Methyl 2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6,7-tetrahydro-1H-cyclopenta[B]pyridine-3-carboxylate and methyl 2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-B]pyridine-3-carboxylate as CAV1.2 activators

Abstract

The present disclosure relates to a method for treating 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. V 1.22 Provided is a compound according to formula (I) or a pharmaceutically acceptable salt thereof as an active agent. [Formula 1] TIFF2023530917000179.tif47170

Description

[Technical field]

[0001] The present invention relates to methyl 2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate and methyl 2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate compounds, pharmaceutical compositions containing them, and Ca2+-receptor-binding proteins 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 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. VCa 1.2 has been shown to be important for neuronal differentiation and migration, neurite outgrowth, synaptic signaling, gene expression and brain plasticity. V 1.2 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 provides a compound according to formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony: A is O or CH2; R 1 is H or F; R 2 is H or F; R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each optionally substituted with 1 to 3 F.

[0006] In a second aspect, the present disclosure provides a compound according to formula (III) or a pharma- ceutically acceptable salt or solvate thereof: [ka] During the ceremony: A is O or CH2; R 1 is H or F; R 2 is H or F; R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1-3 F; R 4 is H or F.

[0007] In a third aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0008] In a fourth 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 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.

[0009] In a fifth 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 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.

[0010] In a sixth 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 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.

[0011] In a seventh 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 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 a compound according to Formula (I) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment.

[0012] In an eighth aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (III) or a pharma- ceutically acceptable salt thereof.

[0013] In a ninth aspect, the disclosure provides a compound of formula (III) 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 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.

[0014] In a tenth 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 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 (III) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment.

[0015] In an eleventh aspect, the present disclosure provides the use of a compound of formula (III) 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 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.

[0016] In a twelfth aspect, the present 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 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 a compound according to formula (III) or a pharma- ceutically acceptable salt thereof to a patient in need of such treatment. [Brief description of the drawings]

[0017] [Figure 1] 1 illustrates a representative XRPD of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form A of the present disclosure. The x-axis shows the scattering angle in °2 theta and the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons. [Diagram 2] 1 illustrates a representative XRPD of [methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B of the present disclosure. The x-axis shows the scattering angle in °2 theta and the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons. [Diagram 3]1 illustrates a representative XRPD of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form C of the present disclosure. The x-axis shows the scattering angle in °2 theta and the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons. [Figure 4] 1 illustrates a representative XRPD of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate A of the present disclosure. The x-axis shows the scattering angle in °2 theta and the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons. [Diagram 5] 1 illustrates a representative XRPD of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate B of the present disclosure. The x-axis shows the scattering angle in °2 theta and the y-axis shows the intensity of the scattered X-ray beam in counts of detected photons. [Figure 6] 1 illustrates simulated myocardial action potentials from an epicardial environment showing the effect of CaV1.2 activation shifting the voltage towards more negative membrane potentials. The x-axis is time (ms) and the y-axis is potential. [Figure 7] Illustrated is a single X-ray crystal of methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of Example 6, confirming that the active enantiomer is the R-enantiomer. [Figure 8]Illustrated is a single X-ray crystal of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of Example 8, confirming that the active enantiomer is the R-enantiomer. [Figure 9] Illustrated is a single X-ray crystal of methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of Example 9, confirming that the active enantiomer is the R-enantiomer. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] 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.

[0019] As used herein, "administration" and "administering" and "administering" refer to the manner in which the compounds described herein are presented to a subject.

[0020] 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.

[0021] As used herein, "halo" or "halogen" as used herein may be fluorine, chlorine, bromine or iodine.

[0022] As used herein, "subject" 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).

[0023] 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.

[0024] 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.

[0025] 5.2. Compounds A compound according to formula (I) or a pharma- ceutically acceptable salt or solvate thereof [ka] During the ceremony: A is O or CH2; R 1 is H or F; R 2 is H or F; R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each optionally substituted with 1 to 3 F.

[0026] One embodiment is a compound of formula (Ia) or a pharma- ceutically acceptable salt or solvate thereof. [ka]

[0027] Another embodiment is a compound of formula (Ib) or a pharma- ceutically acceptable salt or solvate thereof. [ka]

[0028] In another embodiment, A is O.

[0029] In another embodiment, A is CH2.

[0030] In another embodiment, R 1 is H.

[0031] In another embodiment, R 1 is F.

[0032] In another embodiment, R 2 is H.

[0033] In another embodiment, R 2 is F.

[0034] In another embodiment, R 3 is OCHF2.

[0035] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F.

[0036] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is substituted with 1 to 3 F.

[0037] In another embodiment, R 3 is CHF2 or CF3.

[0038] In another embodiment, R 3 is ethyl substituted with one or two F.

[0039] In another embodiment, R 3 is unsubstituted ethyl.

[0040] In another embodiment, R 3 is cyclopropyl which is unsubstituted or substituted with 2 F.

[0041] A compound according to formula (III) or a pharma- ceutically acceptable salt or solvate thereof [ka] During the ceremony: A is O or CH2; R 1 is H or F; R 2 is H or F; R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1-3 F; R 4 is H or F.

[0042] In another embodiment, A is O.

[0043] In another embodiment, A is CH2.

[0044] In another embodiment, R 1 is H.

[0045] In another embodiment, R 1 is F.

[0046] In another embodiment, R 2 is H.

[0047] In another embodiment, R 2 is F.

[0048] In another embodiment, R 3 is OCHF2.

[0049] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F.

[0050] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is substituted with 1 to 3 F.

[0051] In another embodiment, R 3 is CHF2 or CF3.

[0052] In another embodiment, R 3 is ethyl substituted with one or two F.

[0053] In another embodiment, R 3 is unsubstituted ethyl.

[0054] In another embodiment, R 3 is cyclopropyl which is unsubstituted or substituted with 2 F.

[0055] In another embodiment, R 4 is F.

[0056] In another embodiment, R 4 is H.

[0057] The specific compound is Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; and Methyl (S)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate Includes.

[0058] The specific compound is Methyl (R)-4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; and Methyl (R)-2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Further includes:

[0059] 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.

[0060] 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.

[0061] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0062] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0063] 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.

[0064] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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).

[0069] 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.

[0070] 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.

[0071] 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.

[0072] For example, formula (I) is deuterated as shown in formula (II): [ka] or a pharma- ceutically acceptable salt thereof, 1 , R 2 , R 3 and A are as defined in formula (I); R D1 ~R D8 are each independently H or D.

[0073] 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, for example,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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] How to 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.

[0079] 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 autism spectrum disorder; 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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:

[0093] 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.

[0094] 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.

[0095] Crystal morphology The present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate and a method for its preparation. Further, the present disclosure relates to a pharmaceutical composition, preferably comprising a predetermined and / or effective amount of said crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate and at least one pharma- ceutically acceptable excipient. The pharmaceutical compositions of the present disclosure can be used as medicines, in particular for the treatment and / or prevention 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.

[0096] Different solid-state forms of active pharmaceutical ingredients often have different properties. The difference in the physicochemical properties of solid forms can play an important role for the improvement of pharmaceutical compositions, for example, pharmaceutical formulations with improved dissolution profile or improved stability or shelf life can be made available by the improved solid-state form of active pharmaceutical ingredients. Also, the processing or handling of active pharmaceutical ingredients during the formulation process can be improved. The new solid-state forms of active pharmaceutical ingredients can thus have desirable processing properties. They can be easier to handle, better suited for storage, and / or allow better purification compared to known solid forms.

[0097] The crystalline forms of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate may be characterized by analytical methods well known in the pharmaceutical industry for characterizing solids. Such methods include, but are not limited to, XRPD, SXRD, FTIR, Raman, DSC, TGA, and GMS (gravimetric system). The forms may be characterized by one of the above analytical methods or by combining two or more of them.

[0098] Crystalline forms of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate may be referred to herein as being characterized by graphical data "as shown in" the figures. Such data include, for example, powder X-ray diffraction, FTIR and Raman spectroscopy. Those skilled in the art will appreciate that factors such as instrument type, variations in response, and variations in sample orientation, sample concentration and sample purity may result in minor variations in such data when presented in graphical form, such as variations in exact peak positions and intensities. However, comparison of the graphical data in the figures herein with graphical data generated for another or unknown solid form, and confirmation that the two sets of graphical data relate to the same crystalline form, is well within the knowledge of those skilled in the art.

[0099] The term "reflection", as used herein with respect to powder X-ray diffraction, refers to a peak in an X-ray diffractogram, which is caused at a certain diffraction angle (Bragg angle) by constructive interference from X-rays scattered by parallel planes of atoms in a solid material, which are distributed in a regular and repeating pattern in long-range positional order. Such solid materials are classified as crystalline materials, while amorphous materials are defined as solid materials that lack long-range order and exhibit only short-range order, thus resulting in extensive scattering. According to the literature, long-range order spans, for example, approximately 100-1000 atoms, while short-range order spans only a few atoms (see "Fundamentals of Powder Diffraction and Structural Characterization of Materials" by Vitalij K. Pecharsky and Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).

[0100] The term "essentially the same" is meant to take into account variability in reflection positions and relative intensities of reflections in terms of powder X-ray diffraction. For example, typical accuracy of 2-theta values ​​is in the range of ±0.2° 2-theta, preferably ±0.1° 2-theta.

[0101] Furthermore, those skilled in the art will recognize that relative reflected intensities exhibit variability between instruments, as well as variability due to degree of crystallinity, preferred orientation, particle size, sample preparation, and other factors known to those skilled in the art, and should be taken as a qualitative measurement only.

[0102] The terms "solid form" or "solid state form", as used interchangeably herein, refer to any crystalline and / or amorphous phase of a compound.

[0103] As used herein, the term "amorphous" refers to a solid form of a compound that is not crystalline. Amorphous compounds do not have long-range order and do not exhibit a definitive X-ray diffraction pattern of reflections.

[0104] As used herein, the term "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that form the crystals.

[0105] The term "co-crystal," as used herein, refers to a crystalline material that includes two or more different molecular and / or ionic compounds in the same crystal lattice associated by non-ionic and non-covalent bonds, where at least two of the individual molecular and / or ionic compounds are solids at room temperature.

[0106] The term "hydrate" as used herein refers to a crystalline solid in which water is incorporated into or accommodated by the crystal structure, e.g., water is part of the crystal structure or trapped in the crystal (hydrated). Thereby, water can be present in stoichiometric or non-stoichiometric amounts. When water is present in stoichiometric amounts, the hydrate can be referred to by adding a Greek numeral prefix. For example, the hydrate can be referred to as a hemihydrate or a monohydrate depending on the stoichiometry of water / compound. Water content can be measured, for example, by Karl Fischer coulometry.

[0107] The term "dehydrating" or "dehydration" as used herein describes the at least partial removal of water from the crystal structure of a host molecule.

[0108] The term "solvate" as used herein refers to a crystalline solid, where one or more organic solvents are intermingled in or accommodated by the crystal structure, e.g., are part of the crystal structure or are trapped in the crystal (water-containing).Thereby, one or more organic solvents can be present in stoichiometric or non-stoichiometric amounts.When one or more organic solvents are present in stoichiometric amounts, the solvate can be referred to by adding a Greek numeral prefix.For example, the solvate can be referred to as a hemisolvate or monosolvate depending on the stoichiometry of the solvent / compound.The solvent content can be measured, for example, by GC, NMR, SXRD and / or TGA / MS.

[0109] The term "non-hygroscopic", as used herein, refers to a compound that exhibits a maximum water uptake of 2 wt. % in a sorption cycle, based on the weight of the compound, as measured by GMS at a relative humidity ranging from 0 to 95% RH and a temperature of (25.0±0.1)° C.

[0110] As used herein, the term "about" means within a statistically significant range of a value. Such ranges can be within an order of magnitude, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1% of the indicated value or range. Sometimes, such ranges can be within the experimental error inherent in the standard method used to measure and / or determine a given value or range.

[0111] As used herein, the term "substantially free of any other solid forms" means, with respect to a composition comprising a particular solid form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, that the composition comprises at most 20% by weight, preferably at most 10% by weight, more preferably at most 5% by weight, even more preferably at most 2% by weight, and most preferably at most 1% by weight, of any other solid form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, based on the weight of the composition.

[0112] As used herein, "substantially pure" when used in reference to a form means a compound having a purity of greater than 90% by weight, including greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, and greater than 99% by weight, based on the weight of the compound, and also including methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate equal to about 100% by weight. The remaining material includes other forms of the compound and / or reaction impurities and / or process impurities resulting from its preparation. For example, a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate may be considered to be substantially pure in that it has a purity of greater than 90% by weight, as measured by means currently known and generally accepted in the art, with the remaining material being less than 10% by weight comprising other forms of [compound ABC] and / or reaction and / or processing impurities.

[0113] Crystal form A In a further aspect, the present disclosure provides crystalline form A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate. The most prominent X-ray powder diffraction peaks for form A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate are shown in Table 1.

[0114] [Table 1]

[0115] One embodiment of the present disclosure is a Cu-K alpha having a wavelength of 0.15419 nm at a temperature in the range of 20 to 30° C. 1,2 When measured by irradiation, (8.5±0.2)°, (10.4±0.2)°, and (10.8±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, and (22.4±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, and (22.4±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (13.5±0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)° and (22.4±0.2)° The present invention provides Form A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, characterized by having an XRPD pattern including reflections at 2-theta angles of

[0116] In yet another embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15418 nm at a temperature in the range of 20-30° C. 1,2 The present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, Form A, which is characterized by having an XRPD pattern that, when measured by irradiation, is essentially the same as that shown in FIG. 1 of the present disclosure.

[0117] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, Form A, characterized by having a melting point onset temperature of 98±5° C. as measured by DSC at a heating rate of 10 K / min.

[0118] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form A, characterized by having a melting point peak maximum temperature of 104±5° C. as measured by DSC at a heating rate of 10 K / min.

[0119] Crystal form B In a further aspect, the present disclosure provides methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B. The most prominent X-ray powder diffraction peaks for methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B are shown in Table 2.

[0120] [Table 2]

[0121] In one embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15419 nm at a temperature in the range of 20-30° C. 1,2 When measured by irradiation, (12.0±0.2)°, (13.7±0.2)°, and (21.4±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, and (21.4±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, and (23.8±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)°, and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)°, and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (14.5±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)°, and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (14.5±0.2)°, (15.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)° and (23.8±0.2)° The present invention provides Form B of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, characterized by having an XRPD pattern including reflections at 2-theta angles of

[0122] In yet another embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15418 nm at a temperature in the range of 20-30° C. 1,2 The present invention relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B, which is characterized by having an XRPD pattern essentially the same as that shown in FIG. 2 of the present invention, when measured by irradiation.

[0123] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B, characterized by having a melting point onset temperature of 184±5° C. as measured by DSC at a heating rate of 10 K / min.

[0124] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B, characterized by having a melting point peak maximum temperature of 185±5° C. as measured by DSC at a heating rate of 10 K / min.

[0125] Crystal form C In a further embodiment, the present disclosure provides methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form C. The most prominent X-ray powder diffraction peaks for Form C of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate are shown in Table 3.

[0126] [Table 3]

[0127] In one embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15419 nm at a temperature in the range of 20-30° C. 1,2 When measured by irradiation, (10.3±0.2)°, (15.5±0.2)°, and (20.6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, and (20.6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (20.6±0.2)°, and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18.2±0.2)°, (20.6±0.2)°, and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (14.0±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (7.0±0.2)°, (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (14.0±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)° The present invention provides Form C of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, characterized by having an XRPD pattern including reflections at 2-theta angles of

[0128] In yet another embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15418 nm at a temperature in the range of 20-30° C. 1,2 The present invention relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form C, which is characterized by having an XRPD pattern essentially the same as that shown in FIG. 3 of the present invention, when measured by irradiation.

[0129] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form C, characterized by having a melting point onset temperature of 178±5° C. as measured by DSC at a heating rate of 10 K / min.

[0130] In one embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form C, characterized by having a melting point peak maximum temperature of 178±5° C. as measured by DSC at a heating rate of 10 K / min.

[0131] Hydrate A In a further aspect, the present disclosure provides methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate A. The most prominent X-ray powder diffraction peaks for the crystalline form hydrate A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate are shown in Table 4.

[0132] [Table 4]

[0133] In one embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15419 nm at a temperature in the range of 20-30° C. 1,2 When measured by irradiation, (10.0±0.2)°, (10.6±0.2)°, and (23.5±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (14.4±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (14.4±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (11.1±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (11.1±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (20.0±0.2)°, (22.9±0.2)°, (23.5±0.2)° and (25.0±0.2)° The present invention provides a hydrate A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, characterized by having an XPRD pattern including reflections at 2-theta angles of

[0134] In yet another embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15418 nm at a temperature in the range of 20-30° C. 1,2The present invention relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate A, which is characterized by having an XRPD pattern essentially the same as that shown in FIG. 4 of the present invention, when measured by irradiation.

[0135] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate A, characterized by having a broad endothermic event with a peak maximum at a temperature of 109±10° C. as measured by DSC at a heating rate of 10 K / min.

[0136] Hydrate B In a further aspect, the present disclosure provides methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate B. The most prominent X-ray powder diffraction peaks for crystalline hydrate B of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate are shown in Table 5.

[0137] [Table 5]

[0138] In one embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15419 nm at a temperature in the range of 20-30° C. 1,2 When measured by irradiation, (5.5±0.2)°, (8.4±0.2)°, and (13.0±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (13.0±0.2)°, and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0.2)°, and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0.2)°, (16.5±0.2)°, and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (19.6±0.2)°, and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (19.6±0.2)°, and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (17.9±0.2)°, (19.6±0.2)°, and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (17.9±0.2)°, (19.6±0.2)°(20.6±0.2)° and (24.0±0.2)° The present invention provides a hydrate B of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, characterized by having an XRPD pattern including reflections at 2-theta angles of

[0139] In yet another embodiment, the present disclosure provides a Cu-K alpha having a wavelength of 0.15418 nm at a temperature in the range of 20-30° C. 1,2The present invention relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate B, which is characterized by having an XRPD pattern essentially the same as that shown in FIG. 5 of the present invention, when measured by irradiation.

[0140] In another embodiment, the present disclosure relates to a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate hydrate B, characterized by having a broad endothermic event with a peak maximum at a temperature of 93±10° C. as measured by DSC at a heating rate of 10 K / min.

[0141] In another aspect, the present invention relates to a composition comprising a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as defined in any one of the above embodiments, said composition being essentially free of any other solid forms of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate. For example, a composition comprising crystalline hydrate A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of the present disclosure comprises at most 20% by weight, preferably at most 10% by weight, more preferably at most 5% by weight, 4% by weight, 3% by weight, 2% by weight, or 1% by weight of any other solid form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate], based on the weight of the composition.

[0142] Ca V 1.2-HEK293(AUX) cell line In one aspect, the present disclosure provides a method for the preparation of human Ca V1.2 A cell comprising an alpha 1C (α1C) subunit (encoded by human CACNA1C transcript variant 14; GenBank ID: NM_001129840), an alpha 2 delta (α2Δ2) auxiliary subunit (encoded by human CACNA2D2 transcript variant 3; GenBank ID: NM_001174051), and a beta 2 (β2) auxiliary subunit (encoded by human CACNB2 transcript variant 2; GenBank ID: NM_201596), wherein the α1C subunit is constitutively expressed and the α2Δ2 subunit and the β2 subunit are doxycycline-inducible expressed. In another aspect, the disclosure relates to a cell for use in a method for screening a compound for biological activity. In one aspect, the cell is comprised in a stable cell line, e.g., HEK293, that constitutively expresses the α1C subunit and doxycycline-inducibly expresses the α2Δ2 subunit and the β2 subunit. In another embodiment, the stable cell line is generated by DNA transfection or viral transduction, e.g., via lentivirus or baculovirus. In one embodiment, the cells are contained in a cell line, e.g., HEK293, that constitutively expresses the α1C subunit and doxycycline-inducibly expresses the α2Δ2 and β2 subunits from transient DNA transfection. In another embodiment of the disclosure, the compound is Ca V In another aspect, the disclosure relates to a cell for use in a method of identifying an agent for treating, preventing, and / or diagnosing a disease or disorder, such as 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. In some embodiments, the agent is a Ca V 1.2 It is an activator. EXAMPLES

[0143] Intermediates and Examples The following examples are intended to illustrate the present disclosure and are not to be construed as limitations thereon.

[0144] All of the 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 the active enantiomer for methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of Example 6 and methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate of Example 9 was analyzed using single crystal X-ray crystallography, and it was determined that the active enantiomer was the R-enantiomer. Thus, the R-enantiomers of the methyl 2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate and methyl 2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate compounds shown below are expected to be the active enantiomers. [ka] [ka]

[0145] Example numbers (Examples 1, 2, 3, etc.) are given for the active enantiomers which are all assumed to have the R 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 R configuration is the preferred configuration, it remains possible that the S-enantiomer may be the active enantiomer.

[0146] 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.

[0147] 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 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 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

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] LCMS method 4: 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 = 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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

[0164] 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].

[0165] 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].

[0166] Method 3: HPLC [Column: XBRIDGE C18 (21.2 x 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].

[0167] 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)

[0168] 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].

[0169] 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].

[0170] 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].

[0171] 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).

[0172] 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).

[0173] 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).

[0174] 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).

[0175] Method 5: Column: LUX CELLULOSE-4 (10 x 250 mm, 5 micron); Mobile phase: Hexane (A) EtOH: 1:1 (B); Flow rate: 8 mL / min; Isocratic: 90:10 (A:B).

[0176] Method 6: Column: LUX CELLULOSE-4 (10 x 250 mm, 5 micron), Mobile phase: Hexane (A); EtOH:MeOH 1:1 (B); Flow rate: 18 mL / min; Isocratic: 90:10 (A:B).

[0177] Method 7: Column: LUX CELLULOSE-4 (21.2 x 250 mm, 5 micron), Mobile phase: Hexane (A); EtOH:MeOH 1:1 (B); Flow rate: 19 mL / min; Isocratic: 80:20 (A:B).

[0178] Method 8: Column: REGIS (10 x 250 mm, 5 micron), Mobile phase: CO2 (A) MeOH:EtOH 1:1 (B); FLOW: 13 mL / min, Isocratic: 80:20 (A:B).

[0179] Method 9: Column: LUX CELLULOSE-4 (10 x 250 mm, 5 micron); Mobile phase: Hexane (A), 0.1% DEA in EtOH:MeOH (50:50) (B); Flow rate: 7 mL / min; Isocratic: 93:07 (A:B).

[0180] Chiral analytical HPLC method for the analysis of separated isomers: Method 1: Column: Lux, Cellulos-4 (250 x 4.6 mm, 5 micron; Mobile phase: A = n-hexane, B = 0.1% TFA in ethanol; 1 mL / min; Isocratic: 70:30 (A:B)

[0181] Method 2: Column: LUX CELLULOSE-4 (4.6 x 250 mm, 5 micron; Mobile phase: Hexane (A) EtOH: 1:1 (B); Flow rate: 1 mL / min; Isocratic: 50:50 (A:B).

[0182] Method 3: Column: REGIS, (S,S) WHELK-01 (250 x 4.6 mm, 5 micron; Mobile phase: A = n-hexane, B = ethanol; Flow rate: 1 mL / min; Isocratic: 70:30 (A:B).

[0183] 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 EtOAc phases were combined, washed with saturated NaHCO3 solution (2 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→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).

[0184] Intermediate B: Formation of methyl (Z)-3-amino-4-fluorobut-2-enoate Method 1: [ka] A solution of methyl acetate (36.5 g, 492.71 mmol) in tetrahydrofuran (200 mL) was cooled to -78°C under nitrogen atmosphere and lithium diisopropylamide in THF (246.44 mL, 2.0 M, 492.71 mmol) was added slowly to the reaction over a period of 20 minutes, the resulting mixture was stirred at -78°C for 1 hour, followed by the dropwise addition of a solution of 2-fluoroacetonitrile (19.4 g, 328.9 mmol) in tetrahydrofuran (150 mL). The reaction mixture was stirred at -78°C for an additional hour, after which saturated ammonium chloride solution (200 mL) was added and the product was extracted into ethyl acetate (5 L). The EtOAc was washed with saturated brine solution (500 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 as a white crystalline solid, methyl (Z)-3-amino-4-fluorobut-2-enoate (16 g).

[0185] Method 2: [ka] Step 1: A solution of methyl acetate (83.78 g, 1131.0 mmol) in tetrahydrofuran (800 mL) was cooled to -78 °C under nitrogen atmosphere, then lithium diisopropylamide in THF (565.5 mL, 2.0 M, 1131.0 mmol) was added slowly to the reaction over a period of 20 min. The resulting mixture was stirred at -78 °C for 1 h, then ethyl 2-fluoroacetate (100 g, 942.5 mmol) was added dropwise in a solution of tetrahydrofuran (200 mL) and the reaction mixture was stirred at -78 °C for an additional 1 h. Saturated ammonium chloride solution (200 mL) was added to the reaction mixture and the product was extracted into ethyl acetate (5 L). The EtOAc was washed with saturated brine solution (500 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 yellow crystals of methyl 4-fluoro-3-oxobutanoate (60 g). 1 H NMR(400MHz,CDCl3)δ 4.97(s,1H),4.85(s,1H),3.76(d,J=2.3Hz,3H),3.62(d,J=3.7Hz,2H).

[0186] Step 2: To methyl 4-fluoro-3-oxobutanoate (from step 1, 60 g) in a sealed tube was added saturated ammonia solution in methanol (300 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give the title compound as a white solid methyl (Z)-3-amino-4-fluorobut-2-enoate (51 g). 1 H NMR(300MHz,DMSO-d6)δ 4.98(t,J=0.7,0.7Hz,1H),4.82(t,J=0.7,0.7Hz,1H),4.53(q,,1H),3.53(d,J=1.2Hz,3H).

[0187] General Procedure I [ka] Step 1: To a solution of aldehyde (1 mmol) in EtOH (10 mL) was added methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 1 mmol or 1.2 mmol) and ethyl 4-acetoxy-3-oxobutanoate (Intermediate A, 1 mmol or 1.2 mmol). The resulting solution was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to give the title compound (crude).

[0188] Step 2: To the crude intermediate from step 1 in methanol (10 mL) was added potassium carbonate (5 mmol). The resulting solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and it was added to water. The product was extracted into ethyl acetate (100 mL), washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography.

[0189] General Procedure II [ka] To a solution of the aldehyde (1 mmol) in MeOH (10 mL) was added methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 1 mmol or 1.2 mmol) and ethyl 4-acetoxy-3-oxobutanoate (Intermediate A, 1 mmol or 1.2 mmol). The resulting solution was stirred at 75° C. for 16-48 h. The solvent was removed under reduced pressure and the product was purified using silica flash chromatography.

[0190] Example 1: Methyl (R)-4-(2-((R or S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-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 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 mixture was poured into 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).

[0191] 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) and the product was extracted into ethyl acetate (2 L). The EtOAc phase was 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→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).

[0192] 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 dichloromethane (100 mL). It was washed with water (50 mL), brine 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).

[0193] 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), 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 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).

[0194] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 4 (1.0 g, 4.996 mmol), intermediate A (945 mg, 4.996 mmol) and intermediate B (665 mg, 4.996 mmol)) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.4 g, crude). The crude product was used as such in the next step without further purification and analysis.

[0195] Step 6: Methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 5, 1.4 g, 2.884 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%), which gave the title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (125 mg) as an off-white solid. The sample was separated chirally into two products using chiral SFC: column: Lux-cellulose-2, 21×250 mm, 5 um; flow rate: 80 g per minute; co-solvent: 20% 1:1 MeOH:IPA; detection: 344 nm; BPR set point: 125 bar.

[0196] The resulting peaks 1 and 2 from the previous separation were separated into four isomers using chiral SFC: Column: WO1 SS, 21 x 250 mm; Flow rate: 80 g per minute; Co-solvent: 15% IPA; Detection: 344 nm; BPR set point: 150 bar.

[0197] Example 1 20 mg of the title compound (61%) as the second eluting stereoisomer as a white solid SFC Rt=2.49; Mobile phase: 5-55% (1:1) 10 mM NH4OH in MeOH IPA w / CO2, 5 mL / min; Column: Lux Cellulose-2, 4.6 x 100 mm, 5 μm LCMS Rt=2.12 min;MS m / z, 398.3[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz,1H),7.31(td,J=8.0,5.6Hz,1H),7.20-6.83(m,2H),5.78-5.41(m,2H),5.22(s,1H),5.0 3-4.73(m,2H),3.51(s,3H),2.86(td,J=12.4,8.5Hz,1H),2.64-2.53(m,1H),2.18(dt,J=12.2,5.5Hz,1H).

[0198] Example 1b 15 mg of first eluting stereoisomer (46%) as a white solid SFC Rt=2.42; Mobile phase: 5-55% (1:1) 10 mM NH4OH in MeOH IPA w / CO2, 5 mL / min; Column: Lux Cellulose-2, 4.6 x 100 mm, 5 μm LCMS Rt=2.15 min;MS m / z, 398.2[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.08(d,J=3.2Hz,1H),7.33(td,J=8.1,5.8Hz,1H),7.25-6.92(m,2H),5.94-5.54(m,2H),5.27(s,1H),4. 79(d,J=1.4Hz,2H),3.44(s,3H),3.15-3.04(m,1H),2.35-2.19(m,1H),1.88(dtd,J=14.0,8.2,3.2Hz,1H).

[0199] Example 1c 24 mg of the third eluting stereoisomer (73%) as a white solid SFC Rt=2.73 min; Mobile phase: 5-55% (1:1) 10 mM NH4OH in MeOH IPA w / CO2, 5 mL / min; Column: Lux Cellulose-2, 4.6 x 100 mm, 5 μm LCMS Rt=2.16 min;MS m / z, 398.3[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz,1H),7.31(td,J=8.0,5.6Hz,1H),7.18-6.87(m,2H),5.61(dd,J=47.8,4.0Hz,2H),5.22(s,1H) ),4.98-4.78(m,2H),3.51(s,3H),2.86(td,J=12.5,8.5Hz,1H),2.64-2.55(m,1H),2.18(tt,J=12.8,6.8Hz,1H).

[0200] Example 1d 15 mg of the fourth eluting stereoisomer (46%) as a white solid SFC Rt=2.78 min; Mobile phase: 5-55% (1:1) 10 mM NH4OH in MeOH IPA w / CO2, 5 mL / min; Column: Lux Cellulose-2, 4.6 x 100 mm, 5 μm LCMS Rt=2.11 min;MS m / z, 398.1[M+H]+;[Method 3] 1 H NMR:(400MHz,DMSO-d6)δ 10.08(d,J=3.3Hz,1H),7.33(td,J=8.0,5.6Hz,1H),7.14-6.94(m,2H),5.72(dd,J=47.8,4.8Hz,2H),5.27 (s,1H),4.79(d,J=1.4Hz,2H),3.44(s,3H),3.15(d,J=14.7Hz,1H),2.33-2.20(m,1H),1.99-1.79(m,1H).

[0201] Example 2: Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-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 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), the EtOAc phase was 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→1%) afforded the title compound 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane (11.2 g) as a colorless 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).

[0202] Step 2: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclopropyl-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 1, 4.0 g, 24.36 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclopropyl-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (7.0 g, crude). LCMS Rt=1.806 min;MS m / z, 450.3[M+H]+;[Method 7]

[0203] Step 3: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 2, 7.0 g, 15.57 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%), which afforded the title compound, methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (1.15 g) as an off-white solid.

[0204] 150 mg of the racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 6].

[0205] Example 2 50 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt = 6.129 min [Chiral analysis method 1] LCMS Rt=1.538 min;MS m / z, 360.0[MH]-;[Method 7] 1H NMR (400 MHz, CDCl3) δ 7.15-7.05 (m, 1H), 6.92 (ddd, J = 7.8, 1.2, 0.6 Hz, 1H), 6.82 (ddd, J = 10.8, 8.2, 1.3 Hz, 1H), 5.78 (d, J = 0.9 Hz, 1H), 5.71-5.59 (m, 2H), 4.80-4.69 (m, 2H), 3.55 (s, 3H), 2.19-2.15 (m, 1H), 1.34-1.20 (m, 1H), 1.06-0.96 (m, 2H), 0.82-0.71 (m, 1H). No exchangeable NH was observed in the spectrum.

[0206] Example 3: Methyl (R)-4-(2-((R or S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate and Example 4: Methyl (R)-4-(2-((R or S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-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] The title compound was synthesized following a procedure similar to that of step 1 of example 1 using 10 g of 2-bromo-3,5-difluorobenzaldehyde to give 11.5 g of the desired product 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane. 1 H NMR(300MHz,CDCl3)δ 7.20-7.15(m,1H),6.49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H).

[0207] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane [ka] The title compound was synthesized according to a procedure similar to step 2 of example 1 using 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane to give 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (3.45 g). 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).

[0208] 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. The reaction mixture was cooled to room temperature, trifluoromethyltrimethylsilane (16.1 g, 113.1 mmol) and sodium iodide (850 mg, 5.65 mmol) were added, and the resulting solution was stirred at 65° C. for 24 hours. The reaction mixture was then partitioned between ethyl acetate and water, and the organic phase 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).

[0209] 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), saturated NaHCO3 solution (100 mL), and 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→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).

[0210] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using general step 1 of Method I (using the aldehyde from step 4 (1.0 g, 4.58 mmol), intermediate A (862 mg, 4.58 mmol) and intermediate B (608 mg, 4.58 mmol)) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (2.5 g, crude). LCMS Rt=1.683 min;MS m / z, 504[M+H]+;[Method 7]

[0211] Step 6: Methyl 4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 5, 2.5 g, 4.97 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%), which gave the title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (120 mg) as an off-white solid. The racemate was separated into its enantiomers by chiral SFC (mobile phase: 20% IPA / CO2, 80 g / min; column: Whelk-O1SS, 21×250 mm; instrument: Thar80_SN4740).

[0212] Example 3 20.9 mg of the first eluting stereoisomer (68.8%) as a white solid. SFC Rt=2.40 min ((SS)Whelk-O1, 4.6×100 mm, 5 μm, 5→55% IPA in CO2). LCMS Rt=2.27 min;MS m / z, 416.2[M+H]+;[Method 4] 1 H NMR (400 MHz, methanol-d4) δ 6.93-6.73 (m, 2H), 5.90-5.77 (m, 1H), 5.77-5.64 (m, 1H), 5.46 (s, 1H), 4.83 (s, 2H), 3.54 (s, 3H), 3.20-3.02 (m, 1H), 2.09 (tdd, J = 11.8, 7.5, 5.9 Hz, 1H), 1.95 (ddt, J = 16.5, 7.8, 3.4 Hz, 1H).

[0213] Example 4 20.6 mg of the second eluting stereoisomer (67.8%) as a white solid. SFC Rt=2.43 min ((SS)Whelk-O1, 4.6×100 mm, 5 μm, 5→55% IPA in CO2). LCMS Rt=2.21 min;MS m / z, 416.4[M+H]+;[Method 4] 1 H NMR (400MHz, methanol-d4) δ6.93 -6.72(m,2H),5.74(d,J=3.6Hz,1H),5.62(d,J=4.1Hz,1H),5.42(s,1H),5.00-4.90(m,2H) ),3.60(s,3H),2.97-2.80(m,1H),2.68-2.49(m,1H),2.02(tdd,J=11.9,7.8,5.9Hz,1H).

[0214] The remaining stereoisomers were isolated as examples 3b and 4b.

[0215] Example 3b 21.6 mg of the third eluting stereoisomer (74.1%) as a white solid. SFC Rt=2.68 min ((SS)Whelk-O1, 4.6×100 mm, 5 μm, 5→55% IPA in CO2). LCMS Rt=2.22 min;MS m / z, 416.6[M+H]+;[Method 4] 1H NMR (400 MHz, methanol-d4) δ 6.78-6.63 (m, 2H), 5.76-5.64 (m, 1H), 5.64-5.52 (m, 1H), 5.33 (s, 1H), 4.70 (s, 2H), 3.41 (s, 3H), 3.07-2.91 (m, 1H), 1.96 (tdd, J = 11.8, 7.6, 5.9 Hz, 1H), 1.90-1.77 (m, 1H).

[0216] Example 4b 20.6 mg of the fourth eluting stereoisomer (70.7%) as a white solid. SFC Rt=2.79 min ((SS)Whelk-O1, 4.6×100 mm, 5 μm, 5→55% IPA in CO2). LCMS Rt=2.21 min;MS m / z, 416.3[M+H]+;[Method 4] 1 H NMR (400 MHz, methanol-d4) δ 6.91-6.73 (m, 2H), 5.80-5.67 (m, 1H), 5.67-5.55 (m, 1H), 5.41 (d, J = 1.6 Hz, 1H), 4.98-4.88 (m, 2H), 3.59 (s, 3H), 2.98-2.81 (m, 1H), 2.68-2.48 (m, 1H), 2.00 (tdd, J = 11.8, 7.8, 5.9 Hz, 1H).

[0217] Example 5: Methyl (R)-4-(3,5-difluoro-2-((R or S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-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 (prepared from step 2 in Example 4, 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) and the product was extracted into ethyl acetate (500 mL). The EtOAc phase was 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→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).

[0218] 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 phase 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).

[0219] 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 phase 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).

[0220] 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), 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).

[0221] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (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 as a mixture of diastereomers. The crude product was carried on to the next step without purification. LCMS Rt=2.272 min;MS m / z, 472.3[MH]-;[Method 7]

[0222] Step 6: Methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using a mixture of intermediates from step 5, 800 mg, 1.75 mmol) to give methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (2 g crude) as an off-white solid.

[0223] The diastereomeric mixture was separated into its two isomers using Combiflash chromatography (0→80%) to give 100 mg of the first diastereomer as a white solid and 80 mg of the second diastereomer as a white solid.

[0224] Peak 1: 100 mg and peak 2: 80 mg were further separated into their enantiomers using preparative chiral HPLC [Method 7] to give four isomers.

[0225] Example 5 21 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=4.418 min; [Chiral analysis method 2] LCMS Rt=1.514 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR:(400MHz,CD3OD)δ 6.87-6.74(m,2H),6.46-6.18(m,1H),5.75(t,J=1.0Hz,1H),5.63(dd,J=1.6,0.7Hz,1H) ,5.20-5.12(m,1H),4.91-4.81(m,2H),3.53(s,3H),1.83(ddd,J=22.7,6.6,1.4Hz,3H).

[0226] Example 5b 22 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=4.792 min; [Chiral analysis method 2] LCMS Rt=1.513 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR:(400MHz,CD3OD)δ 6.87-6.74(m,2H),6.46-6.18(m,1H),5.75(t,J=1.0Hz,1H),5.63(dd,J=1.6,0.7Hz,1H) ,5.20-5.12(m,1H),4.91-4.81(m,2H),3.53(s,3H),1.83(ddd,J=22.7,6.6,1.4Hz,3H).

[0227] Example 5c 18 mg of the third eluting enantiomer obtained as a white solid. Chiral HPLC Rt=6.777 min; [Chiral analysis method 2] LCMS Rt=1.476 min;MS m / z, 384.1[MH]-;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 6.77-6.63(m,2H),6.48(dd,J=44.3,6.6Hz,1H),5.85-5.77(m,1H),5.70(d,J=4.5Hz, 1H),5.10(s,1H),4.83-4.77(m,2H),3.56(s,3H),1.79(ddd,J=22.5,6.7,1.1Hz,3H).

[0228] Example 5d 16 mg of the fourth eluting enantiomer obtained as a white solid using chiral HPLC method 7. Chiral HPLC Rt=7.475 min; [Chiral analysis method 2] LCMS Rt=2.00 min;MS m / z, 384.2[MH]-;[Method 9] 1 H NMR(400MHz,CDCl3)δ 6.77-6.63(m,2H),6.48(dd,J=44.3,6.6Hz,1H),5.85-5.77(m,1H),5.70(d,J=4.5Hz, 1H),5.10(s,1H),4.83-4.77(m,2H),3.56(s,3H),1.79(ddd,J=22.5,6.7,1.1Hz,3H).

[0229] Example 6: Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-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)-2-fluoroethan-1-one [ka] A solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, Example 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 to the reaction 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 phase was 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(400MHz,CDCl3)δ 7.45(m,1H),7.37(d,J=7.8,1H),7.13(dd,J=9.3,8.2Hz,1H),6.02(s,1H),5.23(d,J=1.4Hz,1H),5.11(d,J=1.3Hz,1H),4.08-3.87(m,4H).

[0230] Step 2: 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 (from step 1, 19.6 g, 85.89 mmol) in methanol (100 mL) was added sodium borohydride (3.9 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 phase was washed with water (250 mL) followed by 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→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,CDCl3)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).

[0231] Step 3: 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 2, 18 g, 78.18 mmol) in dichloromethane (150 mL) was cooled to -78 °C, then diethylaminosulfur trifluoride (DAST) (15.49 mL, 117.28 mmol) was added and the resulting reaction mixture was stirred at -78 °C for 1 h. The reaction mixture was slowly brought to 0 °C and stirred for an additional 1 h. Water (150 mL) was added and the product was extracted with dichloromethane (2 x 200 mL). The combined organic phases were combined, 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(400MHz,CDCl3)δ 7.45(d,J=7.8Hz,1H),7.42-7.35(m,1H),7.12(dd,J=10.6,8.2Hz,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).

[0232] Step 4: 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde [ka] To a solution of 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 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 extracted with diethyl ether (200 mL), washed with water (2×100 mL), brine (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→10%), which gave the title compound 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde (10 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)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)

[0233] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using general step 1 of general procedure I (using the aldehyde from step 4, 9 g, 47.83 mmol), which afforded the title compound 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate as a mixture of diastereomers (25.0 g, crude) as an off-white solid.

[0234] The crude product was used for the next step without further purification and analysis.

[0235] Step 6: Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using the mixture of intermediates from step 5, 25 g, 52.8 mmol) to give the title compound, methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (1 g, crude) as an off-white solid. The diastereomeric mixture was separated into its two isomers using silica flash chromatography (0→80%) to give 1.51 g of the first diastereomer as a white solid and 820 mg of the second diastereomer as a white solid.

[0236] The previously separated diastereomers from peak 1: 200 mg and diastereomers from peak 2: 200 mg were further separated into their enantiomers using preparative chiral HPLC [Method 7] to give four isomers.

[0237] Example 6 56 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=7.623 min; [Chiral analysis method 2] LCMS Rt=1.445 min;MS m / z, 384.0[MH]-;[Method 7] 1H NMR(400MHz,CD3OD)δ 7.41-7.35(m,1H),7.17(dt,J=7.9,1.3Hz,1H),6.98(dd,J=11.4,8.1Hz,1H),6.66-6.33(m,1H),5 .75(d,J=3.7Hz,1H),5.68-5.56(m,1H),5.18(s,1H),5.15-4.91(m,2H),4.85(s,2H),3.52(s,3H).

[0238] The configuration of Example 6, 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 R-enantiomer (Figure 7).

[0239] Example 6b 54 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=8.757 min; [Chiral analysis method 2] LCMS Rt=1.443 min;MS m / z, 386.3[M+H]+;[Method 7] 1 H NMR:(400MHz,CD3OD)δ 7.41-7.35(m,1H),7.17(dt,J=7.9,1.3,1.3Hz,1H),7.10-6.88(m,1H),6.67-6.26(m,1H),5.82-5 .70(m,1H),5.69-5.57(m,1H),5.18(s,1H),5.15-4.91(m,2H),4.85(d,J=0.7Hz,2H),3.52(s,3H).

[0240] Example 6c 67 mg of the third eluting enantiomer obtained as a white solid. Chiral HPLC = Rt = 10.574 min; [Chiral analysis method 2] LCMS Rt=1.379 min;MS m / z, 384.0[MH]-;[Method 7] 1H NMR(400MHz,CD3OD)δ 7.41-7.35(m,1H),7.13(dt,J=7.9,1.3,1.3Hz,1H),6.97(dd,J=11.3,8.2Hz,1H),6.60(ddd,J=47.2,18.0,8.4Hz,1H),5 .75(s,1H),5.63(s,1H),5.14(s,1H),5.12-4.92(m,1H),4.84(s,2H),4.70(ddd,J=44.6,32.7,10.8Hz,1H),3.53(s,3H).

[0241] Example 6d 69 mg of the fourth eluting enantiomer was obtained as a white solid. Chiral HPLC Rt = 13.93 min [Chiral analysis method 2] LCMS Rt=1.379 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.41-7.35(m,1H),7.13(dt,J=7.8,1.3Hz,1H),6.97(dd,J=11.3,8.2Hz,1H),6.60(ddd,J=47.1,17.9,8.3Hz,1H),5.75(s ,1H),5.63(s,1H),5.17-5.11(m,1H),5.11-4.92(m,1H),4.84(s,2H),4.70(ddd,J=45.1,33.0,11.1Hz,1H),3.53(s,3H).

[0242] Example 7: Methyl (R)-4-(2-((R or S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 3-Ethoxycyclopent-2-en-1-one [ka] To a stirred solution of cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene (70 mL) was added pTSA (193 mg, 1.019 mmol) and EtOH (22.61 ml, 387.35 mmol) at room temperature. The resulting mixture was stirred at 120° C. for 10 h using a Dean-Stark apparatus. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) to give the title compound 3-ethoxycyclopent-2-en-1-one (4.3 g) as a brown solid. 1 H NMR(400MHz,CDCl3)δ 5.26(s,1H),4.02(q,J=6.6Hz,2H),2.60-2.55(m,2H),2.44-2.40(m,2H),1.39(t,J=7.2Hz,3H).

[0243] Step 2: 3-Aminocyclopent-2-en-1-one [ka] To a stirred solution of 3-ethoxycyclopent-2-en-1-one (from step 1, 4.3 g, 34.08 mmol) in ethanol (50 mL) was added ammonium hydroxide solution (25 mL, 387.35 mmol) at room temperature. The resulting mixture was stirred at 85° C. for 16 h. Removal of the solvent under reduced pressure afforded the title compound, 3-aminocyclopent-2-en-1-one (3.2 g) as a brown solid. LCMS Rt=0.114 min;MS m / z, 98.2[M+H]+;[Method 1]

[0244] Step 3: Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from Example 6, Step 4, 3.0 g, 15.944 mmol) was added methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 2.54 g, 19.133 mmol) and cyclopentane-1,3-dione (1.56 g, 15.944 mmol) in t-butanol (25 mL). The reaction mixture was stirred at 80° C. for 48 h. The solvent was removed under reduced pressure to afford the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to give the title compound methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (500 mg, crude) as an off-white solid and a mixture of diastereomers. The diastereomeric mixture was separated into its two isomers using silica flash chromatography (0→80%) to give 12 mg of the first diastereomer as a white solid and 15 mg of the second diastereomer as a white solid.

[0245] The diastereomers from the first separated peak 1: 12 mg and peak 2: 15 mg were further separated into their enantiomers using preparative chiral HPLC [Method 7] to give four isomers.

[0246] Example 7 2 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=9.084 min; [Chiral analysis method 4] LCMS Rt=1.477 min;MS m / z, 384.05[M+H]+;[Method 2] 1H NMR(400MHz, methanol-d4)δ 7.36-7.24(m,1H),7.06(d,J=7.8Hz,1H),6.92(dd,J=11.4,8.2Hz,1H),6.87-6.60(m,1H),5.72(s,1H),5.60(s ,1H),5.05(s,1H),4.69(ddd,J=44.8,32.9,10.8Hz,2H),3.54(s,3H),2.70(t,J=5.0Hz,2H),2.43-2.29(m,2H).

[0247] Example 7b 4 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=10.439 min; [Chiral analysis method 4] LCMS Rt=1.477 min;MS m / z, 384.2[M+H]+;[Method 2] 1 H NMR(400MHz, methanol-d4)δ 7.37-7.23(m,1H),7.10-7.02(m,1H),6.92(dd,J=11.4,8.1Hz,1H),6.86-6.60(m,1H),5.72(s,1H),5.60(s ,1H),5.05(s,1H),4.69(ddd,J=44.9,33.5,11.1Hz,2H),3.54(s,3H),2.76-2.66(m,2H),2.42-2.27(m,2H).

[0248] Example 7c 4 mg of the third eluting enantiomer obtained as a white solid. Chiral HPLC Rt=12.453 min; [Chiral analysis method 4] LCMS Rt=1.327 min;MS m / z, 384.2[M+H]+;[Method 2] 1H NMR(400MHz, methanol-d4)δ 7.32(tdd,J=8.1,5.6,1.5Hz,1H),7.08(dt,J=7.8,1.3Hz,1H),6.93(dd,J=11.5,8.1Hz,1H),6.60-6.38(m,1H),5.81-5 .69(m,1H),5.69-5.54(m,1H),5.13-5.07(m,2H),5.07-4.93(m,1H),3.53(s,3H),2.75-2.67(m,2H),2.45-2.22(m,2H).

[0249] Example 7d 4 mg of the fourth eluting enantiomer obtained as a white solid. Chiral HPLC Rt=13.173 min; [Chiral analysis method 4] LCMS Rt=1.33 min;MS m / z, 384.2[M+H]+;[Method 2] 1 H NMR(400MHz, methanol-d4)δ 7.40-7.25(m,1H),7.14-7.05(m,1H),6.93(dd,J=11.4,8.2Hz,1H),6.60-6.38(m,1H),5.80-5.66(m,1H),5. 66-5.53(m,1H),5.13-5.07(m,2H),5.07-4.94(m,1H),3.53(s,3H),2.71(t,J=4.8Hz,2H),2.44-2.21(m,2H).

[0250] Example 8: Methyl (R)-4-(3-fluoro-2-((R or S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-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 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, example 1, 30 g, 121.42 mmol) in THF (300 mL) was cooled to −78° C. under nitrogen atmosphere. Then, n-butyllithium 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),5.30- 5.25(m,1H),4.15-3.95(m,4H),2.75-2.69(m.1H),1.58(dd,J=6.6,22.8Hz,3H).

[0251] 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 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 phase 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).

[0252] 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(300MHz,CDCl3)δ 10.44(d,J=1.0Hz,1H),7.74(d,J=7.7Hz,1H),7.45-7.42(m,1H),7.35-7.30(m,1H),6.45-6.38(m,1H),1.92-1.72(m,3H).

[0253] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 3, 10 g, 58.76 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate as a mixture of diastereomers (13 g, crude). LCMS Rt=1.795 min;MS m / z, 454.2[MH]-;[Method 9]

[0254] Step 5: Methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using the mixture of intermediates from step 4 (13.0 g, 28.54 mmol)) to give the title compound, methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (5 g, crude) as an off-white solid. The diastereomeric mixture was separated by silica flash chromatography (ethyl acetate in hexanes, 0→80%) to give 1.04 g of the first diastereomer and 1.45 g of the second diastereomer.

[0255] The diastereomers were further separated using chiral SFC: column 2.1 x 25.0 cm, Chiralcel OX-H;CO2, co-solvent (solvent B) methanol isocratic method, 25% co-solvent, 80 g / min, system pressure 100 bar.

[0256] Example 8 37 mg of the title compound as the first eluting stereoisomer LCMS Rt=1.95 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt=1.12 min; Mobile phase: 20% MeOH (0.1% isopropylamine) in CO2, 4 mL / min; Column: Chiralcel OX-H, 4.6 x 100 mm 1 H NMR(400MHz,DMSO-d6)δ 10.12(d,J=3.3Hz,1H),7.34(qd,J=7.0,2.9Hz,1H),7.21-6.91(m,2H),6.35(dq,J=45.6,6.6Hz,1H ),5.87-5.45(m,2H),5.03(s,1H),4.86(d,J=2.8Hz,2H),3.44(s,3H),1.80(dd,J=22.9,6.6Hz,3H).

[0257] Example 8b 38 mg as the second eluting stereoisomer LCMS Rt=1.95 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt=1.52 min; Mobile phase: 20% MeOH (0.1% isopropylamine) in CO2, 4 mL / min; Column: Chiralcel OX-H, 4.6 x 100 mm 1 H NMR:(400MHz,DMSO-d6)δ 10.12(d,J=3.3Hz,1H),7.56-7.23(m,1H),7.25-6.94(m,2H),6.35(dd,J=45.5,6.9Hz,1H),5.66(dd ,J=47.9,2.7Hz,2H),5.03(s,1H),4.86(d,J=2.6Hz,2H),3.44(s,3H),1.80(dd,J=22.8,6.5Hz,3H).

[0258] Example 8c 42 mg as the third eluting stereoisomer LCMS Rt=1.88 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt=2.08 min; Mobile phase: 20% MeOH (0.1% isopropylamine) in CO2, 4 mL / min; Column: Chiralcel OX-H, 4.6 x 100 mm 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz,1H),7.33(td,J=8.0,5.4Hz,1H),7.23-6.92(m,2H),6.49(dd,J=44.7,6.8Hz, 1H),5.68(d,J=47.8Hz,2H),4.97(s,1H),4.83(s,2H),3.44(s,3H),1.70(dd,J=22.7,6.6Hz,3H).

[0259] Example 8d 40mg: as the fourth eluting stereoisomer LCMS Rt=1.88 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt=3.01 min; Mobile phase: 20% MeOH (0.1% isopropylamine) in CO2, 4 mL / min; Column: Chiralcel OX-H, 4.6 x 100 mm 1H NMR:(400MHz,DMSO-d6)δ 10.13(d,J=3.4Hz,1H),7.33(td,J=8.0,5.4Hz,1H),7.20-6.93(m,2H),6.69-6.31(m,1H),5 .68(d,J=47.8Hz,2H),4.97(s,1H),4.83(s,2H),3.44(s,3H),1.70(dd,J=22.8,6.5Hz,3H).

[0260] The configuration of Example 8, methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-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 R-enantiomer (Figure 8).

[0261] Example 9: Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethoxy)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using 2-(difluoromethoxy)benzaldehyde (350 mg, 2.033 mmol), intermediate A (382.3 mg, 2.033 mmol) and intermediate B (275.65 mg, 2.033 mmol)) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethoxy)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (600 mg, crude), which was carried forward to the next step without analysis.

[0262] Step 2: Methyl 4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] To the crude intermediate from step 1 (600 mg, 1.30 mmol) in methanol (20 mL) was added potassium hydroxide (293.44 mg, 5.22 mmol). The resulting solution was stirred at 65° C. for 30 minutes. Water was added to the reaction mixture and 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 title compound methyl 4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (100 mg).

[0263] 90 mg of the racemic mixture was separated into its enantiomers using chiral HPLC [Method 4].

[0264] Example 9 40 mg of the first eluting enantiomer as a white solid, 44% yield. Chiral HPLC Rt=6.481 min; [Chiral analysis method 1] LCMS Rt=1.473 min;MS m / z, 370[M+H]+;[Method 7] 1 H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 7.5, 1.9 Hz, 1H), 7.24-7.12 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.81-6.43 (m, 1H), 5.82-5.69 (m, 1H), 5.68-5.56 (m, 1H), 5.19 (s, 1H), 4.77 (d, J = 1.6 Hz, 2H), 3.55 (d, J = 0.7 Hz, 3H). No exchangeable NH protons observed.

[0265] The configuration of Example 9, methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-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 R-enantiomer (Figure 9).

[0266] Example 9b 38 mg of the second eluting enantiomer as a white solid, 42% yield. Chiral HPLC Rt=10.303 min; [Chiral analysis method 1] LCMS Rt=1.475 min;MS m / z, 370.1[M+H]+;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 7.30(dd,J=7.5,1.9Hz,1H),7.24-7.12(m,2H),7.06(d,J=8.0Hz,1H),6.81-6.43 (m,1H),5.82-5.69(m,1H),5.68-5.56(m,1H),5.19(s,1H),4.77(d,J=1.6Hz,2H),3.55(d,J=0.7Hz,3H).

[0267] Example 10: Methyl (R)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 1-Bromo-3,5-difluoro-2-(trifluoromethyl)benzene [ka] A solution of 3,5-difluoro-2-(trifluoromethyl)aniline (10 g, 50.735 mmol) in 48% HBr / H2O (80 mL / 80 mL) in water was cooled to -5°C, then NaNO2 (8.74 g, 126.83 mmol in 100 mL H2O) was added slowly over a period of 5 minutes, and then the resulting mixture was stirred at -5°C for 1 hour. The reaction mixture was treated with CuBr (10.92 g, 76.103 mmol) in portions at -5°C. The reaction mixture was allowed to slowly warm to room temperature and stirred for 4 hours. The reaction mixture was extracted with hexane (3 x 200 mL). The organic phases were combined, washed with saturated brine solution (100 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography in petroleum ether afforded the title compound 1-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (8 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.31(dt,J=7.6,2.2Hz,1H),6.95-6.88(m,1H).

[0268] Step 2: 1,5-Difluoro-2-(trifluoromethyl)-3-vinylbenzene [ka] To a solution of 1-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (from step 1, 12.0 g, 45.99 mmol) and trifluoro(vinyl)-14-borane in isopropyl alcohol (120 mL) was added potassium salt (12.3 g, 91.98 mmol) and triethylamine (19.16 mL, 137.98 mmol). The resulting solution was purged with argon for 10 min, after which [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (3.75 g, 4.599 mmol) was added. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered through a celite pad, washed with ethyl acetate (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by flash chromatography on silica in petroleum ether afforded the title compound 1,5-difluoro-2-(trifluoromethyl)-3-vinylbenzene (6.5 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.16-6.97(m,2H),6.85-6.80(m,1H),5.67(d,J=17.2Hz,1H),5.49(d,J=10.9Hz,1H).

[0269] Step 3: 3,5-Difluoro-2-(trifluoromethyl)benzaldehyde [ka] 1,5-Difluoro-2-(trifluoromethyl)-3-vinylbenzene (from step 2, 6.5 g, 31.23 mmol) and RuCl3·XH2O (647 mg, 3.123 mmol) were added to a solution of diacetoxyiodobenzene (20 g, 62.46 mmol) in dichloromethane:H2O (130 mL:30 mL). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was filtered through a celite pad, washed with dichloromethane (200 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 3,5-difluoro-2-(trifluoromethyl)benzaldehyde (3.0 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.34(m,1H),7.82-7.52(m,1H),7.22-7.07(m,1H).

[0270] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 3 (400 mg, 1.903 mmol)) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (900 mg, crude). LCMS Rt=1.76 min;MS m / z, 496.0[M+H]+;[Method 7]

[0271] Step 5: Methyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 4 (900 mg, 1.8 mmol)). Purification of the crude product by flash chromatography on silica (ethyl acetate in petroleum ether, 0→50%) afforded the title compound, methyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (90 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral HPLC [Method 7].

[0272] Example 10 30 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=5.502 min; [Chiral analysis method 2] LCMS Rt=1.542 min;MS m / z, 406[MH]-;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 7.30(d,J=7.2Hz,1H),6.87(d,J=9.5Hz,1H),6.85 6.75(m,1H),5.79(t,J=1.2,1.2Hz,1H),5.67(t,J=1.1Hz,1H),5.62(s,1H),4.80(d,J=1.2Hz,2H),3.54(s,3H).

[0273] Example 10b 30 mg of the second eluting enantiomer was obtained as a white solid. Chiral HPLC Rt=6.935 min; [Chiral analysis method 1] LCMS Rt=1.542 min;MS m / z, 406[MH]-;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 7.30(d,J=7.2Hz,1H),6.87(d,J=9.5Hz,1H),6.85 6.75(m,1H),5.79(t,J=1.2,1.2Hz,1H),5.67(t,J=1.1Hz,1H),5.62(s,1H),4.80(d,J=1.2Hz,2H),3.54(s,3H).

[0274] Example 11: Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde [ka] A solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, Example 1, 7 g, 28.45 mmol) in THF (70 mL) was cooled to −78° C. under nitrogen atmosphere. Then, n-butyllithium in n-hexane solution (13.66 mL, 2.5 M, 58.5 mmol) was added over 10 min and the resulting mixture was stirred at −78° C. for 45 min. DMF (2.5 g, 34.15 mmol) was added to the resulting mixture and stirred at −78° C. for 1.15 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) 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. 1H NMR(300MHz,CDCl3)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).

[0275] Step 2: 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 1, 7 g, 35.7 mmol) was heated to 70° C. under nitrogen atmosphere and stirred for 30 min. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (12 g, 62.4 mmol) was added slowly over a period of 10 min (mascara turned yellow during addition). The resulting mixture was stirred at 70° C. for an additional 3 h, then cooled to room temperature and diluted with diethyl ether. 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:(300MHz,CDCl3)δ 7.39(dd,J=7.8,1.4Hz,1H),7.31(m,1H),7.11(m,1H),5.87(s,1H),5.39(m,1H),4.21-3.95(m,4H).

[0276] Step 3: 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from step 2, 3 g, 13.04 mmol) in ethyl acetate (60 mL) was added 10% Pd-C (1 g). The resulting reaction mixture was kept in a Parr shaker under hydrogen atmosphere at 60 psi pressure for 48 h at room temperature. 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-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (3 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.42-7.35(m,1H),7.34-7.27(m,1H),7.15-7.08(m,1H),6.31-5.78(m,2H),4.19-4.02(m,4H),3.38(m,2H).

[0277] Step 4: 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde [ka] To a solution of 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 3 g, 12.93 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 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1.9 g) as a colorless liquid. 1H NMR(400MHz,CDCl3)δ 10.14(d,J=1.6Hz,1H),7.70-7.63(m,1H),7.52(td,J=8.0,7.9,5.2Hz,1H),7.35-7.30(m 1H),6.03(m,1H),3.83-3.58(m,2H).

[0278] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 4, 400 mg, 2.12 mmol) to give the title compound 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1 g, crude). LCMS Rt=1.764 min;MS m / z, 473.4[M+H]+;[Method 7]

[0279] Step 6: Methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 5, 1 g, 2.11 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-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (85 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 6].

[0280] Example 11 30 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=6.325 min; [Chiral analysis method 2] LCMS Rt=1.508 min;MS m / z, 386.0[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.34-7.27(m,1H),7.21(m,1H),7.01-6.89(m,2H),6.55-6.17(m,1H),5.81(dd,J=1.7,0.8Hz,1H),5.69 (t,J=1.1Hz,1H),5.08(s,1H),4.78(d,J=0.9Hz,2H),3.94-3.73(m,1H),3.60-3.55(m,1H),3.54(s,3H).

[0281] Example 11b 30 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=8.402 min; [Chiral analysis method 2] LCMS Rt=1.508 min;MS m / z, 386.4[M+H]+;[Method 7] 1H NMR(400MHz,CDCl3)δ 7.34-7.27(m,1H),7.21(td,J=8.0,8.0,5.6Hz,1H),7.01-6.89(m,2H),6.55-6.17(m,1H),5.81(dd,J=1.7,0.8Hz,1H ),5.69(t,J=1.1,1.1Hz,1H),5.08(s,1H),4.78(d,J=0.9Hz,2H),3.94-3.73(m,1H),3.60-3.55(m,1H),3.54(s,3H).

[0282] Example 12: Methyl (R)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] 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, Example 3, 5 g, 18.94 mmol), potassium vinyltrifluoroborate (5.8 g, 37.89 mmol), triethylamine (7.91 mL, 56.82 mmol) in isopropyl alcohol (50 mL) was degassed with argon gas for 10 min, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (1.55 g, 1.89 mmol) was added. The resulting solution was again degassed 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 dissolved in water (1 L) and extracted into ethyl acetate (2 L). The EtOAc was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) to give the title compound 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (3.45 g) as a colorless liquid. Note: Compound is volatile in nature, hexane present in compound. 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).

[0283] Step 3: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde [ka] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (from step 2, 5 g, 23.58 mmol) and ruthenium chloride·XH2O (490 mg, 2.35 mmol) in dichloromethane (50 mL) and water (10 mL) was added (diacetoxyiodo)benzene (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 dissolved in water (200 mL) and the product was extracted into ethyl acetate (500 mL). The organics were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica (ethyl acetate in petroleum ether, 0→10%) to give the title compound 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (3 g) as a colorless liquid. Note: Compound is volatile in nature, hexane present in compound. 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).

[0284] Step 4: 2-(2-(2,2-difluorovinyl)-3,5-difluorophenyl)-1,3-dioxolane [ka] To acetonitrile (4.5 mL) under nitrogen atmosphere was added triphenylphosphine (1.83 g, 7.0 mmol), potassium iodide (775 mg, 4.66 mmol) and 2-1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (from step 3, 500 mg, 2.33 mmol). The reaction was stirred at 70° C. for 30 minutes. Then, 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (783 mg, 4.07 mmol) was added slowly over a period of 10 minutes (mascara turned yellow during the addition) and the resulting mixture was stirred at 70° C. for an additional 3 hours. The reaction mixture was then 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)-3,5-difluorophenyl)-1,3-dioxolane (400 mg) as a pale yellow liquid. 1 H NMR(300MHz,CDCl3)δ 7.19-7.12(m,1H),6.89-6.80(m,1H),5.85(d,J=0.9Hz,1H),5.31(dt,J=26.1,1.5Hz,1H),4.16-3.98(m,4H).

[0285] Step 5: 2-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-1,3-dioxolane [ka] To a solution of 2-(2-(2,2-difluorovinyl)-3,5-difluorophenyl)-1,3-dioxolane (from step 4, 400 mg, 1.61 mmol) in ethyl acetate (10 mL) was added 10% Pd-C (180 mg). The resulting reaction mixture was kept under hydrogen atmosphere at room temperature at 60 psi pressure in a Parr shaker for 48 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-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-1,3-dioxolane (400 mg) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.22-7.12(m,1H),6.81-6.75(m,1H),6.26-5.75(m,2H),4.20-3.99(m,4H),3.36-3.33(m,2H).

[0286] Step 6: 2-(2,2-difluoroethyl)-3,5-difluorobenzaldehyde [ka] To a solution of 2-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-1,3-dioxolane (from step 5, 400 mg, 1.6 mmol) in diethyl ether (10 mL) was added 5N HCl (1 mL). The resulting solution was stirred at room temperature for 3 h. It was washed with water (50 mL), saturated NaHCO3 solution (100 mL), and 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 2-(2,2-difluoroethyl)-3,5-difluorobenzaldehyde (250 mg) as a colorless liquid. 1H NMR(300MHz,CDCl3)δ 10.11(d,J=1.3Hz,1H),7.51-7.34(m,1H),7.20-7.07(m,1H),6.31-5.73(m,1H),3.79-3.56(m,2H).

[0287] Step 7: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 6 (250 mg, 1.21 mmol)) to give the title compound 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (800 mg, crude). LCMS Rt=1.77 min;MS m / z, 491.0[M+]+;[Method 7]

[0288] Step 8: Methyl 4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 7, 800 mg, 1.62 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-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (44 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 6].

[0289] Example 12 11 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=5.674 min; [Chiral analysis method 2] LCMS Rt=1.561 min;MS m / z, 403.9[M+]+;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.87-6.76(m,2H),6.64-6.26(m,1H),5.76(s,1H),5.64(s,1H),5.13(d,J= 1.4Hz,1H),4.87-4.83(m,2H),3.50-3.36(m,1H),3.70(s,2H),3.53(s,3H).

[0290] Example 12b 10 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=7.215 min; [Chiral analysis method 2] LCMS Rt=1.557 min;MS m / z, 403.9[M+]+;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.87-6.76(m,2H),6.64-6.26(m,1H),5.76(s,1H),5.64(s,1H),5.13(d,J= 1.4Hz,1H),4.87-4.83(m,2H),3.50-3.36(m,1H),3.70(s,2H),3.53(s,3H).

[0291] Example 13: Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3,5-difluorobenzaldehyde [ka] To a solution of 2-bromo-3,5-difluorobenzaldehyde (10 g, 45.20 mmol) and cyclopropylboronic acid (4.67 g, 54.2 mmol) in toluene (100 mL) was added 2N K2CO3 (102 mL, 204 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (3.17 g, 3.88 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). The EtOAc phase was 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→1%) afforded the title compound 2-cyclopropyl-3,5-difluorobenzaldehyde (8 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.71(d,J=3Hz,1H),7.40-730(m,1H),7.05-6.90(m,1H),2.05-1.95(m,1H),1.19-1.09(m,2H),0.85-0.75(m,2H).

[0292] Step 2: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclopropyl-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using general step 1 of general procedure I (using the aldehyde from step 1 (1.8 g, 9.88 mmol)) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclopropyl-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (4.61 g, crude). LCMS Rt=1.586 min;MS m / z477.0[M+H]+;[Method 10]

[0293] Step 3: Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 2, 4.61 g, 9.871 mmol). The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%), which afforded the title compound, methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (350 mg) as an off-white solid.

[0294] The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 9].

[0295] Example 13 135 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=5.33 min; [Chiral analysis method 2] LCMS Rt=1.591 min;MS m / z, 380.2[M+H]+;[Method 7] 1 H NMR(300MHz,CD3OD)δ 6.78-6.70(m,1H),6.66(m,1H),5.75(s,1H),5.61(d,J=14.1Hz,2H),4.84(q,J=1.7,1 .7,0.9Hz,2H),3.53(s,3H),2.08(m,1H),1.18(m,1H),1.07-0.87(m,2H),0.75(m,1H).

[0296] Example 14: Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 2: Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from step 1, Example 13, 300 mg, 1.64 mmol) in ethanol (5 mL) was added methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 220 mg, 1.64 mmol) and cyclopentane-1,3-dione (161 mg, 1.64 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to give the title compound methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (55 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 3].

[0297] Example 14 17 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=8.588 min; [Chiral analysis method 3] LCMS Rt=1.548 min;MS m / z, 378.0[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.21(d,J=7.2Hz,1H),6.65-6.48(m,2H),5.78(d,J=0.9Hz,1H),5.65(d,J=0.8Hz,1H),5.60-5.52(m,1H),3.56(s,3H) ),2.75-2.56(m,2H),2.52-2.32(m,2H),2.20-2.13(m,1H),1.34-1.13(m,1H),1.05-0.98(m,2H),0.83-0.69(m,1H).

[0298] Example 14b 17 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=11.651 min; [Chiral analysis method 3] LCMS Rt=1.548 min;MS m / z, 378.0[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.21(d,J=7.2Hz,1H),6.65-6.48(m,2H),5.78(d,J=0.9Hz,1H),5.65(d,J=0.8Hz,1H),5.60-5.52(m,1H),3.56(s,3H) ),2.75-2.56(m,2H),2.52-2.32(m,2H),2.20-2.13(m,1H),1.34-1.13(m,1H),1.05-0.98(m,2H),0.83-0.69(m,1H).

[0299] Example 15: Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(difluoromethyl)-1-fluoro-3-vinylbenzene [ka] To a solution of 1-bromo-2-(difluoromethyl)-3-fluorobenzene (2.0 g, 8.889 mmol) was added potassium vinyltrifluoroborate (2.38 g, 17.78 mmol) and triethylamine (3.7 mL, 26.66 mmol) in isopropyl alcohol (20 mL). The resulting solution was purged with argon for 10 min and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM (725 mg, 0.889 mmol) was added. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was filtered through a celite pad, washed with ethyl acetate (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography in petroleum ether afforded the title compound 2-(difluoromethyl)-1-fluoro-3-vinylbenzene (1.2 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.48-7.40(m,1H),7.30-7.15(m,1H),7.04(t,J=53.4Hz,1H),7.04-6.90(m,2H),5.44(d,J=11.2Hz,1H),5.70(d,J=11.2Hz,1H).

[0300] Step 2: 2-(Difluoromethyl)-3-fluorobenzaldehyde [ka] To a solution of 2-(difluoromethyl)-1-fluoro-3-vinylbenzene (from step 1, 1.2 g, 6.970 mmol) was added RuCl3·XH2O (145 mg, 0.697 mmol) and diacetoxyiodobenzene (6.73 g, 20.91 mmol) in dichloromethane:H2O (20 mL:6 mL). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was filtered through a celite pad, washed with dichloromethane (200 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-(difluoromethyl)-3-fluorobenzaldehyde (500 mg) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 10.42(t,J=2.0Hz,1H),8.44(d,J=8.0Hz,1H),7.70-7.59(m,1H),7.45-7.35(m,1H),7.30(t,J=53.2Hz,1H).

[0301] Step 3: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 2, 500 mg, 2.871 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.5 g, crude). LCMS Rt=1.716 min;MS m / z, 460.1[M+H]+;[Method 7]

[0302] Step 4: Methyl 4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 3, 1.0 g, 2.177 mmol). Purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) afforded the title compound, methyl 4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (280 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 5].

[0303] Example 15 90 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=10.05 min; [Chiral analysis method 2] LCMS Rt=1.947 min;MS m / z, 372.2[M+H]+;[Method 9] 1H NMR (400 MHz, CDCl3) δ 7.44-7.28 (m, 2H), 7.09-6.96 (m, 2H), 5.80 (d, J = 0.8 Hz, 1H), 5.68 (d, J = 0.9 Hz, 1H), 5.20 (s, 1H), 4.80 (d, J = 1.1 Hz, 2H), 3.54 (s, 3H). No exchangeable NH protons were observed in the spectrum.

[0304] Example 15b 90 mg of the second eluting enantiomer was obtained as a white solid. Chiral HPLC Rt=12.05 min; [Chiral analysis method 2] LCMS Rt=2.09 min;MS m / z, 372.2[M+H]+;[Method 9] 1 H NMR(400MHz,CDCl3)δ 7.43-7.33(m,2H),7.10-6.93(m,2H),5.80(d,J=0.8Hz,1H),5.68(d,J=0.9Hz,1H),5.20(s,1H),4.80(d,J=0.9Hz,2H),3.54(s,3H).

[0305] Example 16: Methyl (R)-4-(2-((R or S)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-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] The title compound was synthesized following a procedure similar to that of step 1 of example 1 using 15 g of 2-bromo-3,5-difluorobenzaldehyde to give 15 g of the desired product 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane. 1H NMR(300MHz,CDCl3)δ 7.23-7.18(m,1H),6.95-6.90(m,1H),6.08(t,J=1.1Hz,1H),4.24-3.99(m,4H).

[0306] Step 2: (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane [ka] To a solution of 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane (from step 1, 15.0 g, 56.59 mmol) in freshly distilled THF (150 mL) was added lithium diisopropylamide (31.1 mL, 2.0 M in hexanes, 62.25 mmol) at -78 °C under inert atmosphere and stirred for 30 min. Trimethylsilyl chloride (7.37 g, 67.91 mmol) was added to the reaction mixture and stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated NH4Cl solution (250 mL) and the product was extracted into ethyl acetate (2 x 500 mL). The combined EtOAc phase was washed with brine solution (250 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and purification of the crude product by silica flash chromatography in petroleum ether (100%) afforded the title compound (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane (9.0 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.08(dd,J=8.9,1.6Hz,1H),6.07(d,J=1.3Hz,1H),4.33-3.89(m,4H),0.37(t,J=1.6Hz,9H).

[0307] Step 3: 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethan-1-one [ka] To a solution of (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane (from step 2, 5.0 g, 14.961 mmol) in freshly distilled THF (50 mL) was added n-butyllithium (6.0 mL, 2.5 M in hexanes, 14.961 mmol) slowly at −78° C. under inert atmosphere. Ethyl 2,2-difluoroacetate (3.1 g, 29.9 mmol) was then added to the reaction mixture and stirred at −78° C. for 1 h. The reaction was quenched with saturated NH4Cl solution (250 mL) and extracted into ethyl acetate (2×200 mL). The combined EtOAc phase was washed with brine solution (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-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethan-1-one (2.5 g) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.04(dt,J=8.9,0.8Hz,1H),6.02(s,1H),5.22(d,J=1.6Hz,1H),5.07(d,J=1.6Hz,1H),4.03-3.79(m,4H),0.37(s,9H).

[0308] Step 4: 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethan-1-ol [ka] To a solution of 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethan-1-one (from step 3, 2.5 g, 7.854 mmol) in methanol (20 mL) was added sodium borohydride (594.2 mg, 15.70 mmol) in portions at 0° C. The temperature was slowly raised to room temperature over 1 h and stirred at room temperature for another 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted into ethyl acetate (200 mL). The EtOAc was washed with brine solution (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→30%) afforded the title compound 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethan-1-ol (2.5 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.12(dd,J=9.4,1.2Hz,1H),6.15(s,1H),5.42-5.35(m,1H),4.93-4.47(m,2H),4.19-3.88(m,4H),2.96(dd,J=6.1,2.8Hz,1H),0.36(s,9H).

[0309] Step 5: (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane [ka] To a solution of 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethan-1-ol (from step 4, 2.0 g, 6.24 mmol) in dichloromethane (20 mL) was added diethylaminosulfur trifluoride (DAST) (1.24 mL, 9.36 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h. Water (50 mL) was added to the reaction mixture and the product was extracted into dichloromethane (3×50 mL). The DCM phases were combined, washed with saturated NaHCO3 solution (50 mL), 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→2%) afforded the title compound (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane (1.1 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.23-7.04(m,1H),6.24-6.05(m,1H),6.04(s,1H),5.15-4.89(m,1H),4.70-4.39(m,1H),4.14-3.99(m,4H),0.36(s,9H).

[0310] Step 6: 2-(1,2-difluoroethyl)-3,5-difluoro-4-(trimethylsilyl)benzaldehyde [ka] To a solution of (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane (from step 5, 1.1 g, 3.41 mmol) in diethyl ether (10 mL) was added 6N HCl (11 mL). The resulting solution was stirred at room temperature for 3 h. It was washed with water (50 mL), saturated NaHCO3 solution (100 mL), and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 2-(1,2-difluoroethyl)-3,5-difluoro-4-(trimethylsilyl)benzaldehyde (900 mg) as a colorless liquid. The product was used for the next step without further purification and analysis.

[0311] Step 7: 2-(1,2-difluoroethyl)-3,5-difluorobenzaldehyde [ka] To a solution of (2-(1,2-difluoroethyl)-3,5-difluoro-4-(trimethylsilyl)benzaldehyde (from step 6, 900 mg, 3.23 mmol) in THF (20 mL) was added TBAF (8.0 mL, 1.0 M in THF, 8.08 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (50 mL), which was washed with water (50 mL), saturated NaHCO3 solution (100 mL), and 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, 5→10%) afforded the title compound 2-(1,2-difluoroethyl)-3,5-difluorobenzaldehyde (400 mg) as a colorless liquid. 1 H NMR(600MHz,CDCl3)δ 10.41-10.14(m,1H),7.54(d,J=8.3Hz,1H),7.15-7.06(m,1H),6.34-6.30(m,1H),4.95-4.67(m,2H).

[0312] Step 8: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 7, 490 mg, 2.377 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.0 g, crude). The product was used for the next step without further purification and analysis.

[0313] Step 9: Methyl 4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 8, 1.0 g, 2.03 mmol). Purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) afforded the title compound, methyl 4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (1.0 g, crude) as an off-white solid. The diastereomeric mixture was separated into its two isomers using silica flash chromatography (0→80%) to give 70 mg of the first diastereomer as a white solid and 50 mg of the second diastereomer as a white solid. The first separated diastereomers from peak 1: 70 mg and peak 2: 50 mg were further separated into their enantiomers using preparative chiral SFC [Method 8] to give four isomers.

[0314] Example 16 25 mg of the second eluting enantiomer obtained as a white solid Chiral HPLC Rt=12.95 min; [Chiral analysis method 3] LCMS Rt=1.52 min;MS m / z, 402.2[MH]-;[Method 7] 1 H NMR(600MHz,CDCl3)δ 7.29(d,J=6.8Hz,1H),6.80-6.69(m,2H),6.41(dd,J=48.5,17.2Hz,1H),5.80(s,1H),5.72(s,1H),5.36-4.69(m,5H),3.59(s,3H).

[0315] Example 16b 25 mg of the first eluting enantiomer obtained as a white solid Chiral HPLC RT, 10.54 min; [Chiral Analysis Method 3] LCMS Rt=1.52 min;MS m / z, 402.0[MH]-;[Method 7] 1H NMR(600MHz,CDCl3)δ 7.29(d,J=6.8Hz,1H),6.80-6.69(m,2H),6.41(dd,J=48.5,17.2Hz,1H),5.80(s,1H),5.72(s,1H),5.36-4.69(m,5H),3.59(s,3H).

[0316] Example 16c 15mg of the third enantiomer eluting as a white solid Chiral HPLC Rt=14.54 min; [Chiral analysis method 3] LCMS Rt=1.472 min;MS m / z, 402.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.92-6.80(m,2H),6.70-6.48(m,1H),5.76(s,1H),5.64(s,1H),5.48(s,1H),5.16(s,1H),5.15-4.51(m,4H),3.55(s,3H).

[0317] Example 16d 15 mg of the fourth enantiomer eluted as a white solid Chiral HPLC Rt=18.97 min; [Chiral analysis method 3] LCMS Rt=1.466 min;MS m / z, 402.2[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.92-6.80(m,2H),6.70-6.48(m,1H),5.76(s,1H),5.64(s,1H),5.48(s,1H),5.16(s,1H),5.15-4.51(m,4H),3.55(s,3H).

[0318] Example 17: Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using general procedure I (using commercially available 3-fluoro-2-(trifluoromethyl)benzaldehyde, 1.4 g, 7.28 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (2 g, crude). The product was used for the next step without further purification and analysis.

[0319] Step 2: Methyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (from step 2, 2 g, 4.18 mmol). Purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) afforded the title compound, methyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (240 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using preparative chiral HPLC [Method 5].

[0320] Example 17 80 mg of the first eluting enantiomer as a white solid, 33% yield. Chiral HPLC Rt=7.549 min; [Chiral analysis method 1] LCMS Rt=1.485 min;MS m / z, 390.1[M+H]+;[Method 7] 1 H NMR(600MHz,CD3OD)δ 7.62-7.46(m,1H),7.35-7.30(m,1H),7.20-7.02(m,1H),5.75-5.69(m,1H) ,5.68-5.60(m,1H),5.58-5.50(m,1H),4.84(d,J=5.1Hz,2H),3.47(s,3H).

[0321] Example 18: Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-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] The title compound was synthesized according to a procedure similar to that of Step 1 of Example 1 using 15 g of 2-bromo-3,5-difluorobenzaldehyde to give 15.4 g of 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane. 1 H NMR(300MHz,CDCl3)δ 7.20-7.15(m,1H),6.49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H).

[0322] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane [ka] The title compound was synthesized according to a procedure similar to Step 2 of Example 1 using 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane to give 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (3.0 g). 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).

[0323] Step 3: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde [ka] The title compound was synthesized according to a procedure similar to that of Step 1 of Example 5 to give 22-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (1.0 g). 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).

[0324] Step 4: 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxolane [ka] The title compound was synthesized according to a procedure similar to that of Step 3 of Example 5 to give 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxolane (570 mg). 1H NMR(300MHz,CDCl3)δ 7.29-7.25(m,1H),7.06(t,J=1.1Hz,1H),6.95-6.84(m,1H),6.13(t,J=1.2Hz,1H),4.30-3.86(m,4H).

[0325] Step 5: 2-(Difluoromethyl)-3,5-difluorobenzaldehyde [ka] To a solution of 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxolane (from step 4, 570 mg, 2.41 mmol) in diethyl ether (10 mL) was added 6N HCl (10 mL) at 0° C. The reaction mixture thus obtained was stirred at room temperature for 6 h. The reaction mixture was extracted into diethyl ether (50 mL) and washed with water (30 mL). The organic phase was washed with saturated NaHCO3 solution (30 mL), brine (30 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to afford crude compound 2-(difluoromethyl)-3,5-difluorobenzaldehyde (360 mg) as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.42(s,1H),7.74-7.54(m,1H),7.25(dd,J=46.8,10.4Hz,1H),7.15 -7.10(m,1H).

[0326] Step 6: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] The title compound was synthesized using step 1 of general procedure I (using the aldehyde from step 5, 360 mg, 1.87 mmol) to give 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (720 mg, crude). LCMS Rt=1.698 min;MS m / z, 476.1[MH]-;[Method 7]

[0327] Step 7: Methyl 4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (using intermediate from step 6, 720 mg, 1.50 mmol). Purification of the crude product by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) afforded the title compound, methyl 4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (120 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 7].

[0328] Example 18 30 mg of the first eluting enantiomer obtained as a white solid, 25% yield. Chiral HPLC Rt=17.629 min; [Chiral analysis method 1] LCMS Rt=1.454 min;MS m / z, 388.2[MH]-;[Method 7] 1H NMR(400MHz,CD3OD)δ 7.40-7.38(m,1H),6.93(dd,J=10.3,7.6Hz,2H),5.77(d,J=0.8Hz,1H),5. 65(d,J=0.7Hz,1H),5.27(d,J=1.6Hz,1H),4.89-4.86(m,2H),3.51(s,3H).

[0329] Example 18b 36 mg of the second eluting enantiomer obtained as a white solid, 30% yield. Chiral HPLC Rt=19.634 min; [Chiral analysis method 1] LCMS Rt=1.454 min;MS m / z, 388.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.40-7.38(m,1H),6.93(dd,J=10.3,7.6Hz,2H),5.77(d,J=0.8Hz,1H),5. 65(d,J=0.7Hz,1H),5.27(d,J=1.6Hz,1H),4.89-4.86(m,2H),3.51(s,3H).

[0330] Example 19: Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using general procedure II using commercially available 2-(difluoromethoxy)-3-fluorobenzaldehyde (249 mg, 1.311 mmol). The crude was purified by automated flash column chromatography on a 24 g Si-column eluting with a 0-100% gradient of EtOAc in heptane and further purified by mass-directed reversed-phase preparative chromatography; conditions: Xbridge C18OBD, 30×50 mm, 5 um, column ACN / H2O w / NH3OH, 5 mL / min, 1.5 mL injection. The racemate was separated into its individual enantiomers using chiral SFC (mobile phase: 5-25% MeOH in CO2, 80 g / min; column: (RR)Whelk-O1, 21×250 mm).

[0331] Example 19 8.6 mg of the second eluting enantiomer (4%) Chiral SFC Rt=2.61 min (Mobile phase: 5-55% MeOH, Column: (RR) 4.6 x 100 mm, 5 um column in Whelk-O1; 6 min run) LCMS Rt=1.94 min;MS m / z, 388.2[M+H]+;[Method 4] 1 H NMR(400MHz, methylene chloride-d2)δ 7.46(d,J=6.8Hz,1H),7.29-7.05(m,3H),6.93(t,J=74.16Hz,1H),5.88-5.56(m,2H),5.23(s,1H),4.81(s,2H),3.57(s,3H).

[0332] Example 19b 9.5 mg of first eluting enantiomer (4%) Chiral SFC Rt=2.41 min (Mobile phase: 5-55% MeOH, Column: (RR) 4.6 x 100 mm, 5 um column in Whelk-O1; 6 min run) LCMS Rt=1.90 min;MS m / z, 388.2[M+H]+;[Method 4] 1H NMR(400MHz, methylene chloride-d2)δ 7.46(d,J=6.8Hz,1H),7.29-7.05(m,3H),6.93(t,J=74.16Hz,1H),5.88-5.56(m,2H),5.23(s,1H),4.81(s,2H),3.57(s,3H).

[0333] Example 20: Methyl (R)-4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using general procedure II using commercially available 2-(difluoromethoxy)-5-fluorobenzaldehyde (229 mg, 1.206 mmol). The crude was purified by automated flash column chromatography on a 24 g Si-column eluting with a 0-100% gradient of EtOAc in heptane and further purified by mass-directed reversed-phase preparative chromatography; conditions: Xbridge C18OBD, 30×50 mm, 5 um column ACN / H2O w / NH3OH, 5 mL / min, 1.5 mL injection. The racemate was separated into its individual enantiomers using chiral SFC (mobile phase: 5-25% MeOH in CO2, 80 g / min; column: (RR)Whelk-O1, 21×250 mm).

[0334] Example 20 10mg of the second eluting enantiomer Chiral SFC Rt=2.51 min (Mobile phase: 5-55% MeOH, Column: (RR) 4.6 x 100 mm, 5 um column in Whelk-O1; 6 min run) LCMS Rt=1.91 min;MS m / z, 388.1[M+H]+;[Method 4] 1H NMR(400MHz,DMSO-d6)δ 10.11(d,J=3.3Hz,1H),7.32-6.85(m,4H),5.79-5.65(m,1H),5.65-5.48(m,1H),5.05(s,1H),4.83(s,2H),3.45(s,3H).

[0335] Example 20b 12mg of first eluting enantiomer Chiral SFC Rt=2.31 min (Mobile phase: 5-55% MeOH, Column: (RR) 4.6 x 100 mm, 5 um column in Whelk-O1; 6 min run) LCMS Rt=1.91 min;MS m / z, 388.0[M+H]+;[Method 4] 1 H NMR(400MHz,DMSO-d6)δ 10.11(d,J=2.0Hz,1H),7.33-6.80(m,4H),5.77-5.65(m,1H),5.64-5.51(m,1H),5.05(s,1H),4.83(s,2H),3.45(s,3H).

[0336] Example 21: Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-5-fluorobenzaldehyde [ka] A degassed solution of 2-bromo-5-fluorobenzaldehyde (2.03 g, 10.00 mmol), cyclopropaneboronic acid (1.031 g, 12.00 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.817 g, 1.000 mmol) in dioxane (20 mL) and 2.0 M aqueous K2CO3 (10.00 mL, 20.00 mmol) was stirred and heated to 80 °C. Upon completion, the reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4 and concentrated. The crude was purified by silica flash chromatography [0-20% ethyl acetate in heptane] to give 800 mg of the title compound (49% yield). The crude product was accepted without further purification.

[0337] Step 2: Methyl 4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared by general procedure II from ethyl 4-chloro-3-oxobutanoate (346 mg, 2.10 mmol), 2-cyclopropyl-5-fluorobenzaldehyde (345 mg, 2.10 mmol) prepared in step 1, and methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 280 mg, 2.10 mmol). Racemic methyl 4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was separated into its enantiomers using chiral SFC (mobile phase: 25% methanol with 0.2% NH4OH / CO2, 80 g / min; column: (SS) Whelk-O1, 4.6×100 mm).

[0338] Example 21 21.4 mg of the first eluting enantiomer (5.6%) as a white solid. Chiral SFC Rt = 2.41 min (mobile phase: 5-55% MeOH w / 10 mM NH4OH / CO2, 5 mL / min, 120 bar; column: (SS) Whelk-O1, 4.6 x 100 mm, 5 µm). LCMS Rt=0.95 min; MS m / z, 362.5[M+H]+; [Method 4]. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.08 (s, 1H), 7.08-6.95 (m, 1H), 6.93 -6.82 (m, 2H), 5.78-5.58 (m, 2H), 5.37 (s, 1H), 4.90-4.77 (m, 2H), 3.45 (s, 3H), 1.00-0.80 (m, 3H), 0.54-0.46 (m, 1H). The benzyl CH on the cyclopropyl is hidden under the DMSO peak.

[0339] Example 21b 10.3 mg of the second eluting enantiomer (2.7%) as a white solid. Chiral SFC Rt = 2.69 min (mobile phase: 5-55% MeOH w / 10 mM NH4OH / CO2, 5 mL / min, 120 bar; column: (SS) Whelk-O1, 4.6 x 100 mm, 5 µm). LCMS Rt=0.95 min; MS m / z, 362.5[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.08(s,1H),7.08-6.95(m,1H),6.93-6.82(m,2H),5.78-5.58(m,2H),5.37( s,1H),4.90-4.77(m,2H),3.45(s,3H),1.00-0.80(m,3H),0.54-0.46(m,1H).

[0340] Example 22: Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropylbenzaldehyde [ka] A solution of degassed 2-bromobenzaldehyde (1 g, 5.40 mmol), cyclopropaneboronic acid (0.557 g, 6.49 mmol), PdCl2(dppf)·CH2Cl2 adduct (0.441 g, 0.540 mmol) in dioxane (15 mL), and 2.0 M aqueous K2CO3 (5.40 mL, 10.81 mmol) was stirred and heated to 80 °C. Upon completion, the reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4 and concentrated. The crude was purified by silica flash chromatography [0-20% ethyl acetate in heptane] to give 420 mg of the title compound (53% yield). The crude product was accepted without further purification.

[0341] Step 2: Methyl 4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared by general procedure II from ethyl 4-chloro-3-oxobutanoate (0.204 mL, 1.500 mmol), 2-cyclopropylbenzaldehyde (219 mg, 1.5 mmol) (prepared in step 1) and methyl (Z)-3-amino-4-fluorobut-2-enoate (intermediate B, 200 mg, 1.50 mmol). Racemic methyl-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate carboxylate was separated into its enantiomers using chiral SFC (mobile phase: 5-55% methanol with 10 mM NH4OH / CO2, 3 mL / min; column: (SS)WHO; 1 4.6 x 100 mm).

[0342] Example 22 7.9 mg of the first eluting enantiomer (3.0%) as a white solid. Chiral SFC Rt=2.77 min LCMS Rt=0.93 min; MS m / z, 344.5[M+H]+; [Method 4]. 1 H NMR (400MHz, methanol-d4) δ ppm 6.91-7.23(m,4H),5.73(d,J=1.96Hz,1H),5.61(d,J=2.93Hz,1H),5.48(s,1H), 4.82(s,2H),3.50(s,3H),2.53-2.65(m,1H),0.86-0.99(m,3H),0.58(d,J=5.87Hz,1H).

[0343] Example 22b 7.5 mg of the second eluting enantiomer (2.9%) as a white solid. Chiral SFC Rt=3.19 min LCMS Rt=0.93 min; MS m / z, 344.5[M+H]+; [Method 4]. 1 H NMR (400MHz, methanol-d4) δ ppm 6.91-7.23(m,4H),5.73(d,J=1.96Hz,1H),5.61(d,J=2.93Hz,1H),5.48(s,1H), 4.82(s,2H),3.50(s,3H),2.53-2.65(m,1H),0.86-0.99(m,3H),0.58(d,J=5.87Hz,1H).

[0344] Example 23: Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared by general procedure II from ethyl 4-chloro-3-oxobutanoate (0.318 mL, 2.342 mmol), commercially available 5-fluoro-2-(trifluoromethyl)benzaldehyde (450 mg, 2.342 mmol) and methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 312 mg, 2.342 mmol). Racemic methyl 4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was separated into its enantiomers using chiral SFC (mobile phase: 15% methanol with 0.2% ammonium hydroxide / CO2, 80 g / min; column: 2.0 x 25.0 cm, ChromegaChiral CC4).

[0345] Example 23 12.2 mg of the first eluting enantiomer (2.7%) as a white solid. Chiral SFC Rt = 1.29 min (column: 4.6 x 100 mm, Chiralcel OZ-H; isocratic 15% methanol with 0.1% isopropylamine; 125 bar LCMS Rt=0.92 min; MS m / z, 390.0[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.16(br s,1H),7.70(dd,J=8.80,5.38Hz,1H),7.20-7.30(m,2H),5.72(s,1H),5.60(s,1H),5.20(s,1H),4.74-4.91(m,2H),3.38(s,3H).

[0346] Example 23b 14.0 mg of the second eluting enantiomer (3.0%) as a white solid. Chiral SFC Rt=1.74 min (Column: 4.6×100 mm, Chiralcel OZ-H; isocratic 15% methanol with 0.1% isopropylamine; 125 bar) LCMS Rt=0.92 min; MS m / z, 390.0[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.16(br s,1H),7.70(dd,J=8.80,5.38Hz,1H),7.20-7.30(m,2H),5.72(s,1H),5.60(s,1H),5.20(s,1H),4.74-4.91(m,2H),3.38(s,3H).

[0347] Example 24: Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared from ethyl 4-chloro-3-oxobutanoate (0.286 mL, 2.10 mmol), commercially available 2-trifluoromethylbenzaldehyde (366 mg, 2.10 mmol) and methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 280 mg, 2.10 mmol) by general procedure II. Racemic methyl 2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate was separated into its enantiomers using chiral SFC (mobile phase: 20% methanol with 0.2% ammonium hydroxide, 80 g / min; column: 2.0 x 25.0 cm, ChromegaChiral CC4).

[0348] Example 24 7.9 mg of the first eluting enantiomer (2.0%) as a white solid. Chiral SFC Rt=1.19 min (mobile phase: 20% methanol with 0.1% isopropylamine / CO2, 4 mL / min; column: Chiralcel OZ-H; 1 4.6×100 mm). LCMS Rt=0.91 min; MS m / z, 370.0[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.12(br s,1H),7.60(d,J=7.82Hz,2H),7.49(d,J=7.83Hz,1H),7.31-7.42(m,1H),5.70(s,1H),5.58(s,1H),5.19(s,1H),4.81(s,2H),3.37(s,3H).

[0349] Example 24b 9.3 mg of the second eluting enantiomer (2.4%) as a white solid. Chiral SFC Rt=1.72 min (mobile phase: 20% methanol with 0.1% isopropylamine / CO2, 4 mL / min; column: Chiralcel OZ-H; 1 4.6×100 mm). LCMS Rt=0.91 min; MS m / z, 370.0[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.12(br s,1H),7.60(d,J=7.82Hz,2H),7.49(d,J=7.83Hz,1H),7.31-7.42(m,1H),5.70(s,1H),5.58(s,1H),5.19(s,1H),4.81(s,2H),3.37(s,3H).

[0350] Example 25: Methyl (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of 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 EtOAc (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).

[0351] Step 2: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde [ka] A solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, 7 g, 28.45 mmol) in THF (70 mL) was cooled to −78° C. under nitrogen atmosphere. Then, n-butyllithium in n-hexane solution (13.66 mL, 2.5 M, 58.5 mmol) was added over 10 min. The resulting mixture was stirred at −78° C. for 45 min, then DMF (2.5 g, 34.15 mmol) was added and the resulting mixture was stirred at −78° C. for 1.15 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) 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).

[0352] Step 3: 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of acetonitrile (65 mL) under nitrogen atmosphere was added 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). The reaction was stirred at 70° C. for 30 minutes, then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (12 g, 62.4 mmol) was added slowly over a period of 10 minutes (mascara turned yellow during the addition). The resulting mixture was stirred at 70° C. for an additional 3 hours, then cooled to room temperature, diluted with diethyl ether, and the precipitated solid was removed by filtration and washed with diethyl ether (100 mL). The resulting 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).

[0353] Step 4: 2-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane [ka] 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 2.7 g, 11.73 mmol) and a solution of tetrabutylammonium fluoride in THF (13.7 g, 1 M, 13.7 mmol) were heated to 70° C. in a closed system for 2 h. The reaction was cooled and diluted with diethyl ether, which was washed with water (50 mL), saturated NaHCO3 solution (100 mL), and 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).

[0354] 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.

[0355] Step 6: 3-Ethoxycyclopent-2-en-1-one [ka] To a stirred solution of cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene (70 mL) was added pTSA (193 mg, 1.019 mmol) and EtOH (22.61 ml, 387.35 mmol) at room temperature. The resulting mixture was stirred at 120° C. for 10 h using a Dean-Stark apparatus. The solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) to give the title compound 3-ethoxycyclopent-2-en-1-one (4.3 g) as a brown solid. 1 H NMR(400MHz,CDCl3)δ 5.26(s,1H),4.02(q,J=6.6Hz,2H),2.60-2.55(m,2H),2.44-2.40(m,2H),1.39(t,J=7.2Hz,3H).

[0356] Step 7: 3-Aminocyclopent-2-en-1-one [ka] To a stirred solution of 3-ethoxycyclopent-2-en-1-one (from step 6, 4.3 g, 34.08 mmol) in ethanol (50 mL) was added ammonium hydroxide solution (25 mL, 387.35 mmol) at room temperature. The resulting mixture was stirred at 85° C. for 16 h. Removal of the solvent under reduced pressure afforded the title compound, 3-aminocyclopent-2-en-1-one (3.2 g) as a brown solid. LCMS Rt=0.114 min;MS m / z, 98.2[M+H]+;[Method 7]

[0357] Step 8: Methyl 4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from step 5, 200 mg, 0.9708 mmol), methyl 4-fluoro-3-oxobutanoate (method 2, step 1 of intermediate B, 130 mg, 0.9708 mmol) in EtOH (2 mL) was added 3-aminocyclopent-2-en-1-one (from step 7, 94 mg, 0.9708 mmol). The reaction mixture was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica (ethyl acetate in petroleum ether, 0→70%) to give the title compound as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 6].

[0358] Example 25 The second eluting enantiomer (25 mg) was obtained as a white solid. Chiral HPLC Rt=7.610 min; [Chiral analysis method 4] LCMS Rt=1.533 min;MS m / z, 401.75[M+]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.31-7.25(m,1H),7.04(d,J=8Hz,1H),6.97-6.90(m,1H),5.76(d,J=3.2Hz,1H),5.64(d,J=2 .8Hz,2H),5.08(s,1H),4.79-4.60(m,2H),3.70-3.55(m,2H),3.44(s,3H),2.66-2.61(m,2H).

[0359] Example 25b First eluting enantiomer (24 mg) as a white solid. Chiral HPLC Rt 7.103 min; [Chiral analysis method 4] LCMS Rt=1.533 min;MS m / z, 401.75[M+]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.31-7.25(m,1H),7.04(d,J=8Hz,1H),6.97-6.90(m,1H),5.76(d,J=3.2Hz,1H),5.64(d,J=2 .8Hz,2H),5.08(s,1H),4.79-4.60(m,2H),3.70-3.55(m,2H),3.44(s,3H),2.66-2.61(m,2H).

[0360] Example 26: Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane [ka] To a solution of 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from Example 25, step 3, 3 g, 13.04 mmol) in ethyl acetate (60 mL) was added 10% Pd-C (1 g). The resulting reaction mixture was kept in a Parr shaker under hydrogen atmosphere at room temperature at a pressure of 60 psi for 48 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-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (3 g) as a colorless liquid. 1H NMR(300MHz,CDCl3)δ 7.42-7.35(m,1H),7.34-7.27(m,1H),7.15-7.08(m,1H),6.31-5.78(m,2H),4.19-4.02(m,4H),3.38(m,2H).

[0361] Step 2: 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde [ka] To a solution of 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (from step 1, 3 g, 12.93 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), and 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 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1.9 g) as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 10.14(d,J=1.6Hz,1H),7.70-7.63(m,1H),7.52(td,J=8.0,7.9,5.2Hz,1H),7.35-7.30(m 1H),6.03(m,1H),3.83-3.58(m,2H).

[0362] Step 3: Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate and methyl (S)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from step 2, 200 mg, 1.063 mmol), methyl 4-fluoro-3-oxobutanoate (method 2 of intermediate B, step 1, 142 mg, 1.063 mmol) in EtOH (2 mL) was added 3-aminocyclopent-2-en-1-one (example 25, step 7, 103 mg, 1.063 mmol). The reaction mixture was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to give the title compound as an off-white solid (100 mg). The racemic mixture was separated into its enantiomers using chiral preparative HPLC [method 6].

[0363] Example 26 The first eluting enantiomer (25 mg) was obtained as a white solid. Chiral HPLC Rt 7.341 min; [Chiral analysis method 4] LCMS Rt=1.505 min;MS m / z, 384.2[M+1]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.25-7.17(m,1H),7.01(d,J=8Hz,1H),6.92-6.85(m,1H),6.80-6.40(m,1H),5.76(d,J=3.2Hz,1H),5.64(d,J=2 .8Hz,1H),5.08(s,1H),4.79-4.60(m,2H),3.70-3.55(m,2H),3.60-3.40(m,1H),3.52(s,3H),2.75-2.65(m,2H).

[0364] Example 26b The second eluting enantiomer (26 mg) was obtained as a white solid. Chiral HPLC Rt 9.044 min; [Chiral analysis method 4] LCMS Rt=1.505 min;MS m / z, 384.2[M+1]+;[Method 12] 1H NMR(400MHz,CD3OD)δ 7.25-7.17(m,1H),7.01(d,J=8Hz,1H),6.92-6.85(m,1H),6.80-6.40(m,1H),5.76(d,J=3.2Hz,1H),5.64(d,J=2 .8Hz,1H),5.08(s,1H),4.79-4.60(m,2H),3.70-3.55(m,2H),3.60-3.40(m,1H),3.52(s,3H),2.75-2.65(m,2H).

[0365] Example 27: Methyl (R)-4-(3-fluoro-2-((R or S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol [ka] To a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from Example 25, step 1, 30 g, 121.42 mmol) in THF (300 mL) was added n-BuLi in n-hexane solution (58.3 mL, 2.5 M, 147.71 mmol) dropwise over 10 min at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 h, then acetaldehyde (6.42 g, 145.71 mmol) was added and the reaction 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), washed with 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),5.30- 5.25(m,1H),4.15-3.95(m,4H),2.75-2.69(m.1H),1.58(dd,J=6.6,22.8Hz,3H).

[0366] 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 to RT and stirred 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).

[0367] Step 3: 3-Fluoro-2-(1-fluoroethyl)benzaldehyde [ka] To a solution of 2-(3-fluoro-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), and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 3-fluoro-2-(1-fluoroethyl)benzaldehyde (6.5 g) as a colorless liquid. (Note: the resulting aldehyde is volatile in nature).

[0368] Step 4: Methyl 4-(3-fluoro-2-((R or S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from step 3, 1 g, 5.876 mmol), methyl 4-fluoro-3-oxobutanoate (method 2 of intermediate B, step 1, 780 mg, 5.876 mmol) in EtOH (10 mL) was added 3-aminocyclopent-2-en-1-one (example 25, step 7, 570 mg, 5.876 mmol). The reaction mixture was stirred at 80° C. for 18 h. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to give the title compound as a diastereomeric mixture of methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (220 mg) as an off-white solid.

[0369] The diastereomeric mixture was separated into its two isomers using chiral preparative purification [Method 2].

[0370] The first peak from the diastereomeric separation was separated into its enantiomers, peak 1 and peak 2, using chiral preparative purification [Method 5].

[0371] Example 27 The second eluting enantiomer (55 mg) was obtained as a white solid. Chiral HPLC Rt=5.729 min; [Chiral analysis method 2] LCMS Rt=2.25 min;MS m / z, 364.1[MH]-;[Method 7] 1H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6.96-6.75(m,2H),6.52-6.30(m,1H),5.79(s,1H),5.67(s,1H),5.05 (s,1H),3.59(s,3H),2.80-2.60(m,2H),2.50-2.35(m,2H),2.01(dd,J=6.4,23.2Hz,3H).

[0372] Example 27b The first eluting enantiomer (55 mg) was obtained as a white solid. Chiral HPLC Rt=5.678 min; [Chiral analysis method 2] LCMS Rt=2.25 min;MS m / z, 364.1[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6.96-6.75(m,2H),6.52-6.30(m,1H),5.79(s,1H),5.67(s,1H),5.05 (s,1H),3.59(s,3H),2.80-2.60(m,2H),2.50-2.35(m,2H),2.01(dd,J=6.4,23.2Hz,3H).

[0373] The second peak from the diastereomeric separation was resolved into its enantiomers, peak 3 and peak 4, using chiral preparative purification [Method 10].

[0374] Example 27c Third enantiomer eluting as a white solid (10 mg). Chiral HPLC Rt=8.702 min; [Chiral analysis method 2] LCMS Rt=2.22 min;MS m / z, 364.1[MH]-;[Method 7] 1H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6.96-6.75(m,2H),6.80-6.60(m,1H),5.79(s,1H),5.69(s,1H),5.03 (s,1H),3.54(s,3H),2.75-2.58(m,2H),2.50-2.45(m,2H),1.83(dd,J=6.4,22.4Hz,3H).

[0375] Example 27d Fourth enantiomer eluted as a white solid (10 mg). Chiral HPLC Rt=9.851 min; [Chiral analysis method 2] LCMS Rt=2.22 min;MS m / z, 364.1[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6.96-6.75(m,2H),6.80-6.60(m,1H),5.79(s,1H),5.69(s,1H),5.03 (s,1H),3.54(s,3H),2.75-2.58(m,2H),2.50-2.45(m,2H),1.83(dd,J=6.4,22.4Hz,3H).

[0376] Example 28: Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3-fluorobenzaldehyde [ka] To a solution of 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). The EtOAc phase was 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→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).

[0377] Step 2: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from step 1, 900 mg, 5.481 mmol), methyl (Z)-3-amino-4-fluorobut-2-enoate (Intermediate B, 537.76 mg, 5.481 mmol) in ethanol (5 mL) was added cyclopentane-1,3-dione (875.68161 mg, 5.481 mmol). The reaction mixture was stirred at 80° C. for 16 h. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→70%) to give the title compound methyl-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (130 mg) as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 11].

[0378] Example 28 The first eluting enantiomer (46 mg) was obtained as a white solid. Chiral HPLC Rt=10.37 min; [Chiral analysis method 3] LCMS Rt=1.47 min;MS m / z, 360.2[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.10-7.01(m,1H),6.95-6.90(m,1H),6.78-6.71(m,1H),5.68(d,J=0.9Hz,1H),5.58-5.52(m,2H),3.53 (s,3H),2.70-2.65(m,2H),2.45-2.12(m,4H),1.34-1.25(m,1H),1.05-0.89(m,2H),0.80-0.69(m,1H).

[0379] Example 28b The second eluting enantiomer (48 mg) was obtained as a white solid. Chiral HPLC Rt=15.216 min; [Chiral analysis method 3] LCMS Rt=1.47 min;MS m / z, 360.2[M+H]+;[Method 7] 1H NMR(400MHz,CDCl3)δ 7.10-7.01(m,1H),6.95-6.90(m,1H),6.78-6.71(m,1H),5.68(d,J=0.9Hz,1H),5.58-5.52(m,2H),3.53 (s,3H),2.70-2.65(m,2H),2.45-2.12(m,4H),1.34-1.25(m,1H),1.05-0.89(m,2H),0.80-0.69(m,1H).

[0380] Example 29: Methyl (R)-4-(3,5-difluoro-2-((S or R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[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 3, 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 dissolved in 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. 1H 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).

[0381] 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 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).

[0382] 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 (100 mL) at 0 °C and diluted with ethyl acetate (100 mL). The organic layer was separated 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).

[0383] 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) and dried over Na2SO4. The solvent was removed under reduced pressure to give 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).

[0384] Step 5: 3-Ethoxycyclopent-2-en-1-one [ka] To a stirred solution of cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene (70 mL) was added pTSA (193 mg, 1.019 mmol) and EtOH (22.61 ml, 387.35 mmol) at room temperature. The resulting mixture was stirred at 120° C. for 10 h using a Dean-Stark apparatus. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) to give the title compound 3-ethoxycyclopent-2-en-1-one (4.3 g) as a brown solid. 1 H NMR(400MHz,CDCl3)δ 5.26(s,1H),4.02(q,J=6.6Hz,2H),2.60-2.55(m,2H),2.44-2.40(m,2H),1.39(t,J=7.2Hz,3H).

[0385] Step 6: 3-Aminocyclopent-2-en-1-one [ka] To a stirred solution of 3-ethoxycyclopent-2-en-1-one (from step 5, 4.3 g, 34.08 mmol) in ethanol (50 mL) was added ammonium hydroxide solution (25 mL, 387.35 mmol) at room temperature. The resulting mixture was stirred at 85° C. for 16 h. Removal of the solvent under reduced pressure afforded the title compound, 3-aminocyclopent-2-en-1-one (3.2 g) as a brown solid. LCMS RT=0.114 min;MS m / z, 98.2[M+H]+;[Method 7]

[0386] Step 7: Methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] To a solution of the aldehyde (from step 4, 700 mg, 3.7204 mmol), methyl 4-fluoro-3-oxobutanoate (step 1 of Intermediate B; method 2, 598.73 mg, 4.4645 mmol) and 3-aminocyclopent-2-en-1-one (step 6, 361.32 mg, 3.7204 mmol) in t-butanol (15 mL). The reaction mixture was stirred at 80° C. for 48 h. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by silica flash chromatography (ethyl acetate in petroleum ether, 0→50%) to give the title compound methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate (580 mg) as an off-white solid and as a mixture of diastereomers and the first diastereomer as an off-white solid (320 mg, peak 1). The mixture (580 mg) was further purified by preparative HPLC purification (Method 8) to give the second diastereomer as an off-white solid (80 mg, peak 2).

[0387] Peak 1: 160 mg and Peak 2: 80 mg were further separated into their enantiomers using preparative chiral HPLC [Method 11] to give the four isomers of Example 29.

[0388] Example 29 50 mg of the first eluting enantiomer obtained as a white solid using chiral HPLC [Method 11]. LCMS RT=1.445 min;MS m / z, 382.1[MH]-;[Method 7] This was further purified by preparative HPLC purification [Method 9] to give an off-white solid (25 mg). Chiral HPLC: RT: 8.905 min; [Chiral analysis method 3] LCMS RT=1.445 min;MS m / z, 382.1[MH]-;[Method 13] 1 H NMR(400MHz,DMSO-d6)δ 10.10(s,1H),7.06(ddd,J=11.6,8.8,2.6Hz,1H),6.82-6.68(m,1H),6.36(dq,J=45.3,6.5Hz,1H),5.75-5.64(m,1H) ),5.63-5.50(m,1H),4.97(s,1H),3.45(s,3H),2.70-2.59(m,2H),2.25-2.09(m,2H),1.84(dd,J=23.0,6.5Hz,3H).

[0389] Example 29b 55 mg of the second eluting enantiomer obtained as a white solid using chiral HPLC [Method 11]. Chiral HPLC: RT: 10.197 min; [Chiral analysis method 3] LCMS RT=1.510 min;MS m / z, 382.1[MH]-;[Method 13] 1 H NMR(400MHz,DMSO-d6)δ 10.10(s,1H),7.06(ddd,J=11.6,8.8,2.6Hz,1H),6.82-6.67(m,1H),6.36(dq,J=45.4,6.6Hz,1H),5.75-5.64(m,1H) ),5.63-5.48(m,1H),4.97(s,1H),3.45(s,3H),2.71-2.59(m,2H),2.27-2.16(m,2H),1.84(dd,J=23.0,6.5Hz,3H).

[0390] Example 29c 24.2 mg of the third eluting enantiomer obtained as a white solid using chiral HPLC [Method 11]. Chiral HPLC: RT: 14.455 min; [Chiral analysis method 3] LCMS RT=1.504 min;MS m / z, 382.0[MH]-;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),7.14-6.96(m,1H),6.75(d,J=9.8Hz,1H),6.63(dq,J=44.2,6.8Hz,1H),5.71(s,1H),5.59(s ,1H),4.88(s,1H),3.47(s,3H),2.62(q,J=4.5Hz,2H),2.25(t,J=4.9Hz,2H),1.68(dd,J=22.8,6.5Hz,3H).

[0391] Example 29d 32.4 mg of the fourth eluting enantiomer obtained as a white solid using chiral HPLC [Method 11]. Chiral HPLC: RT: 18.561 min [Chiral analysis method 3] LCMS RT=1.514 min;MS m / z, 382.0[MH]-;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),7.05-7.00(m,1H),6.75(d,J=9.7Hz,1H),6.62(dt,J=44.2,6.6Hz,1H),5.71(s,1H),5.59(s ,1H),4.88(s,1H),3.47(s,3H),2.62(q,J=4.6Hz,2H),2.25(t,J=4.9Hz,2H),1.68(dd,J=22.8,6.4Hz,3H).

[0392] Example 30: Methyl (R)-4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: Methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] The title compound was synthesized using general method I (using 2-ethylbenzaldehyde, 0.2 g, 1.44 mmol). The crude product was purified by silica column chromatography (2→3% methanol in DCM), which gave the title compound as a cream solid. Methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (0.165 g, 43%). LCMS Rt=1.506 min; MS m / z, 331.85 [M+H]+; [Method 10]

[0393] The racemic sample was separated into its enantiomers by chiral HPLC (Column: LUX CELLULOSE-4, (250 MM x 21.2 MM x 5 microns); Mobile phase: N-Hexane (A) EtOH:MeOH, 1:1 (B), Flow rate: 15 mL).

[0394] Example 30 First eluting enantiomer, 30mg as a pale yellow solid. Chiral HPLC Rt=5.952 min (Column: LUX CELLULOSE-4 (150 x 4.6 mm x 5μ); Mobile phase: A = n-hexane, B: ethanol:methanol (50:50); Flow rate: 1.0 mL / min). LCMS Rt=1.53 min;MS m / z, 332.0[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),7.13-7.10(m,4H),5.71(s,1H),5.59(s,1H),4.98(s,1H),4.82(s,2H),3.44(s,3H),2.98-2.92(m,2H),1.25(t,J=7.8Hz,3H).

[0395] Example 30b Second eluting enantiomer, 29mg as a pale yellow solid. Chiral HPLC Rt=7.581 min (Column: LUX CELLULOSE-4 (150×4.6 mm×5μ); Mobile phase: A=n-hexane, B: ethanol:methanol (50:50); Flow rate: 1.0 ml / min). LCMS Rt=1.528 min;MS m / z, 332.0[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),7.13-7.10(m,4H),5.71(s,1H),5.59(s,1H),4.98(s,1H),4.82(s,2H),3.44(s,3H),2.98-2.92(m,2H),1.25(t,J=7.8Hz,3H).

[0396] Example 31: Methyl (R)-2-(difluoromethyl)-4-(3-fluoro-2-((R or S)-1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 5-Ethyl 3-methyl 2-(dimethoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] A stirred solution of methyl 4,4-dimethoxy-3-oxobutanoate (2.0 g, 11.35 mmol), 3-fluoro-2-(1-fluoroethyl)benzaldehyde (from Example 27, step 3, 1.93 g, 11.35 mmol) and ethyl (Z)-3-aminobut-2-enoate (1.46 g, 11.35 mmol) in ethanol (20 mL) was heated to 90° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude compound as a brown liquid. The crude compound was purified by silica flash chromatography (9→10% ethyl acetate in hexanes) to give the title compound as a yellow sticky liquid. 5-Ethyl 3-methyl 2-(dimethoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (1.7 g, 34%).

[0397] Compounds were accepted directly as crude without further analysis.

[0398] Step 2: 3-Ethyl 5-methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] A stirred solution of 5-ethyl 3-methyl 2-(dimethoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (from step 1, 1.7 g, 3.86 mmol) in 1,4-dioxane (10.0 mL) was cooled to 0° C. 6N aqueous hydrochloric acid (15.0 mL) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and the product was extracted into ethyl acetate. The combined organic layers were washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude compound was purified by silica flash chromatography (12→15% ethyl acetate in hexanes) to give diastereomer 1 (400 mg, 26%) and diastereomer 2 (300 mg, 20%) of the title compound as a yellow sticky liquid.

[0399] Diastereomer 1 LCMS Rt=1.606 min;MS m / z, 392.0[MH]-;[Method 10] 1 H NMR(300MHz,DMSO-d6)δ 10.13(s,1H),9.05(s,1H),7.33(dd,J=13.8,7.2Hz,1H),7.10-7.02(m,2H),6.45-6.23(m,1H),5.19(s ,1H),4.06-3.98(m,2H),3.63(s,3H),2.35(s,3H),1.76(dd,J=22.8,6.6Hz,3H),1.13(t,J=6.9Hz,3H)

[0400] Diastereomer 2 LCMS Rt=1.461 min;MS m / z, 392.0[MH]-;[Method 14] 1H NMR(300MHz,DMSO-d6)δ 10.12(s,1H),9.07(s,1H),7.33(dd,J=13.8,7.2Hz,1H),7.10-7.03(m,2H),6.44-6.22(m,1H),5.18(s ,1H),4.13-3.87(m,2H),3.67(s,3H),2.35(s,3H),1.74(dd,J=22.8,6.6Hz,3H),1.11(t,J=6.9Hz,3H).

[0401] Step 3: 5-Ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate [ka] A stirred solution of 3-ethyl 5-methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylate (from diastereoisomer 1 in step 2, 0.40 g, 1.01 mmol) in dichloromethane (5.0 mL) was cooled to −78° C. Diethylaminosulfur trifluoride (0.16 mL, 1.22 mmol) was added portionwise at −78° C. and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cold water and the product was extracted into dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to give the title compound as a brown viscous liquid. 5-Ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (0.3 g). LCMS Rt=1.632 min;MS m / z, 414.0[MH]-;[Method 10] 1H NMR(300MHz,DMSO-d6)δ 9.38(s,1H),7.58-7.23(m,2H),7.09-7.01(m,2H),6.43-6.22(m,1H),5.12(s,1H),4.08- 3.97(m,2H),3.58(s,3H),2.34(s,3H),1.75(dd,J=23.1,6.0Hz,3H),1.13(t,J=6.9Hz,3H)

[0402] Step 4: 3-Ethyl 5-methyl 2-(bromomethyl)-6-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate [ka] A solution of 5-ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (from step 3, 0.3 g, 0.722 mmol) in dichloromethane (5.0 mL) was cooled to −78° C. Pyridinium tribromide (0.254 g, 0.794 mmol) was added at −78° C. and stirred at the same temperature for 1 h. The reaction mixture was then stirred at room temperature for 30 min. The reaction mixture was diluted with ice-cold water and the product was extracted into dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude compound was purified by silica flash chromatography (10→12% ethyl acetate in hexanes) to give the title compound as a yellow sticky liquid. 3-Ethyl 5-methyl 2-(bromomethyl)-6-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.2 g, 56%) LCMS Rt=1.653 min;MS m / z, 491.95[MH]-;[Method 10] 1H NMR(300MHz,DMSO-d6)δ 9.38(s,1H),7.58-7.23(m,2H),7.09-7.01(m,2H),6.43-6.22(m,1H),5.12(s,1H),4.08- 3.97(m,2H),3.58(s,3H),2.34(s,3H),1.75(dd,J=23.1,6.0Hz,3H),1.13(t,J=6.9Hz,3H)

[0403] Step 5: Methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] To a solution of 3-ethyl 5-methyl 2-(bromomethyl)-6-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (from step 4, 0.1 g, 0.202 mmol) in chloroform (5.0 mL) was added potassium hydroxide (0.005 g, 0.101 mmol) at room temperature. The reaction mixture was heated to 60° C. and stirred for 8 hours. Tetra-n-butylammonium iodide (0.007 g, 0.020 mmol) was added at room temperature and the reaction mixture was heated to 65° C. for 12 hours. The reaction mixture was diluted with water and the product was extracted into dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: ZORBAX XDB (250 mm x 21.2 mm), 5.0μ; mobile phase: A = water, B = ACN; flow rate: 18 ml / min) to give the title compound as a cream-colored solid: methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (20 mg, 26%). LCMS Rt=1.503 min;MS m / z, 384.05[MH]-;[Method 10]

[0404] The racemic sample was separated into its enantiomers by chiral HPLC (Column: CHIRALPAK IJ, 250 MM x 4.3 MM x 5 microns; Mobile phase: A = Hexane, B = 0.1% HCOOH in MeOH:EtOH, 1:1, Flow rate: 5 mL).

[0405] Example 31: First eluting peak on chiral HPLC, 3.4mg as a cream coloured solid. Chiral HPLC Rt=6.393 min (Column: CHIRAL PAK IJ (250×4.6 mm×5μ); Mobile phase: A: n-hexane, B: ethanol; Flow rate: 1.0 mL / min. LCMS Rt=1.502 min;MS m / z, 384.05[MH]-[Method 10] 1 H NMR(300MHz,DMSO-d6)δ 10.43(s,1H),7.64-7.28(m,2H),7.10-7.02(m,2H),6.44-6.22(m,1H),5.13(s,1H),4.88(s,2H),3.49(s,3H),1.80(dd,J=22.8,6.0Hz,3H)

[0406] Example 31b Second eluting peak on chiral HPLC, 3mg as a cream coloured solid. Chiral HPLC Rt=7.605 min (Column: CHIRAL PAK IJ (250×4.6 mm×5μ); Mobile phase: A: n-hexane, B: ethanol; Flow rate: 1.0 mL / min. LCMS Rt=1.500 min; MS m / z, 384.05[MH]-. [Method 10] 1 H NMR(300MHz,DMSO-d6)δ 10.42(s,1H),7.59-7.32(m,2H),7.10-7.02(m,2H),6.42-6.25(m,1H),5.13(s ,1H),4.88(dd,J=19.2,16.4Hz,2H),3.49(s,3H),1.80(dd,J=23.2,6.4Hz,3H).

[0407] Crystal morphology X-ray powder diffraction measurement (XRPD) XRPD was performed using a nickel filter monochromator and a Cu-K alpha 1,2 The diffractograms were recorded on a Bruker D8Advance diffractometer equipped with a LYNXEYE (1D mode) detector with an open angle of 2.948° using illumination (wavelength 0.15419 nm). Diffractograms were recorded at ambient conditions with a tube voltage of 40 kV and a tube current of 40 mA, applying a step size of 0.0164° (2-theta value) in the angle range of 2° to 40° 2-theta with 0.3 seconds per step. The scan time was 768 seconds. Typical accuracy of the 2-theta value is in the range of ±0.2° 2-theta, preferably ±0.1° 2-theta. Thus, for example, the diffraction peaks of crystalline form A of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate occurring at 10.4°2-theta can occur in the range of (10.4-0.2)° to (10.4+0.2)°2-theta, preferably (10.4-0.1)° to (10.4+0.1)°2-theta, on most X-ray diffractometers under standard conditions.

[0408] Crystal form A Crude methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (130 g, 0.35 mol) was slurried in ethyl ether (520 ml) at room temperature for 3 hours to give a suspension which was filtered. The wet cake was then dried under vacuum at 60° C. for 72 hours to give methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form A (100 g, 0.27 mol) in 77% yield.

[0409] Crystal form B Crystalline Form B was prepared by dissolving 100 mg of Form A in enough isopropyl acetate to obtain a solution. Sufficient heptane was then added at 55° C. until a cloudy suspension was obtained. The suspension was held at 55° C. for a certain period of time, then cooled to 25° C. and equilibrated at 25° C. for 2-4 hours. The solid portion was isolated and analyzed by XRPD, which confirmed the presence of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form B.

[0410] Alternative synthesis: 400 mL of heptane was added into a 500 mL reactor and heated to 55° C. 20 g of Form A was added into 60 mL of isopropyl acetate at room temperature. Approximately 2 g of Form B was added as seed crystals to the reactor at 55° C., and the resulting mixture was equilibrated at 55° C. for 30 minutes. Then, a solution of Form A free form in isopropyl acetate was added dropwise into the reactor using a syringe pump within 2 hours. The resulting mixture was equilibrated at 55° C. for 2 hours. The mixture was then cooled to 25° C. within 6 hours, and then equilibrated at 25° C. for another 10 hours. The suspension was then filtered, and the wet cake was dried under vacuum at 50° C. for 4 hours. Approximately 21 g of final product was obtained, which was confirmed to correspond to Form B by XRPD. The water content by KF was 0.3%.

[0411] Crystal form C Approximately 100 mg of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate and various stoichiometric amounts of citric acid (base:acid ratios of 4:1, 3:1, 2:1 or 1:1) were crystallized in tert-butyl methyl ether. The resulting solid form corresponded to methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Form C.

[0412] Alternative synthesis: 40 mL of heptane was added into a 100 mL EasyMax reactor at 25° C. 2 g of Form A was dissolved in 5 mL of isopropyl acetate at room temperature. 20 mg of seed crystals of Form C were then added to the reactor at 25° C. The resulting mixture was equilibrated at 25° C. for 30 minutes. A solution of Form A free form in isopropyl acetate was added dropwise to the reactor within a period of 2 hours using a syringe pump. The resulting mixture was equilibrated at 25° C. for 2 hours. In-process control showed a mixture of Form C and hydrate A. The solid material was then slurried in 10 mL of isopropyl acetate / heptane (1 / 7) for 2 days. The suspension was then filtered and dried at 40° C. for 18 hours. XRPD of the final product corresponded to Form C. Water content by KF was 0.3%.

[0413] Crystalline form hydrate A 1.97 g of Form A was weighed into a 100 mL EasyMax glass vial and dispersed in 35 mL of water, and the suspension was stirred at less than 50° C. with overhead stirring at 300 rpm for 3 hours, then cooled to 25° C. at approximately 0.07° C. / min over 6 hours, after which stirring was continued at 25° C. for 24 hours. The solid material was isolated by filtration. XRPD of the solid form corresponded to Hydrate A.

[0414] Alternative synthesis: Hydrate A was obtained by evaporative crystallization of a clear saturated solution of crystalline form B in, for example, acetone, acetonitrile / water (99.5:0.5), ethyl acetate or water. Hydrate A shows a mass loss of about 4.1% by TGA, which is close to the monohydrate (calculated water content of 4.7%). Hydrate A is slightly hygroscopic. The water uptake from 10% to 95% RH is about 0.2% at 25°C.

[0415] Crystalline form hydrate B 2 g of Form A was weighed into a 100 mL EasyMax glass vial and dispersed in 30 mL of methanol, and the suspension was stirred with overhead stirring at 300 rpm at <25° C. for 20 hours. The solid material was isolated by filtration, and the solid was exposed to 92% RH for 1 day. The solid material corresponded to Hydrate B, as confirmed by XRPD.

[0416] Alternative synthesis: Hydrate B was obtained by air drying of crystalline form B in methanol solvate. Hydrate B shows a mass loss of about 4.4% by TGA, which is also close to the monohydrate (calculated water content of 4.7%). Hydrate B starts to dehydrate below 20% RH, losing about 4.4% water down to 0% RH. With the subsequent increase in relative humidity, it absorbs only about 3% water at 25° C.

[0417] Differential scanning calorimetry Differential scanning calorimetry was performed using a TA Discovery DSC under nitrogen with a scan rate of 10 C / min over a temperature range of 30-300 C and a flow rate of 25 mL / min. The sample mass used was approximately 2 mg.

[0418] Biological Data Many known calcium channel activators are VWe 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 6 shows a simulated myocardial action potential from an epicardial environment, showing the Ca concentration at potential (mV) versus time (ms). V These 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.

[0419] 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.

[0420] Ca V 1.2-Generation and maintenance of HEK293(AUX) cell line Monoclonal Ca V1.2-HEK293(AUX) cell line is a human Ca V It constitutively expresses 1.2 alpha 1C (α1C) 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 self-cleavage 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.

[0421] To maintain the cell line, the cells were passaged twice a week. At each passage, the growth medium (Table 6) 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 the D-PBS and TrypLE™ Express enzyme were removed immediately after rinsing. The plates were then placed at room temperature for 3-5 minutes. Next, 10 mL of warm 37°C complete medium was added to run over the cell growing surface and the dissociated cells were collected. The cells were counted and the T175cm 2 2-3 x 10 per flask 6 The cells were seeded into new flasks at a target density of 100 cells.

[0422] [Table 6]

[0423] 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 6) 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.

[0424] (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 1.5-3 million cells per QPatch run (Table 7). Each experimental run uses 1.5 mL of cells.

[0425] 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 7 and 8, respectively. A dose-response assay protocol was used to measure the peak inward current (Emax) and potency (EC 50 The 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 Vslope G(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.

[0426] [Table 7]

[0427] [Table 8]

[0428] [Table 9]

[0429] [Table 10]

[0430] 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).

[0431] 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.

[0432] 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.

[0433] 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.

[0434] 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.

[0435] result

[0436] [Table 11]

[0437] [Table 12]

[0438] 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.

[0439] [Table 13]

[0440] [Table 14] The invention as originally claimed in the present application is set forth below. [1] A compound according to formula (I) or a pharma- ceutically acceptable salt or solvate thereof. [ka] (In the formula: A is O or CH 2 and; R 1 is H or F; R 2 is H or F; R 3 each optionally substituted with 1 to 3 F, OCHF 2 , methyl, ethyl, or cyclopropyl). [2] The compound according to [1], which is a compound of formula (Ia) or a pharma- ceutically acceptable salt or solvate thereof: [ka] [3] The compound according to [1], which is a compound of formula (Ib) or a pharma- ceutically acceptable salt or solvate thereof: [ka] [4] The compound according to any one of [1] to [3], wherein A is O. [5] R 2 The compound according to [4], wherein is F. [6] R 2 The compound according to [4], wherein is H. [7] R 3 But, O.C.H.F. 2 The compound according to [4], [8] R 3 is methyl, ethyl, or cyclopropyl, each of which is substituted with 1 to 3 F. [9] R 3 But CHF 2 or CF 3 The compound according to [4],

[10] R 3 is ethyl substituted with one or two F, or cyclopropyl unsubstituted or substituted with two F.

[11] A is C.H. 2 The compound according to any one of [1] to [3],

[12] R 2 The compound according to

[11] , wherein

[13] R 3 is ethyl substituted with 1 to 3 F.

[14] A compound according to formula (III) or a pharma- ceutically acceptable salt or solvate thereof.

change

[15] The compound according to

[14] , wherein A is O.

[16] R 2 The compound according to

[15] , wherein

[17] R 2 The compound according to

[15] , wherein

[18] R 3 But, O.C.H.F. 2 The compound according to

[15] ,

[19] R 3 is methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F.

[20] R 3 But CHF 2 or CF 3 The compound according to

[15] ,

[21] R 3 is ethyl optionally substituted with one or two F, or cyclopropyl that is unsubstituted or substituted with two F.

[22] R 3 is ethyl.

[23] R 4 The compound according to

[15] , wherein

[24] R 4 The compound according to

[15] , wherein

[25] A is C.H. 2 The compound according to

[14] , wherein

[26] R 2 The compound according to

[23] , wherein

[27] R 3 is ethyl substituted with 1 to 3 F.

[28] R 4 The compound according to

[23] , wherein

[29] R 4 The compound according to

[23] , wherein

[30] Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; and Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; or a pharma- ceutically acceptable salt or solvate thereof. The compound according to [1], selected from the group consisting of:

[31] Ethyl (R)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; and Methyl (S)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate; or a pharma- ceutically acceptable salt or solvate thereof. The compound according to [1], selected from the group consisting of:

[32] The compound according to

[14] , which is methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate or a pharma- ceutically acceptable salt or solvate thereof.

[33] A crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate.

[34] The crystalline form according to

[33] , which is Form A.

[35] The crystalline form according to

[33] , which is form B.

[36] The crystalline form according to

[33] , which is Form C.

[37] A crystalline hydrated form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate.

[38] The crystalline hydrated form described in

[37] , which is Hydrate A.

[39] The crystalline hydrated form described in

[37] , which is Hydrate B.

[40] A pharmaceutical composition comprising a compound according to any one of [1] to

[32] and a pharma- ceutically acceptable excipient.

[41] A method for treating 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 to a patient in need of such treatment an effective amount of a compound according to any one of [1] to

[32] or a pharmacologic acceptable salt thereof.

[42] A method for treating 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 to a patient in need of such treatment a compound according to any one of [1] to

[32] or a pharmacologic acceptable salt thereof.

Claims

1. A compound according to formula (I) or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 1】 (In the formula: A is O or CH ２ and R １ is H or F; R ２ is H or F; R ３ each of which is optionally substituted with 1 to 3 F; ２ , methyl, ethyl, or cyclopropyl).

2. 2. The compound of claim 1 which is a compound of formula (Ia) or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 2】

3. 2. The compound of claim 1 which is a compound of formula (Ib) or a pharma- ceutically acceptable salt or solvate thereof: 【Chemistry 3】

4. The compound according to any one of claims 1 to 3, wherein A is O.

5. R ２ The compound of claim 4 , wherein is F or H.

6. R ３ However, O.C.H.F. ２ , C.H.F. ２ Or CF ３ 5. The compound of claim 4,

7. R ３ The compound of claim 4, wherein is methyl, ethyl, or cyclopropyl, each of which is substituted with 1 to 3 F.

8. R ３ 5. The compound of claim 4, wherein is ethyl substituted with one or two F, or cyclopropyl that is unsubstituted or substituted with two F.

9. Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; Methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; and Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; or a pharma- ceutically acceptable salt or solvate thereof.

2. The compound of claim 1 selected from the group consisting of:

10. 【Fig. 4】 or a pharma- ceutically acceptable salt or solvate thereof.

11. A crystal of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate.

12. When measured with Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 to 30°C, (8.5±0.2)°, (10.4±0.2)° and (10.8±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)° and (22.4±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, and (22.4±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (21.6±0.2)° and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (13.5±0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)° and (22.4±0.2)° 12. The crystal of claim 11, which is form A having an XRPD pattern including a reflection at a 2 theta angle of:

13. When measured with Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 to 30°C, (12.0±0.2)°, (13.7±0.2)°, and (21.4±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, and (21.4±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21.4±0.2)° and (23.8±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)°, and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)°, and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (14.5±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)°, and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (14.5±0.2)°, (15.7±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2)° and (23.8±0.2)° 12. The crystal of claim 11, which is form B having an XRPD pattern including a reflection at a 2 theta angle of:

14. When measured with Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 to 30°C, (10.3±0.2)°, (15.5±0.2)° and (20.6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, and (20.6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (20.6±0.2)°, and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18.2±0.2)°, (20.6±0.2)°, and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (14.0±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)°, and (23.2±0.2)°; or (7.0±0.2)°, (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12.8±0.2)°, (14.0±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)° 12. The crystal of claim 11, which is form C having an XRPD pattern including a reflection at a 2 theta angle of:

15. Crystalline hydrate of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate.

16. When measured with Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 to 30°C, (10.0±0.2)°, (10.6±0.2)° and (23.5±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (14.4±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (14.4±0.2)°, (22.9±0.2)°, (23.5±0.2)° and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (11.1±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (22.9±0.2)°, (23.5±0.2)°, and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (11.1±0.2)°, (12.8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (20.0±0.2)°, (22.9±0.2)°, (23.5±0.2)° and (25.0±0.2)° 16. The crystalline hydrate of claim 15, which is Hydrate A having an XPRD pattern including a reflection at a 2 theta angle of

17. When measured with Cu-K alpha 1,2 radiation having a wavelength of 0.15419 nm at a temperature in the range of 20 to 30°C, (5.5±0.2)°, (8.4±0.2)° and (13.0±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (13.0±0.2)°, and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0.2)°, and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0.2)°, (16.5±0.2)°, and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (19.6±0.2)°, and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (19.6±0.2)°, and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (17.9±0.2)°, (19.6±0.2)°, and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0.2)°, (13.0±0.2)°, (16.5±0.2)°, (17.9±0.2)°, (19.6±0.2)° (20.6±0.2)° and (24.0±0.2)° 16. The crystalline hydrate of claim 15, which is Hydrate B having an XRPD pattern including a reflection at a 2 theta angle of:

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, the crystal according to any one of claims 11 to 14, or the crystalline hydrate according to any one of claims 15 to 17, and a pharma- ceutically acceptable excipient.

19. 19. The pharmaceutical composition of claim 18 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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