mL), saturated NaHCO3 solution (100 mL), brine and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→5%) afforded the title compound 3-fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde (1.2 g) as a colorless liquid. The crude product was used as such in the next step without further purification.

[0159] Step 6: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using step 1 of general method II (using the aldehyde from step 5, 150 mg, 0.728 mmol) to give the title compound, 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (100 mg, crude). LCMS Rt=1.736 min; MS m / z, 474.1[M+H]+; [Method 1].

[0160] Step 7: Methyl 4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using step 2 of general method II (using intermediate from step 5, 100 mg, 0.211 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) to give the title compound, methyl 4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (40 mg) as an off-white solid. LCMS Rt=1.508 min;MS m / z, 386.3[M+H]+;[Method 7] The racemic mixture was separated into its enantiomers using chiral HPLC [Method 3].

[0161] Example 9 11 mg of first eluting enantiomer (22%) as a white solid Chiral HPLC Rt=6.264 min (mobile phase: A=n-hexane, B=0.1% TFA in ethanol:methanol (1:1); 1 mL / min; isocratic: 80:20 (A:B); Column: Lux, Cellulose-4 (250×4.6 mm, 5 microns). LCMS Rt=1.508 min;MS m / z, 386.3[M+H]+;[Method 7] 1 H NMR (400 MHz, chloroform-d) δ 7.41 (s, 1H), 7.25-7.19 (m, 1H), 7.02-6.98 (m, 1H), 6.93 (ddd, J = 9.5, 8.1, 1.3 Hz, 1H), 5.15 (s, 1H), 4.66-4.57 (m, 2H), 4.43 (ddd, J = 19.7, 11.2, 5.9 Hz, 1H), 3.80-3.63 (m, 1H), 3.45 (s, 3H), 2.44 (s, 3H).

[0162] Example 9b 11 mg of the second eluting enantiomer (22%) as a white solid Chiral HPLC Rt = 6.708 min (mobile phase: A = n-hexane, B = 0.1% TFA in ethanol:methanol (1:1); 1 mL / min; isocratic: 80:20 (A:B); Column: Lux, Cellulose-4 (250 x 4.6 mm, 5 microns). LCMS Rt=1.509 min;MS m / z386.4[M+H]+;[Method 7] 1 H NMR (400 MHz, chloroform-d) δ 7.56 (s, 1H), 7.25-7.19 (m, 1H), 7.02-6.98 (m, 1H), 6.93 (dd, J = 9.5, 8.1 Hz, 1H), 5.15 (s, 1H), 4.66-4.57 (m, 2H), 4.43 (m, 1H), 3.80-3.63 (m, 1H), 3.45 (s, 3H), 2.44 (s, 3H).

[0163] Example 10. Methyl (S)-4-(3-fluoro-2-((S or R)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol [ka] A solution of commercially available 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from Example 1, step 1, 30 g, 121.42 mmol) in THF (300 mL) was cooled to −78° C. under nitrogen atmosphere. n-BuLi in n-hexane solution (58.3 mL, 2.5 M, 147.71 mmol) was added over 10 min and the resulting mixture was stirred at −78° C. for 1 h. Acetaldehyde (6.42 g, 145.71 mmol) was added and the resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phase was washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol (15 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.38(d,J=8.0Hz,1H),7.30-7.18(m,1H),7.10-7.01(m,1H),6.15(s,1H),5.29(td,J= 6.9, 13.5Hz, 1H), 4.15-3.95 (m, 4H), 2.75-2.69 (m. 1H), 1.58 (dd, J=6.6, 22.8Hz, 3H).

[0164] Step 2: 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane [ka] To a solution of 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol (from step 1, 15 g, 70.68 mmol) in dichloromethane (150 mL) at -78 °C was added diethylaminosulfur trifluoride (19.3 mL, 141.37 mmol). The resulting solution was warmed and stirred at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (20 mL) at 0 °C and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0 → 10%) afforded the title compound 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (8.5 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.38(d,J=7.5Hz,1H),7.30-7.18(m,1H),7.13-7.01(m,1H),6.20-5.95(m,1H),6.10(s,1H),4.16-4.02(m,4H),1.74(dd,J=7.2,23.1Hz,3H).

[0165] Step 3: 3-Fluoro-2-(1-fluoroethyl)benzaldehyde [ka] To a solution of 2-(3-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (from step 2, 8.5 g, 69.38 mmol) in diethyl ether (150 mL) was added 4N HCl (85 mL) at room temperature. The resulting solution was stirred at room temperature for 3 h. It was washed with water (100 mL), saturated NaHCO3 solution (200 mL), brine and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 3-difluoro-2-(1-fluoroethyl)benzaldehyde (6.5 g) as a colorless liquid. (Note: the resulting aldehyde is volatile in nature). 1H NMR (300 MHz, chloroform-d) δ 10.44 (d, J = 1.0 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.47 (td, J = 8.1, 8.0, 5.2 Hz, 1H), 7.35-7.30 (m, 1H), 6.41 (dq, J = 46.8, 6.6 Hz, 1H), 1.92-1.72 (m, 3H).

[0166] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using step 1 of general method II (using aldehyde from step 3, 1000 mg, 1.88 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate along with 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate as crude, which was taken directly into step 5.

[0167] Step 5: Methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using step 2 of general method II (using a mixture of intermediates from step 4). Two purifications of the crude product by silica flash chromatography (ethyl acetate in heptane, 0→100%) afforded separated diastereomers (200 mg each) of the title compound, methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, as off-white solids.

[0168] 200 mg of the first eluting diastereomer was separated into its enantiomers using chiral SFC (column: SS Whelk-01, 21 x 250 mm; flow rate: 80 g per min; co-solvent: 25% MeOH w / NH3; detection: 340 nm; BPR set point: 150 bar).

[0169] Example 10 80 mg of first eluting enantiomer as a white solid. Chiral SFC Rt = 2.0 min ((S,S)Whelk-O1 (3.5μ) 3×100 mm; 5-55% MeOH w 0.1% NH3 / CO2, 2.5 mL / min, 1800 psi). LCMS Rt=2.01 min;MS m / z, 348.3[MH]-;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 99.87(s,1H),7.32(m,1H),7.06-6.97(m,2H),6.44-6.23(m,1H),4.98 (s,1H),4.92-4.77(m,2H),3.43(s,3H),2.32(s,3H),1.86-1.75(m,3).

[0170] The remaining stereoisomers were not characterized.

[0171] Example 11. Methyl (S)-4-(2-((R or S)-1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of commercially available 2-bromo-3-fluorobenzaldehyde (60 g, 295.56 mmol) and ethylene glycol (65.4 mL, 1182.2 mmol) in toluene (600 mL) was added p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol). The resulting solution was stirred at 120° C. for 24 h using a Dean-Stark apparatus. The reaction was added to water (2 L) and extracted into ethyl acetate (3 L). The ethyl acetate was washed with saturated NaHCO3 solution (1 L), brine, and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (60 g) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.40 (dd, J = 7.8, 1.6 Hz, 1H), 7.35-7.25 (m, 1H), 7.13 (m, 1H), 6.10 (s, 1H), 4.30-3.90 (m, 4H).

[0172] Step 2: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethan-1-one [ka] A solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, 26 g, 105.23 mmol) in THF (250 mL) was cooled to −78° C. under nitrogen atmosphere. n-Butyllithium in n-hexane solution (44.19 mL, 2.5 M, 110.49 mmol) was then added and the reaction was stirred at −78° C. for 30 min. Ethyl 2-fluoroacetate (22.33 g, 210.47 mmol) was then added and the resulting mixture was stirred at −78° C. for an additional 60 min. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water (250 mL), brine (250 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethan-1-one (16.2 g) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 7.45 (m, 1H), 7.37 (d, J = 7.8, 1H), 7.13 (dd, J = 9.3, 8.2 Hz, 1H), 6.02 (s, 1H), 5.23 (d, J = 1.4 Hz, 1H), 5.11 (d, J = 1.3 Hz, 1H), 4.08-3.87 (m, 4H).

[0173] Step 3: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethan-1-ol [ka] To a stirred solution of 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethan-1-one (19.6 g, 85.89 mmol) in methanol (100 mL) was added sodium borohydride (3.899 g, 103.07 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water (250 mL), brine (250 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→30%) afforded the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethan-1-ol (18 g) as a colorless liquid. 1 H NMR(400MHz,chloroform-d)δ 7.44(dd,J=7.9,1.2Hz,1H),7.33(dd,J=8.0,8.0Hz,1H),7.10(dd,J= 8.2,1.3Hz,1H),6.13(s,1H),5.47(m,1H),4.98-4.51(m,2H),4.22-3.97(m,4H),3.04(m,1H).

[0174] Step 4: 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane [ka] A solution of 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethan-1-ol (from step 3, 18 g, 78.18 mmol) in dichloromethane (150 mL) was cooled to -78 °C, then diethylaminosulfur trifluoride (15.49 mL, 117.28 mmol) was added and the resulting reaction mixture was stirred at -78 °C for 1 h, then slowly brought to 0 °C and stirred for an additional 1 h. Water (150 mL) was added and the product was extracted into dichloromethane (2 x 200 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (2 x 200 mL), water (200 mL), brine (200 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (12.4 g) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 7.45 (d, J = 7.8 Hz, 1H), 7.42-7.35 (m, 1H), 7.12 (dd, J = 10.6, 8.2 Hz, 1H), 6.21 (m, 1H), 6.04 (s, 1H), 5.22-4.85 (m, 1H), 4.75-4.42 (m, 1H), 4.20-3.97 (m, 4H).

[0175] Step 5: 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde [ka] To a solution of 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (from step 4, 12.4 g, 53.40 mmol) in diethyl ether (150 mL) was added 2N HCl (100 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 8 h. The reaction mixture was added to water (100 ml) and extracted with diethyl ether (200 mL). The organic phase was washed with water (100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde (10 g) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 10.30 (s, 1H), 7.88-7.70 (m, 1H), 7.56 (m, 1H), 7.44-7.30 (m, 1H), 6.70-6.36 (m, 1H), 4.95-4.70 (m, 2H)

[0176] Step 6: Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using general method I (using the aldehyde from step 5, 450 mg, 2.39 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to afford the title compound, methyl-4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (400 mg) as a mixture of diastereomers and as an off-white solid.

[0177] The diastereomeric mixture (400 mg) was separated using preparative HPLC [Method 7].

[0178] 60 mg of first eluting diastereomer as a white solid. LCMS Rt=1.463 min;MS m / z, 365.85[MH]-;[Method 11] 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),7.42-7.39(m,1H),7.17-6.96(m,2H),6.48-6.47(m,1H),5.22- 4.69(m,2H),5.04(s,1H),4.89-4.83(m,2H),3.42(s,3H),2.37-2.30(m,3H).

[0179] 56.4 mg of the second diastereomer eluting as a white solid. LCMS Rt=1.466 min;MS m / z, 365.85[MH]-;[Method 12] 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),7.45-7.43(m,1H),7.17-6.96(m,2H),6.49-6.46(m,1H),5.22- 4.69(m,2H),5.04(s,1H),4.89-4.83(m,2H),3.42(s,3H),2.37-2.30(m,3H).

[0180] The second eluting diastereomer was further separated into its enantiomers using chiral SFC (mobile phase: 12% MeOH / CO2, 70 mL / min; column: OZ-H (2 x 25 cm)).

[0181] Example 11 22.8 mg of the first eluting enantiomer (77%) as a white solid. SFC Rt = 2.81 min ((SS)Whelk-O1, 4.6 × 100 mm, 5 μm, 5 → 55% (1:1) MeOH / IPA (10 mM NH4OH / CO2)). LCMS Rt=1.89 min;MS m / z, 366.1[MH]-;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),7.50-7.37(m,1H),7.14-7.00(m,2H),6.48(ddd,J=48.9,17.8, 8.6Hz,1H),5.20-4.93(m,3H),4.92-4.80(m,2H),3.43(s,3H),2.33(s,3H).

[0182] Example 11b 22.0 mg of the second eluting enantiomer (74.1%) as a white solid SFC Rt = 2.93 min ((SS)Whelk-O1, 4.6 × 100 mm, 5 μm, 5 → 55% (1:1) MeOH / IPA (10 mM NH4OH / CO2)). LCMS Rt=1.87 min;MS m / z, 365.9[MH]-;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 9.93(s,1H),7.49-7.35(m,1H),7.14-7.00(m,2H),6.48(ddd,J=48.5,17.8,8 .3Hz,1H),5.22-4.93(m,3H),4.86(d,J=3.8Hz,2H),3.43(s,3H),2.33(s,3H).

[0183] Example 12. Methyl (S)-4-(2-ethyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 3,5-Difluoro-2-vinylbenzaldehyde [ka] To a solution of commercially available 2-bromo-3,5-difluorobenzaldehyde (600 mg, 2.71 mmol) and potassium vinyltrifluoroborate (727 mg, 5.42 mmol) in 2-propanol (20 mL) was added trimethylamine (1.13 mL, 8.14 mmol). The resulting reaction mixture was degassed with nitrogen, followed by the addition of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (221 mg, 0.271 mmol). The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered through a celite pad, washed with diethyl ether (50 mL), and the filtrate was concentrated under reduced pressure, and purification of the crude product by silica flash chromatography (ethyl acetate in hexanes, 0 → 5%) afforded the title compound 3,5-difluoro-2-vinylbenzaldehyde (400 mg) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 10.21 (d, J = 2.8 Hz, 1H), 7.43 (dd, J = 8.3-2.7, 1H), 7.13-6.88 (m, 2H), 5.82 (dd, J = 11.4, 1.1 Hz, 1H), 5.58 (dt, J = 17.6, 1.1 Hz, 1H).

[0184] Step 2: (2-ethyl-3,5-difluorophenyl)methanol [ka] To a solution of 3,5-difluoro-2-vinylbenzaldehyde (from step 1, 400 mg, 2.37 mmol) in ethanol (10 mL) was added 10% Pd-C (80 mg). The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere for 6 h. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→30%) afforded the title compound (2-ethyl-3,5-difluorophenyl)methanol (300 mg) as a colorless liquid. 1 H NMR (400 MHz, chloroform-d) δ 7.05-6.92 (m, 1H), 6.79-6.67 (m, 1H), 4.73 (d, J = 5.8 Hz, 2H), 2.64 (q, J = 7.1 Hz, 2H), 1.69 (t, J = 6.0 Hz, 1H), 1.15 (t, J = 7.1 Hz, 3H).

[0185] Step 3: 2-Ethyl-3,5-difluorobenzaldehyde [ka] To a solution of (2-ethyl-3,5-difluorophenyl)methanol (from step 2, 300 mg, 1.74 mmol) in dichloromethane (15 mL) was added pyridinium chlorochromate (751 mg, 3.48 mmol) in one portion at 0° C. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (30 mL), filtered over a celite pad, and washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure, which afforded the title compound as a brown liquid 2-ethyl-3,5-difluorobenzaldehyde (250 mg). The crude product was used as such in the next step without further purification.

[0186] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-ethyl-3,5-difluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] To a solution of 2-ethyl-3,5-difluorobenzaldehyde (from step 3, 250 mg, 1.46 mmol) in dioxane (15 mL) was added methyl (Z)-3-aminobut-2-enoate (169.54 mg, 1.46 mmol) and ethyl 4-acetoxy-3-oxobutanoate (Intermediate A, 276.47 mg, 1.46 mmol). The resulting reaction mixture was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature, added to water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-ethyl-3,5-difluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (250 mg) as a brown liquid. The crude product was used as such in the next step without further purification. LCMS Rt=1.838 min;MS m / z, 438.3[M+H]+;[Method 8]

[0187] Step 5: Methyl 4-(2-ethyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(2-ethyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using the procedure from Example 3, step 6 (using intermediate from step 4, 350 mg, 0.80 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to afford the title compound, methyl 4-(2-ethyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (80 mg) as an off-white solid. LCMS Rt=1.536 min;MS m / z, 350.3[M+H]+;[Method 7] The racemate was separated into its individual enantiomers using chiral HPLC [Method 4].

[0188] Example 12 27.8 mg of first eluting enantiomer (34%) as a white solid Chiral HPLC Rt = 5.00 min (Mobile phase: A = n-hexane, B = ethanol (1:1); 1 mL / min; Isocratic: 70:30 (A:B); Column: Lux, Cellulose-4 (250 x 4.6 mm, 5 microns). LCMS Rt=1.536 min;MS m / z, 350.3[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),6.97(dd,J=11.2,8.9Hz,1H),6.71(dt,J=9.8,1.8Hz,1H),4.98(s,1H),4.83(q,J=16.1Hz,2H), 3.44(s,3H),3.00(dd,J=14.3,7.6Hz,1H),2.77(dd,J=14.6,7.4Hz,1H),2.32(s,3H),1.20(q,J=8.0Hz,3H).

[0189] Example 12b 28.3 mg of the second eluting enantiomer (35%) as a white solid Chiral HPLC Rt=5.601 min (mobile phase: A=n-hexane, B=ethanol (1:1); 1 mL / min; isocratic: 70:30 (A:B); Column: Lux, Cellulose-4 (250×4.6 mm, 5 microns). LCMS Rt=1.534 min;MS m / z, 350.3[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),6.97(dd,J=11.2,8.9,Hz,1H),6.71(dt,J=9.8,1.8Hz,1H),4.98(s,1H),4.83(q,J=16.1Hz,2H) ,3.44(s,3H),3.00(dd,J=14.3,7.6Hz,1H),2.77(dd,J=14.6,7.4Hz,1H),2.32(s,3H),1.20(q,J=8.0Hz,3H).

[0190] Example 13. Methyl (S)-4-(2-ethyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 3-Fluoro-2-vinylbenzaldehyde [ka] To a solution of commercially available 2-bromo-3-fluorobenzaldehyde (800 mg, 3.94 mmol) and potassium vinyltrifluoroborate (1.055 g, 7.88 mmol) in 2-propanol (25 mL) was added trimethylamine (1.64 mL, 11.82 mmol). The resulting reaction mixture was degassed with nitrogen and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (321 mg, 0.394 mmol) was added. The resulting reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered over a celite pad, washed with diethyl ether (50 mL), the filtrate was concentrated under reduced pressure, and purification of the crude product by silica flash chromatography (ethyl acetate in hexanes, 0 → 5%) afforded the title compound 3-fluoro-2-vinylbenzaldehyde (500 mg) as a yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ 10.23 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.39 (m, 1H), 7.30 (m, 1H), 7.09 (d, J = 17.7 Hz, 1H), 5.81 (m, 1H), 5.64 (d, J = 17.7 Hz, 1H).

[0191] Step 2: (2-ethyl-3-fluorophenyl)methanol [ka] To a solution of 3-fluoro-2-vinylbenzaldehyde (from step 1, 500 mg, 3.33 mmol) in ethanol (10 mL) was added 10% Pd-C (100 mg). The resulting reaction mixture was stirred at room temperature under hydrogen atmosphere for 6 h. The reaction mixture was filtered over a celite pad and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→30%) afforded the title compound (2-ethyl-3-fluorophenyl)methanol (400 mg) as a colorless liquid. 1H NMR (300 MHz, chloroform-d) δ 7.20-7.14 (m, 2H), 7.04-6.94 (m, 1H), 4.72 (s, 2H), 2.64 (q, J = 7.1 Hz, 2H), 1.67 (br s, 1H), 1.15 (t, J = 7.1 Hz, 3H).

[0192] Step 3: 2-Ethyl-3-fluorobenzaldehyde [ka] To a solution of (2-ethyl-3-fluorophenyl)methanol (from step 2, 400 mg, 2.59 mmol) in dichloromethane (15 mL) was added Des-Martin periodinane (1.65 g, 3.89 mmol) in one portion at 0° C. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with dichloromethane (20 mL), filtered over a celite pad and washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%) afforded the title compound 2-ethyl-3-fluorobenzaldehyde (150 mg) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 10.22 (s, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.38-7.22 (m, 2H), 3.10 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0193] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-ethyl-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-ethyl-3-fluorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate was synthesized using general method II, step 1 (using the aldehyde from step 3, 140 mg, 0.92 mmol) to give (160 mg, crude). LCMS Rt=1.758 min;MS m / z, 420.1[M+H]+;[Method 7]

[0194] Step 5: Methyl 4-(2-ethyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(2-ethyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using the procedure from Example 3, step 6 (using intermediate from step 4, 160 mg, 0.38 mmol). Purification of the crude product by preparative HPLC [Method 4] afforded the title compound, methyl 4-(2-ethyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (50 mg) as an off-white solid. LCMS Rt=1.463 min;MS m / z, 332.1[M+H]+;[Method 7] The racemate was separated into its individual enantiomers using chiral HPLC [Method 4].

[0195] Example 13 19.2 mg of first eluting enantiomer (38%) as a white solid Chiral HPLC Rt=6.025 min (Mobile phase: A=n-hexane, B=ethanol (1:1); 1 mL / min; Isocratic: 70:30 (A:B); Column: Lux, 5 micron, Cellulose-4 (250×4.6 mm, 5 micron). LCMS Rt=1.457 min;MS m / z, 332.2[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),7.14(d,J=8.0,1H),6.98-6.87(m,2H),4.95(s,1H),4.89-4.75(m,2H),3 .43(s,3H),3.09-2.91(m,1H),2.87-2.74(m,1H),2.31(s,3H),1.21(t,J=7.5Hz,3H).

[0196] Example 13b 20.3 mg of the second eluting enantiomer (40%) as a white solid Chiral HPLC Rt=6.792 min (Mobile phase: A=n-hexane, B=ethanol (1:1); 1 mL / min; Isocratic: 70:30 (A:B); Column: Lux, 5 micron, Cellulose-4 (250×4.6 mm, 5 micron). LCMS Rt=1.463 min;MS m / z, 332.0[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),7.14(d,J=8.0,1H),6.98-6.87(m,2H),4.95(s,1H),4.89-4.75(m,2H),3 .43(s,3H),3.09-2.91(m,1H),2.87-2.74(m,1H),2.31(s,3H),1.21(t,J=7.5Hz,3H).

[0197] Example 14. (S)-Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3,5-difluorobenzaldehyde [ka] To a mixture of 2-bromo-3,5-difluorobenzaldehyde (13 g, 58.8 mmol) and cyclopropylboronic acid (6.06 g, 70.6 mmol) in dioxane (60 mL) was added K2CO3 (2N solution) (58.8 mL, 118 mmol) and PdCl2(dppf)·CH2Cl2 adduct (4.8 g, 5.88 mmol). The reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was filtered over a celite pad. Water (75 mL) was added and the product was extracted with ethyl acetate (2 x 100 ml). The ethyl acetate phases were combined, washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and purification by automated flash column chromatography (ethyl acetate in heptane, 0 → 50%) afforded the title compound 2-cyclopropyl-3,5-difluorobenzaldehyde (7.2 g) as a colorless liquid. LCMS Rt=0.99 min; [Method 2] 1 H NMR (400 MHz, chloroform-d) δ 10.68 (s, 1H), 7.38-7.26 (m, 1H), 6.91 (ddd, J = 10.6, 8.1, 2.8 Hz, 1H), 1.96-1.83 (m, 1H), 1.29-1.08 (m, 2H), 0.69 (q, J = 5.7 Hz, 2H).

[0198] Step 2: Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using general method I (using the aldehyde from step 1, 6.5 g, 35.7 mmol). The reaction mixture was concentrated to half. The resulting solid was collected by filtration and washed with DCM / methanol (95:5) (20 mL) and water (30 mL). 3.3 g of a pale yellow solid was obtained as product. The filtrate was concentrated and purified by silica flash chromatography (ethyl acetate in heptane, 0→100%) to give a second batch of product (730 mg), but both solids were combined to give the title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, as a pale yellow solid. LCMS Rt=1.01 min;MS m / z, 362.2[M+H]+;[Method 2]

[0199] The racemic mixture was separated into its enantiomers using chiral SFC (mobile phase: 30% IPA; column: (SS) Whelk-O1, 30×250 mm).

[0200] Example 14 1.85 g of the first eluting enantiomer (27.2%) as a pale yellow solid SFC Rt=2.96 min (Whelk-O1SS, 4.6×100 mm, 5 μm, 5-55% IPA in CO2, 5 mL / min) LCMS Rt=2.19 min;MS m / z, 362.2[M+H]+;[Method 4] 1H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),6.92(ddd,J=11.4,8.9,2.8Hz,1H),6.79-6.69(m,1H),5.48(d,J=1.9Hz,1H),4.93-4. 75(m,2H),3.47(d,J=2.0Hz,3H),2.31(d,J=1.5Hz,3H),2.10-1.97(m,1H),1.19-1.08(m,1H),1.01- 0.87(m,2H),0.74-0.62(m,1H).

[0201] The configuration of Example 14, methyl 2-methyl-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, was determined by single crystal X-ray crystallography, which confirmed that the active enantiomer was the S-enantiomer (Figure 2).

[0202] Example 14b 2.02 g of the second eluting enantiomer (29.8%) as a pale yellow solid SFC Rt = 3.32 min (Whelk-O1SS, 4.6 x 100 mm, 5 μm, 5-55% IPA in CO2, 5 mL / min) LCMS Rt=2.16 min;MS m / z, 362.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),6.92(ddd,J=11.4,8.9,2.8Hz,1H),6.79-6.69(m,1H),5.48(d,J=1.9Hz,1H),4.93-4.75(m,2H),3.47( d,J=2.0Hz,3H),2.31(d,J=1.5Hz,3H),2.10-1.97(m,1H),1.19-1.08(m,1H),1.01-0,87(m,2H),0.74-0.62(m,1H).

[0203] Example 15. (S)-Methyl 4-(3-fluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: (S)-Methyl 4-(2-bromo-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Racemic methyl (S)-methyl 4-(2-bromo-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using general procedure I using commercially available 2-bromo-3-fluorobenzaldehyde (15 g, 73.9 mmol). The solid thus obtained in the reaction mixture was collected by filtration and dried to give 9 g of a yellow solid (31.9%). The racemate was separated into its enantiomers using a chiral SFC column: SS Whelk-O1, 30×250 mm; flow rate: 80 g per minute; co-solvent: 40% MeOH; detection: 340 nm; BPR set point: 125 bar.

[0204] Obtain 4.12 g of the first eluting enantiomer (27.7%) as a pale yellow solid. SFC Rt=2.93 min; SS Whelk O1; 5-55% MeOH in CO2, 5 mL / min LCMS Rt=1.79 min;MS m / z, 382.0[M+0]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 9.90(s,1H),7.34(td,J=8.1,5.7Hz,1H),7.23-7.01(m,2H),5.22(s,1H),4.83(d,J=2.1Hz,2H),3.42(s,3H),2.31(s,3H).

[0205] Step 2: (S)-Methyl 4-(3-fluoro-2-(prop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A round-bottom flask equipped with a magnetic stir bar is charged with (S)-methyl 4-(2-bromo-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (from step 1, 2000 mg, 5.23 mmol), isopropenylboronic acid pinacol ester (1.553 mL, 7.85 mmol), dioxane (26.2 mL), 2 M aqueous potassium phosphate tribasic (5.23 mL, 10.47 mmol), and Pd-118 (171 mg, 0.262 mmol). The vial is sealed, flushed with nitrogen, and then microwaved at 100° C. for 1 h. The reaction mixture is diluted with water and extracted with EtOAc (4×20 mL). The combined organic extracts are washed with brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure. Purification of the crude product by silica flash column chromatography (0→75% ethyl acetate in heptane) afforded the title compound (S)-methyl 4-(3-fluoro-2-(prop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (1.34 g, 64.9%) as a pale yellow solid. LCMS Rt=2.06 min;MS m / z, 344.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.79(s,1H),7.23(td,J=7.9,5.9Hz,1H),7.05(dd,J=7.9,1.4Hz,1H),6.99-6.93(m,1H),5.43(s, 1H),5.40-5.37(m,1H),5.04(s,1H),4.81(d,J=5.4Hz,2H),3.47(s,3H),2.23(s,3H),2.07(s,3H).

[0206] Step 3: (S)-Methyl 4-(3-fluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A reaction vial equipped with a magnetic stir bar is charged with (S)-methyl 4-(3-fluoro-2-(prop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (from step 2, 300 mg, 0.874 mmol), palladium on carbon (93 mg, 0.874 mmol), and EtOH (3 mL). The vial is sealed and fitted with a balloon of hydrogen (1.761 mg, 0.874 mmol). The vial is evacuated, refilled with hydrogen, and allowed to stir at room temperature for 24 h. The reaction mixture is diluted with methanol and filtered through a pad of celite. The filter is rinsed with 100 mL of methanol. The collected filtrate is concentrated under reduced pressure. Purification of the crude product by silica flash column chromatography (ethyl acetate in heptane, 0→100%) afforded the title compound (S)-methyl 4-(3-fluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as an off-white solid (141.5 mg, 44.5%).

[0207] Example 15 LCMS Rt=2.26 min;MS m / z, 346.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.81(s,1H),7.13(td,J=8.0,5.6Hz,1H),6.97-6.92(m,1H),6.88(ddd,J=12.6,8.0,1.3Hz,1H),5.06(s,1H) ,4.81(d,J=4.9Hz,2H),3.67(p,J=7.3Hz,1H),3.45(s,3H),2.31(s,3H),1.34(ddd,J=25.8,7.0,1.7Hz,6H).

[0208] Example 16. (S)-Methyl 4-(3-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: (S)-Methyl 4-(3-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A microwave reaction vial is charged with (S)-methyl 4-(2-bromo-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (intermediate from step 1, Example 15, 215 mg, 0.563 mmol), 4,4,5,5-tetramethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborolane (125 mg, 0.563 mmol), 1,4-dioxane (2 mL), 2M aqueous potassium phosphate tribasic (0.563 mL, 1.126 mmol), and Pd-118 (36.7 mg, 0.056 mmol). The vial is sealed, flushed with nitrogen, and then heated to 120° C. in a Biotage microwave reactor for 3 h. The reaction mixture is then diluted with water and extracted with EtOAc (3×10 mL). The combined organic extracts are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude product by HPLC chromatography (column: X-bridge, 30×50 mm, 5 μm; MeCN / H2O w / 5 mM NH4OH; 75 mL / min; 1.5 mL injection volume), followed by lyophilization, afforded the title compound (S)-methyl 4-(3-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as a white powder (14.2 mg, 5.7%).

[0209] Example 16 LCMS Rt=2.15 min;MS m / z, 398.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.88(d,J=24.3Hz,1H),7.42(td,J=8.1,5.9Hz,1H),7.18(d,J=7.9Hz,1H),7.10(ddd,J=9.7,8.1,1 .4Hz,1H),6.82(s,1H),6.47(s,1H),4.92(s,1H),4.86(d,J=3.2Hz,2H),3.37(s,3H),2.25(s,3H).

[0210] Example 17. (S)-Methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: Methyl (S)-4-(3-fluoro-2-(2-oxoethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A microwave reaction vial is charged with (S)-methyl 4-(2-bromo-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (intermediate from step 1, example 15, 100 mg, 0.262 mmol), vinyloxy-trimethylsilane (0.060 mL, 0.392 mmol), DMA (2.5 mL), N-cyclohexyl-N-methylcyclohexanamine (0.086 mL, 0.392 mmol), and bis(tri-t-butylphosphine)palladium(0) (6.69 mg, 0.013 mmol). The vial is sealed and flushed with nitrogen, then heated to 120° C. for 1 h in a Biotage microwave reactor. The reaction mixture is diluted with water and extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification of the crude product by silica flash column chromatography (ethyl acetate in heptane, 0→100%) afforded the title compound methyl (S)-4-(3-fluoro-2-(2-oxoethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as a yellow solid (95.1 mg, 105%). LCMS Rt=0.76 min;MS m / z, 346.3[M+H]+;[Method 2] 1 H NMR(400MHz,DMSO-d6)δ 9.87(s,1H),9.67(d,J=1.9Hz,1H),7.30(td,J=8.0,6.1Hz,1H),7.07-7.00(m,2H),4.92(s,1H),4.82( d,J=3.2Hz,2H),4.14(dt,J=17.6,2.5Hz,1H),3.93(dt,J=17.4,1.8Hz,1H),3.37(s,3H),2.33(s,3H).

[0211] Step 2: (S)-Methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A reaction vial is charged with methyl (S)-4-(3-fluoro-2-(2-oxoethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (95.1 mg, 0.275 mmol) and DCM (2.5 mL) and then cooled to -78°C. DAST (0.073 mL, 0.551 mmol) is carefully added dropwise to the reaction mixture. The reaction mixture is stirred at -78°C for 1 h, then the cooling bath is removed and the mixture is stirred at room temperature for 3 h. After the reaction time has elapsed, the reaction mixture is cooled to 0°C and water is added dropwise to the mixture. The product is extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification of the crude product by preparative HPLC chromatography (column: Xbridge C18 OBD, 30 × 50 mm, 5 μm column; mobile phase: MeCN / HO w / 5 mM NH4OH; 75 mL / min; 1.5 mL injection volume) followed by lyophilization afforded the title compound (S)-methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as a white powder (9.6 mg, 8.5%).

[0212] Example 17 LCMS Rt=2.00 min;MS m / z, 368.2[M+H]+;[Method 4] 1 H NMR(400MHz, methanol-d4)δ 7.14(td,J=7.9,5.5Hz,1H),6.96(dd,J=7.8,1.4Hz,1H),6.85-6.77(m,1H),6.41(tt, J=56.2,4.7Hz,1H),4.95(s,1H),4.71(s,2H),3.42(s,3H),3.21(s,2H),2.29(s,3H).

[0213] Example 18. Methyl (S)-4-(3,5-difluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: Methyl (S)-4-(2-bromo-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Racemic methyl (S)-4-(2-bromo-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was synthesized using general procedure I using commercially available 2-bromo-3,5-difluorobenzaldehyde (120 g, 542.98 mmol). The solid thus obtained in the reaction mixture was collected by filtration and dried to give 80 g of a yellow solid (36.82%). The racemate was separated into its enantiomers using a chiral SFC column: Whelk O1 (S, S), 250×4.6 mm, ID, 5 μm mobile phase: A is CO2, B is MEOH (0.05% DEA), gradient: B 40%; flow rate: 2.5 mL / min; back pressure: 100 bar; column temperature: 25° C.

[0214] Obtain 37.7 g of the first eluting enantiomer (47.1%) as a pale yellow solid. SFC Rt=3.364 min;SS Whelk O1_5_MeOH_DEA_40_25ML LCMS Rt=1.97 min;MS m / z, 400.1[M+0]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),7.28(td,J=8.8,2.9Hz,1H),6.95(ddd,J=9.3,2.9,1.5Hz,1H),5.25(s,1H),4.95-4.69(m,2H),3.43(s,3H),2.32(s,3H).

[0215] Step 2: Methyl (S)-4-(3,5-difluoro-2-(prop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A round-bottom flask equipped with a magnetic stir bar is charged with methyl (S)-4-(2-bromo-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (500 mg, 1.25 mmol), isopropenylboronic acid pinacol ester (0.433 mL, 2.19 mmol), 1,4-dioxane (6 mL), 2 M aqueous potassium phosphate tribasic (1.25 mL, 2.5 mmol), and Pd-118 (40.7 mg, 0.062 mmol). The vial is sealed, flushed with nitrogen, and then heated to 120° C. in a microwave reactor for 1 h. The reaction mixture is diluted with water and extracted with EtOAc (3×15 mL). The combined organic extracts are washed with brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. Purification of the crude product by silica flash column chromatography (ethyl acetate in heptane, 0→100%) afforded the title compound, methyl (S)-4-(3,5-difluoro-2-(prop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, as a light brown solid (293.5 mg, 56.6%). LCMS Rt=2.18 min;MS m / z, 362.2[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),7.02(ddd,J=11.1,8.7,2.6Hz,1H),6.91-6.76(m,1H),5.43(s,1H),5.4 0(s,1H),5.06(s,1H),4.82(q,J=16.1Hz,2H),3.50(s,3H),2.25(s,3H),2.06(s,3H).

[0216] Step 3: Methyl (S)-4-(3,5-difluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] A reaction vial is charged with methyl (S)-4-(3,5-difluoro-2-(prop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (100 mg, 0.277 mmol), palladium on carbon (29.5 mg, 0.277 mmol), and EtOH (3 mL). The vial is sealed and fitted with a balloon of hydrogen. The vial is evacuated and refilled with hydrogen (3x), then stirred at room temperature. After the reaction is complete, the mixture is diluted with MeOH and filtered over a pad of celite. The pad is washed with 50 mL of MeOH. The collected filtrate is concentrated under reduced pressure. Purification of the crude product by preparative HPLC chromatography (column: Xbridge C18OBD, 30×50 mm, 5 μm column; mobile phase: MeCN / HO w / 5 mM NH4OH; 75 mL / min; 1.5 mL injection volume) followed by lyophilization afforded the title compound, methyl (S)-4-(3,5-difluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as a white powder (22.9 mg, 21.6%).

[0217] Example 18 LCMS Rt=2.37;MS m / z, 364.1[M+H]+;[Method 4] 1 H NMR(400MHz, methanol-d4)δ 6.68-6.46(m,2H),5.10(s,1H),4.70(d,J=3.1Hz,2H),3.58(pq,J=6.9,3 .0Hz,1H),3.45(s,3H),2.29(s,3H),1.27(ddd,J=27.5,7.0,1.7Hz,6H).

[0218] Example 19: (S)-Methyl 4-(3,5-difluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] (S)-Methyl 4-(3,5-difluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was prepared similarly to Example 18 in step 2 using 4,4,5,5-tetramethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborolane (305 mg, 1.374 mmol). The crude material was purified by automated flash column chromatography on a 12 g Si-column packed with DCM eluting with a 0-100% gradient of EtOAc in heptane and further purified by mass-directed reverse-phase preparative chromatography; conditions: Xbridge C18OBD, 30 x 50 mm, 5 μm column ACN / HO w / 0.1% formic acid, 75 mL / min, 1.5 mL injection. Obtain 23 mg of the title compound as a white solid (yield = 4%).

[0219] Example 19 LCMS Rt=2.24 min;MS m / z, 416.1[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 9.95(s,1H),7.20(ddd,J=10.8,8.5,2.6Hz,1H),6.97(dd,J=9.8,2.6Hz,1H),6.79(s,1 H),6.49(s,1H),4.94(s,1H),4.86(d,J=9.9Hz,2H),3.41(s,3H),2.25(d,J=4.1Hz,3H).

[0220] NOESY NMR confirmed that the observed doubling of several aliphatic peaks (small peaks at different ppm not noted above) are all associated with the parent compound, indicating the presence of interchangeable rotamers or atropisomers.

[0221] Example 20: Methyl (S)-4-(3-fluoro-2-(3-fluorocyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 3-(benzyloxy)-1-(2-bromo-6-fluorophenyl)cyclobutan-1-ol [ka] To a stirred solution of 1-bromo-3-fluorobenzene (5 g, 28.57 mmol) in THF (40 mL) was added LDA (2 M solution in THF) (15.71 mL, 31.42 mmol) at -78°C and the reaction mixture was stirred for 15 min. Then 3-oxocyclobutylbenzoate (5.03 mmol, 28.57 mmol) was added at -78°C and the reaction mixture was stirred for 2 h. The reaction was monitored by TLC. The reaction mass was quenched with saturated NH4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica flash chromatography (ethyl acetate in hexane, 50%) to obtain the title compound 3-(benzyloxy)-1-(2-bromo-6-fluorophenyl)cyclobutan-1-ol (5.5 g, 55%) as a light brown liquid. 1 H NMR (600MHz, CDCl3) δ 7.40-7.32 (m, 5H), 7.31-7.30 (m, 1H), 7.13-7.09 (m, 1H), 7.01 (t, J = 9.6Hz, 1H), 4.56 (s, 2H), 4.13-4.09 (m, 1H), 3.31 (s, 1H), 3.09-3.06 (m, 2H), 2.77-2.74 (m, 2H) (OH protons not observed).

[0222] Step 2: 2-(3-(benzyloxy)cyclobutyl)-1-bromo-3-fluorobenzene [ka] To a cooled and stirred solution of 3-(benzyloxy)-1-(2-bromo-6-fluorophenyl)cyclobutan-1-ol (step 1, 5.5 g, 15.66 mmol) in TFA (6.0 mL, 78.3 mmol) was added Et3SiH (5.0 mL, 31.32 mmol) at 0° C. The resulting reaction mixture was warmed to RT and stirred for 1 h. Water was added to the reaction mixture and the product was extracted with DCM. The combined organic layers were combined, washed with saturated NaHCO3 solution, water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in hexanes, 10%) to give the title compound 2-(3-(benzyloxy)cyclobutyl)-1-bromo-3-fluorobenzene (3.9 g, 74%) as a light brown liquid. 1 H NMR(300MHz,CDCl3)δ 7.41-7.27(m,6H),7.06-6.94(m,2H),4.49(s,2H),4.03-3.98(m,1H),3.37-3.27(m,1H),2.82-2.66(m,2H),2.62-2.45(m,2H)

[0223] Step 3: 2-(3-(benzyloxy)cyclobutyl)-1-fluoro-3-vinylbenzene [ka] To a stirred solution of 2-(3-(benzyloxy)cyclobutyl)-1-bromo-3-fluorobenzene (step 2, 3.4 g, 10.14 mmol) in IPA (50 mL) was added potassium vinyltrifluoroborate (2.71 g, 20.28 mmol) followed by Et3N (4.28 mL, 30.42 mmol) and the flask was purged with argon gas for 10 min. Pd(dppf)Cl2·DCM (0.827 g, 1.014 mmol) was added and purged again with argon gas for another 5 min. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mixture was filtered over celite and the celite bed was washed with EtOAc. The filtrate was concentrated under reduced pressure. The crude product was purified by silica flash chromatography (ethyl acetate in hexanes, 10%) to give the title compound 2-(3-(benzyloxy)cyclobutyl)-1-fluoro-3-vinylbenzene (1.7 g, 59%) as a light brown liquid. 1 H NMR(400MHz,CDCl3)δ 7.38-7.28(m,5H),7.21-7.04(m,2H),6.95-6.84(m,2H),5.54(d,J=17.2Hz,1H),5.31-5.28(m ,1H),4.47(s,2H),4.01-3.95(m,1H),3.22-3.16(m,1H),2.75-2.71(m,2H),2.46-2.40(m,2H)

[0224] Step 4: 2-(3-(benzyloxy)cyclobutyl)-3-fluorobenzaldehyde [ka] Ozone gas was purged into a stirred solution of 2-(3-(benzyloxy)cyclobutyl)-1-fluoro-3-vinylbenzene (step 3, 1.5 g, 5.31 mmol) in DCM (10 mL) at -78 °C for 30 min. The reaction mixture was then quenched with DMS (0.89 mL, 12.04 mmol) at the same temperature and stirred for another 50 min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (10% ethyl acetate in hexanes) to give the title compound 2-(3-(benzyloxy)cyclobutyl)-3-fluorobenzaldehyde (0.55 g, 36%) as a light brown liquid. 1 H NMR(300MHz,CDCl3)δ 10.23(s,1H),7.68-7.26(m,8H),4.47(s,2H),4.10-4.01(m,1H),3.80-3.68(m,1H),2.91-2.63(m,2H),2.47-2.37(m,2H)

[0225] Steps 5 and 6: Methyl 4-(2-(3-(benzyloxy)cyclobutyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using general method II (using the aldehyde from step 4, 0.55 g, 1.93 mmol). The crude product was purified by silica flash chromatography (80% ethyl acetate in hexanes) to give the title compound, methyl 4-(2-(3-(benzyloxy)cyclobutyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (0.31 g, 48%) as an off-white solid. LCMS Rt=1.566 min;MS m / z, 462.05[MH]-;[Method 10]

[0226] Step 7: Methyl 4-(3-fluoro-2-(3-hydroxycyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] To a stirred solution of methyl 4-(2-(3-(benzyloxy)cyclobutyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (step 6, 0.26 g, 0.56 mmol) in EtOH:THF (1:1, 10 mL) was added Pd / C (130 mg, 50 mol%) and the reaction mixture was stirred at room temperature under H2 atmosphere for 6 h. The reaction mixture was filtered through a bed of celite, washed with ethanol and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC (column: ZORBAX (150 mm x 21.2 mm), 5.0μ; mobile phase: A = water; B = ACN; flow rate: 20 mL / min) to give the title compound, methyl 4-(3-fluoro-2-(3-hydroxycyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (115 mg, 61%) as an off-white solid. LCMS Rt=1.395 min;MS m / z, 372.1[MH]-;[Method 10]

[0227] Step 8: Methyl 4-(3-fluoro-2-(3-fluorocyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] To a cooled and stirred solution of methyl 4-(3-fluoro-2-(3-hydroxycyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (Step 7, 100 mg, 0.27 mmol) in DCM (1.5 mL) was added DAST (0.15 mL, 1.20 mmol) dropwise at -78 °C. The resulting reaction mixture was allowed to warm slowly to room temperature and stirred for 2 h. Water was added to the reaction mixture and the product was extracted with DCM. The combined organic layers were washed with saturated NaHCO3 solution, water, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC (column: ZORBAX (21.2 mm x 150 mm); mobile phase: A = water; B = ACN; flow rate: 20 ml / min) to give the title compound, methyl 4-(3-fluoro-2-(3-fluorocyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (17 mg, 17%) as an off-white solid. LCMS Rt=1.524 min;MS m / z, 374.15[MH]-;[Method 10]

[0228] The racemic sample was separated into its enantiomers by chiral HPLC (Column: REGIS WHELK, 250 MM x 21.2 MM x 5 microns; Mobile phase: N-Hexane (A) EtOH:MeOH, 1:1 (B), Flow rate: 15 ML / min).

[0229] Example 20 5 mg of first eluting enantiomer as an off-white solid. Chiral HPLC Rt=7.987 min (Column: REGIS, (S,S)WHELK-01 (150×4.6 mm, 5 microns); Mobile phase: A=n-hexane, B=ethanol; Flow rate: 1.0 ml / min). LCMS Rt=1.556 min;MS m / z, 375.8[M+H]+;[Method 10] 1H NMR(400MHz,DMSO-d6)δ 9.81(s,1H),7.18-7.15(m,1H),6.98-6.93(m,2H),5.60-5.21(m,1H),5.02(s,1H),4.80( dd,J=19.6,16.0Hz,2H),4.60-4.51(m,1H),3.43(s,3H),2.93-2.59(m,4H),2.31(s,3H).

[0230] Example 20b 6 mg of the second enantiomer eluting as an off-white solid. Chiral HPLC Rt=8.934 min (Column: REGIS, (S,S)WHELK-01 (150×4.6 mm , 5 microns); Mobile phase: A=n-hexane, B=ethanol; Flow rate: 1.0 ml / min). LCMS Rt=1.554 min;MS m / z, 376.1[M+H]+;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 9.81(s,1H),7.18-7.15(m,1H),6.98-6.93(m,2H),5.60-5.21(m,1H),5.02(s,1H),4.80( dd,J=19.6,16.0Hz,2H),4.60-4.51(m,1H),3.43(s,3H),2.93-2.59(m,4H),2.31(s,3H).

[0231] Biological Data Many known calcium channel activators are V We have demonstrated complex mechanisms of activating 1.2. These molecules not only increase the peak current, but also have additional mechanisms to increase intracellular calcium concentration, for example by shifting the voltage sensitivity of the channel to more negative membrane potentials. Figure 1 shows a simulated myocardial action potential from an epicardial environment, showing the Ca concentration at potential (mV) versus time (ms). VThese further mechanisms are illustrated by showing the effect of shifting the voltage of 1.2 activation towards more negative membrane potentials. These further mechanisms may promote or encourage cardiovascular effects, e.g., increased blood pressure, changes in heart rate or contractility, and / or arrhythmias due to QT prolongation. For example, the effect of Ca on action potential duration and arrhythmia propensity is shown to be significant using the O'Hara-Rudy model. V The effect of 1.2 modulation was investigated. It was identified that a hyperpolarizing shift in the activation curve of >12 mV could potentially result in a QT prolongation of >15% and an increased risk of arrhythmias. Therefore, minimizing the shift in voltage sensitivity could result in compounds with a reduced risk of QT prolongation and cardiac arrhythmias.

[0232] The compounds of formula (I) are highly potent Ca2+ receptor antagonists with a biophysical profile that minimizes the cardiovascular risks outlined above. V 1.2 activators. First, the compounds of formula (I) limit their effect on voltage sensitivity by minimizing the hyperpolarizing shift to <9 mV, reducing the potential for arrhythmias. Second, the compounds of formula (I) inhibit Ca V 1.2 peak current by at most 2.5-fold, thereby limiting channel overactivation. Third, the compounds of formula (I) inhibit Ca2+, a pathophysiological mechanism underlying the cardiac symptoms of Timothy syndrome. V 1.2 Do not delay channel inactivation Additionally, compounds of formula (I) are designed to maximize brain exposure by not exhibiting significant efflux in the brain.

[0233] Ca V 1.2-Generation and maintenance of HEK293(AUX) cell line Monoclonal Ca V 1.2-HEK293(AUX) cell line is a human Ca VIt constitutively expresses 1.2 alpha 1 (α1) subunit (CACNA1C) and has doxycycline-inducible expression of alpha 2 delta (α2△2) auxiliary subunit (CACNA2D2) and beta 2 (β2) auxiliary subunit (CACNB2). To generate the cell line, expression vectors pcDNA5.0 / FRT-TO-CACNA2D2-FCS-P2A-CACNB2 and pCMV6-Entry-CACNA1C were established by gene synthesis and cloning, where pcDNA5.0 / FRT-TO plasmid is from Invitrogen, pCMV6-Entry is from Origene, FCS represents the furin cleavage site, P2A is a peptide autocleavage sequence derived from porcine teschovirus-1, and FRT is the flippase recognition target site. Next, the parental line Flp-In™ 293T-Rex (Invitrogen) was transfected with pcDNA5.0 / FRT-TO-CACNA2D2-FCS-P2A-CACNB2 and the Flippase vector pOG44 (Invitrogen) to establish the targeted integration of the CACNA2D2-FCS-P2A-CACNB2 expression cassette into the pre-engineered FRT site in Flp-In™ 293T-Rex. This intermediate cell line was then transfected with pCMV6-Entry-CACNA1C to establish stable CACNA1C expression. Clonal isolation was achieved under neomycin selection. A cell clone (2-19B) with good voltage-dependent barium currents (see electrophysiology methods below) was identified as Ca V 1.2 Activators were selected for characterization.

[0234] To maintain the cell line, cells were passaged twice a week. At each passage, the growth medium (Table 1) was completely removed and the cells were rinsed sequentially with 10 ml of D-PBS and 5 ml of warm TrypLE™ Express enzyme (Gibco). Both D-PBS and TrypLE™ Express enzyme were removed immediately after rinsing. The plate was then placed at room temperature for 3-5 minutes. Next, 10 mL of warm 37°C complete medium was added to run over the surface on which the cells were growing and the dissociated cells were collected. Cells were counted and T175cm2 2-3 x 10 per flask 6 The cells were seeded into new flasks at a target density of 100 cells.

[0235] [Table 1]

[0236] Ca V 1.2-Ca using HEK293(AUX) cell line and QPatch V 1.2 Electrophysiological characterization of activators 24 h prior to electrophysiology experiments, doxycycline (1 µg / ml) was added to the growth medium (Table 1) and 25 µM verapamil was co-applied to prevent cell death caused by calcium influx. Cell confluency should reach 70%-80% immediately prior to the experiment.

[0237] (For example, T175cm 2 To harvest the cells (from the flask), the growth medium was completely removed and the cells were rinsed with 10 mL of D-PBS. The D-PBS was aspirated, 10 mL of Detachin (Genlantis) was added, and the plate was placed in a 37 °C incubator for 10 min. The detached cells were placed in a 15 mL conical tube and spun at 1000 rpm for 2 min. The supernatant was removed and the cells were resuspended in QPatch complete medium to the desired cell density of 1.5 to 3 million cells per QPatch run (Table 2). Each experimental run uses 1.5 mL of cells.

[0238] The cell suspension was then loaded onto the Sophion QPatch platform using whole-cell voltage clamp and Ca measurements were performed on single-hole QPlates. V Barium currents conducted through 1.2 were measured. The extracellular and intracellular patch clamp solutions are described in Tables 3 and 4, respectively. A dose-response assay protocol was used to measure the peak inward current (Emax) and potency (EC 50The maximum fold change in EC was determined. The protocol had eight liquid periods. The first liquid period was to stabilize the current amplitude, which was monitored using repeated 200 ms voltage pulses stepping from -80 mV to 0 mV. The second liquid period was to determine the baseline current amplitude in the presence of vehicle control, using a single 20 ms voltage pulse stepping from -80 mV to 0 mV. The third through eighth liquid periods were used to confirm the 6 dose response to compound treatment, also using a single 20 ms voltage pulse stepping from -80 mV to 0 mV. EC 50 is expressed by the following equation I concentration =I base +(I full -I base ) * c n / (XC 50 n +c n ) where c is the concentration and n is the Hill coefficient constant. full is the maximum achievable current, and I base is 0. Using the channel biophysics assay protocol, the current-voltage relationship (I-V curve), the mean channel activation voltage (V 1 / 2 Channel gating properties were determined, including V, fraction of channel inactivation (tau), and tail current amplitude. 1 / 2 is the equation G(V)=G Vmin +(G Vmax -G Vmin ) / (1+exp(-(V-V1 / 2) / V slope )) (wherein G represents conductance, G Vmin is equal to 0, and G Vmax is the maximum conductance, and V slopeG(V) was derived from fitting a slope factor (G(V)=I(V) / (V-0.06) for each experimentally applied depolarized potential (V) and the corresponding current amplitude (I(V)), where 0.06 was the experimentally determined reversal potential in volts. The protocol had four liquid periods. The first liquid period was to stabilize the current amplitude, which was monitored using repeated 200 ms voltage pulses stepwise varying from -80 mV to 0 mV. Upon stabilization of the current amplitude, a baseline value for tau of inactivation was determined by a single exponential fit of the inactivation phase of the current trace. The second liquid period was to measure the baseline value that constitutes the current-voltage curve in the presence of vehicle control, and the third liquid period was to measure the effect of the compound on the current-voltage curve. During each of these two liquid periods, cells were subjected to ten 20 ms voltage pulses, each stepping from -80 mV to incremental values ​​ranging from -55 mV to +35 mV (increment size 10 mV). During the fourth liquid period, a 200 ms voltage pulse from -80 mV to 0 mV was again delivered to measure the effect of the compound on inactivated tau.

[0239] [Table 2]

[0240] [Table 3]

[0241] [Table 4]

[0242] [Table 5]

[0243] Assessment of compound exposure - cFos induction (PK-PD) relationships in wild-type mice Animal Care and Ethics. All animals were housed with controlled temperature and light cycle (22°C, 12-h light / 12-h dark cycle) and unrestricted access to food and water. All animal experiments were performed in accordance with the Institutional Guide for the Care and Use of Laboratory Animals approved by the Institutional Animal Care and Use Committee (IACUC) of Novartis Institutes for BioMedical Research, Inc. (Cambridge, MA, USA).

[0244] Compound administration and brain tissue collection. Wild-type C57BL / 6J male mice were obtained from Jackson laboratories (Bar Harbor, ME). V 1.2 Acute single dose effects of activators were evaluated in male 8-week-old mice (n=6 mice per compound). Each compound was dissolved in 10% PEG300, 10% Solutol, 10% Cremophore EL, and 70% phosphate buffered saline and administered intraperitoneally (ip) at concentrations ranging from 1 mg / kg to 30 mg / kg depending on the compound. One hour after compound administration, animals were euthanized by exsanguination under deep anesthesia. Blood was collected in EDTA tubes for downstream analysis of drug levels. Brains were quickly removed from the skull and the cerebral cortex and cerebellum were locally dissected. Cerebellar samples were snap frozen in liquid nitrogen to assess compound exposure. Cortical samples for cFos assessment were placed in 500 μl of RNAlater solution (ThermoFisher) to preserve the integrity of the RNA in the samples. Samples were kept in RNAlater at 4° C. for at least 24 hours and then transferred to −80° C. for storage prior to processing.

[0245] Quantification of cFos mRNA induction. Tissue homogenization was performed using the TissueLyser system for 96-well plates (Qiagen). First, frozen cortical samples were thawed, removed from RNAlater, and placed in a TissueLyser tube with Buffer RLT containing 0.5% Reagent DX and one 5 mm TissueLyser metal bead. The TissueLyser tube was loaded into a TissueLyser II tissue homogenizer for three rounds of homogenization, each lasting 5 min with a bead beating frequency of 30 Hz. Total RNA was purified from the homogenates using the RNeasy96Plus kit (Qiagen), and RNA concentration and A260 / A280 ratios were quantified by Nanodrop (ThermoFisher), and all samples were normalized to a concentration of 100 ng / μL. RNA was reverse transcribed into cDNA using the Superscript III First-strand synthesis SuperMix kit (ThermoFisher). For each sample, 6 μL of RNA (600 ng total) was mixed with 1 μL of Oligo dT and 1 μl of Annealing Buffer and heated to 65° C. for 5 minutes. Then, 10 μL of 2× First-Strand Reaction Mix and 2 μl of Enzyme Mix were added to achieve a total reaction volume of 20 uL. Samples were heated to 50° C. for 50 minutes and then to 85° C. for 5 minutes to complete cDNA synthesis.

[0246] Quantitative PCR was performed on the cDNA samples using the Quantitect Multiplex RT-PCR kit (Qiagen) in a 384-well assay format. Each PCR well contained 2 μl of cDNA (60 ng total), 10 μL of RT-PCR mastermix, 1 μL of cFos FAM Taqman probe (Mm00487425_m1(FAM)#4351368), 1 μL of GAPDH VIC Taqman probe (Mm99999915-g1(VIC)#4448486), 0.2 μl of Multiplex RT mix and 5.8 μl of RNase-free water. Samples were heated to 95°C for 15 min and then cycled between 94°C for 45 s and 60°C for 45 s for 45 cycles on a ViiA7 real-time PCR system (ThermoFisher). cFos Ct values ​​were exported, normalized to GAPDH Ct values, and converted to expressive relative fold changes using the delta-delta Ct relative quantification method. cFos fold changes between compound treatments and vehicle were analyzed by one-way ANOVA followed by Tukey post-hoc comparisons.

[0247] Quantification of compound exposure. Cerebellar tissue samples were homogenized (5x dilution) in 4 ml of 20% acetonitrile and 80% phosphate buffered saline per gram of tissue. Tissue was homogenized using one of three methods: handheld probe system, 30 s for 4 min, 100 s for 1 ... -1 TissueLyser system with 5 mm steel beads at 350 Hz or OMNI Bead Ruptor Elite homogenizer for 30 seconds to 1 minute depending on tissue type. Tissue samples were added to a 96-well plate (12.5 uL of sample) and processed for quantification by mass spectrometry.

[0248] result

[0249] [Table 6]

[0250] Comparative Example Other Ca V 1.2 activators are known, but these compounds are not potent and / or do not possess the desired biophysical properties required to activate the channel and have sufficient brain exposure, while at the same time minimizing cardiovascular risks, such as increased blood pressure, changes in heart rate or contractility, and / or arrhythmias due to QT prolongation.

[0251] [Table 7]

[0252] [Table 8]

Claims

1. A compound according to formula (I) or a pharma- ceutically acceptable salt thereof 【Chemistry 1】 (In the formula: R １ is H or halo; R ２ is ethyl, isopropyl, isopropenyl, cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 3 halo.

2. A compound according to claim 1 of formula (Ia): or a pharma- ceutically acceptable salt thereof. 【Chemistry 2】

3. A compound according to claim 1 of formula (Ib): or a pharma- ceutically acceptable salt thereof. 【Chemistry 3】

4. R １ The compound according to any one of claims 1 to 3, wherein is H or F.

5. R １ The compound according to any one of claims 1 to 3, wherein is H.

6. R １ The compound according to any one of claims 1 to 3, wherein is F.

7. R ２ The compound according to any one of claims 1 to 6, wherein is ethyl, isopropyl, isopropenyl, cyclopropyl or cyclobutyl, each of which is optionally substituted with 1 to 3 F.

8. R ２ The compound according to any one of claims 1 to 6, wherein is cyclopropyl optionally substituted with 1 to 3 F.

9. R ２ The compound according to any one of claims 1 to 6, wherein is ethyl optionally substituted with 1 to 3 F.

10. R ２ The compound according to any one of claims 1 to 6, wherein is isopropyl optionally substituted with 1 to 3 F.

11. Methyl (S)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-cyclobutyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-cyclopropyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-(2-fluoropropan-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-ethyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(2-ethyl-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(3-fluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(3-fluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-isopropylphenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (S)-Methyl 4-(3,5-difluoro-2-(3,3,3-trifluoroprop-1-en-2-yl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; and Methyl (S)-4-(3-fluoro-2-(3-fluorocyclobutyl)phenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate 2. The compound of claim 1 selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

13. 12. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome.

14. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharma- ceutically acceptable salt thereof for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome.

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