Compounds as CAV1.2 activators

Abstract

The present disclosure provides a compound according to formula (I) or a pharmaceutically acceptable salt thereof as Ca V 1.22 Activators are used to treat 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.

Description

1. 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 the same, and such compounds as Ca V 1.2 Use of activators for the treatment of calcium signaling defects and / or synaptic dysfunction in the following diseases: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada Syndrome, short QT syndrome, and early repolarization syndrome. 2. Background technology

[0002] Advances in human genomics have revealed the genetic basis of psychiatric disorders. Genome-wide association studies (GWAS) of schizophrenia have identified more than a hundred disease-associated loci, including Ca V 1.2 and other genes involved in neuronal calcium signaling. GWAS analyses across disorders have identified Ca V 1.2 and its β subunit (CACNB2) are closely associated with schizophrenia, bipolar disorder, major depressive disorder, ADHD, and autism spectrum disorder. In addition to evidence from GWAS, exome sequencing of schizophrenia patients has shown that Ca V 1.2 and other gene members of the neuronal calcium signaling pathway, including CACNA2D, CACNB, and CAMK2 genes. V 1.2 has been shown to be important for neuronal differentiation and migration, neurite outgrowth, synaptic signaling, gene expression, and brain plasticity. It has been shown to play a role in mood, learning and memory, executive function, and the brain's reward response.

[0003] Ca V 1.2 is widely expressed throughout the body and plays a major role in multiple organ systems, including the cardiovascular system; however, Ca V 1.2 The physiological function of Ca in the cardiovascular system is different from that in the brain. VCa 1.2 is a key factor in action potential generation in the heart and a key driver of intracellular signaling and gene expression in neurons, but plays a minimal role in action potential generation. V 1.2 The mutation p.G406R results in different cellular phenotypes between cardiomyocytes and neurons. Ca2+ leads to specific cardiovascular disorders (Brugada syndrome and long QT syndrome type 8) V 1.2 Mutation is Ca V 1.2 Further evidence for different functions in the heart and brain.

[0004] Calcium channel activators have been reported previously, but further investigation of their use in neuropsychiatric disorders has been limited due to their effects on the cardiovascular system. In fact, many of these molecules were originally investigated and developed for their potential therapeutic use in heart failure. Most of the Ca2+-related GWAS studies in psychiatric disorders have been reported in the literature. V The 1.2 SNPs are located in the introns of the gene, and these risk SNPs have been shown to be associated with a reduction in mRNA expression, which in many cases leads to an overall reduction in calcium current amplitude. Therefore, a small molecule that can increase the overall current amplitude may be most beneficial to patients. 3. Summary of the invention

[0005] The present disclosure provides a compound according to formula (I) or a pharmaceutically acceptable salt thereof

[0006]

[0007] in:

[0008] A is O or CH2;

[0009] R 1 is H or F;

[0010] R 2 is H or F; and

[0011] R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F groups.

[0012] In a second aspect, the present disclosure provides a compound according to formula (III), or a pharmaceutically acceptable salt or solvate thereof,

[0013]

[0014] in:

[0015] A is O or CH2;

[0016] R 1 is H or F;

[0017] R 2 is H or F;

[0018] R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F; and

[0019] R 4 It is H or F.

[0020] In a third aspect, the present disclosure provides a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0021] In a fourth aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, particularly in the treatment of: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada Syndrome, short QT syndrome, and early repolarization syndrome.

[0022] In a fifth aspect, the present disclosure provides methods for treating: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome, the method comprising administering to a patient in need of treatment an effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof.

[0023] In a sixth aspect, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada Syndrome, short QT syndrome, and early repolarization syndrome.

[0024] In a seventh aspect, the present disclosure provides methods for treating: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome, the method comprising administering a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

[0025] In an eighth aspect, the present disclosure provides a pharmaceutical composition comprising a compound having formula (III) or a pharmaceutically acceptable salt thereof.

[0026] In a ninth aspect, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof for use in therapy, particularly in the treatment of: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada Syndrome, short QT syndrome, and early repolarization syndrome.

[0027] In a tenth aspect, the present disclosure provides a method for treating: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome, the method comprising administering to a patient in need of treatment an effective amount of a compound according to formula (III) or a pharmaceutically acceptable salt thereof.

[0028] In an eleventh aspect, the present disclosure provides the use of a compound of formula (III) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada Syndrome, short QT syndrome, and early repolarization syndrome.

[0029] In a twelfth aspect, the present disclosure provides a method for treating: 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 autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac disorders, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome, the method comprising administering to a patient in need of treatment a compound according to formula (III) or a pharmaceutically acceptable salt thereof. 4. Description of the drawings

[0030] Figure 1 : A representative XRPD of 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 of the present disclosure is shown. The x-axis shows the scattering angle (in °2-θ) and the y-axis shows the intensity of the scattered X-ray beam (in counts of detected photons).

[0031] Figure 2: A representative XRPD of 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 of the present disclosure is shown. The x-axis shows the scattering angle (in °2-θ) and the y-axis shows the intensity of the scattered X-ray beam (in counts of detected photons).

[0032] Figure 3 : A representative XRPD of 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 of the present disclosure of the present invention is shown. The x-axis shows the scattering angle (in °2-θ) and the y-axis shows the intensity of the scattered X-ray beam (in counts of detected photons).

[0033] Figure 4 : 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 is shown. The x-axis shows the scattering angle (in °2-θ) and the y-axis shows the intensity of the scattered X-ray beam (in counts of detected photons).

[0034] Figure 5 : 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 is shown. The x-axis shows the scattering angle (in °2-θ) and the y-axis shows the intensity of the scattered X-ray beam (in counts of detected photons).

[0035] Figure 6 : Simulated cardiac action potentials from the epicardial environment are shown, which show that Ca V 1.2 Effect of voltage shift of activation toward more negative membrane potentials. The x-axis is time (ms) and the y-axis is potential.

[0036] Figure 7 : Single crystal X-ray of 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) was shown, confirming that the active enantiomer was the R-enantiomer.

[0037] Figure 8: Single crystal X-ray 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 shown, confirming that the active enantiomer was the R-enantiomer.

[0038] Fig. 9 : Single crystal X-ray 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 shown, confirming that the active enantiomer was the R-enantiomer. 5. Specific implementation methods

[0039] 5.1. Definitions

[0040] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, 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.

[0041] As used herein, "administration," "administering," and "administer" refer to the manner in which a compound described herein is presented to a subject.

[0042] As used herein, "optionally substituted" means that the group referenced may be substituted at one or more positions with any one or any combination of the groups listed thereafter.

[0043] As used herein, "halo" or "halogen" as used herein may be fluoro, chloro, bromo or iodo.

[0044] As used herein, "subject" refers to a living organism suffering from one or more of the diseases or disorders 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 disorders, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome) that can be treated by administering a pharmaceutical composition described herein. 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 suffering from, at risk for, or likely to suffer from a disorder 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 disorders, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome).

[0045] Unless the context requires otherwise, throughout this specification and the claims that follow, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of stated integers or steps or groups of integers or steps but not the exclusion of any other integers or steps or groups of integers or steps.

[0046] If there is a discrepancy between a depicted structure and the chemical name given for that structure, the depicted structure shall prevail. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated, for example, by bold or dashed lines, that structure or portion of that structure shall be interpreted as encompassing all stereoisomers of that structure or portion of that structure.

[0047] 5.2. Compounds

[0048] A compound according to formula (I), or a pharmaceutically acceptable salt or solvate thereof

[0049]

[0050] in:

[0051] A is O or CH2;

[0052] R 1 is H or F;

[0053] R 2is H or F; and

[0054] R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F groups.

[0055] One embodiment is a compound having formula (Ia), or a pharmaceutically acceptable salt or solvate thereof,

[0056]

[0057] Another embodiment is a compound having formula (Ib), or a pharmaceutically acceptable salt or solvate thereof,

[0058]

[0059] In another embodiment, A is O.

[0060] In another embodiment, A is CH2.

[0061] In another embodiment, R 1 It's H.

[0062] In another embodiment, R 1 It's F.

[0063] In another embodiment, R 2 It's H.

[0064] In another embodiment, R 2 It's F.

[0065] In another embodiment, R 3 It's OCHF2.

[0066] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F groups.

[0067] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is substituted by 1 to 3 F groups.

[0068] In another embodiment, R 3 It is CHF2 or CF3.

[0069] In another embodiment, R 3 It is ethyl substituted by 1 or 2 F groups.

[0070] In another embodiment, R 3 It is an unsubstituted ethyl group.

[0071] In another embodiment, R3 is cyclopropyl which is unsubstituted or substituted by 2 F groups.

[0072] A compound according to formula (III), or a pharmaceutically acceptable salt or solvate thereof,

[0073]

[0074] in:

[0075] A is O or CH2;

[0076] R 1 is H or F;

[0077] R 2 is H or F;

[0078] R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F; and

[0079] R 4 It is H or F.

[0080] In another embodiment, A is O.

[0081] In another embodiment, A is CH2.

[0082] In another embodiment, R 1 It's H.

[0083] In another embodiment, R 1 It's F.

[0084] In another embodiment, R 2 It's H.

[0085] In another embodiment, R 2 It's F.

[0086] In another embodiment, R 3 It's OCHF2.

[0087] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F groups.

[0088] In another embodiment, R 3 is methyl, ethyl, or cyclopropyl, each of which is substituted by 1 to 3 F groups.

[0089] In another embodiment, R 3 It is CHF2 or CF3.

[0090] In another embodiment, R3 It is ethyl substituted by 1 or 2 F groups.

[0091] In another embodiment, R 3 It is an unsubstituted ethyl group.

[0092] In another embodiment, R 3 is cyclopropyl which is unsubstituted or substituted by 2 F groups.

[0093] In another embodiment, R 4 It's F.

[0094] In another embodiment, R 4 It's H.

[0095] Specific compounds include:

[0096] 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;

[0097] 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;

[0098] (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0099] 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;

[0100] 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;

[0101] 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;

[0102] 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;

[0103] 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;

[0104] 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;

[0105] 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;

[0106] 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;

[0107] 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;

[0108] Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0109] Methyl (R)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0110] Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0111] 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;

[0112] Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0113] Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate;

[0114] Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0115] 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;

[0116] 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;

[0117] Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0118] Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0119] Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0120] Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0121] Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0122] Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0123] Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0124] Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate;

[0125] (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;

[0126] Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate;

[0127] 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;

[0128] 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;

[0129] Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate;

[0130] 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

[0131] 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.

[0132] Specific compounds further include:

[0133] Methyl (R)-4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate; and

[0134] Methyl (R)-2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate.

[0135] Depending on the choice of starting materials and procedures, the compounds may exist in the form of possible stereoisomers or as mixtures thereof (e.g., as pure optical isomers or as mixtures of stereoisomers, such as racemates and diastereomeric mixtures), depending on the number of asymmetric carbon atoms. The present disclosure is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0136] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salts" particularly include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure are able to form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0137] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0138] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0139] 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.

[0140] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0141] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns 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 ammonium, potassium, sodium, calcium, and magnesium salts.

[0142] 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, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0143] In another aspect, the disclosure provides compounds of the disclosure in the form of acetate, ascorbate, adipate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate The invention can also be used in the form of salts of p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate, p-hydroxybenzoate

[0144] The compounds of the present disclosure, i.e. compounds of formula (I) containing groups capable of acting as hydrogen bond donors and / or acceptors, are capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting or contacting the compound of formula (I) with the co-crystal former in solution under crystallization conditions and isolating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Therefore, the present disclosure further provides co-crystals comprising compounds of formula (I).

[0145] In addition, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the disclosure includes both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compounds disclosed herein (including their pharmaceutically acceptable salts) and one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field, and they are known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0146] The present disclosure includes unlabeled forms and isotopically labeled forms of compounds of formula (I). Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that may be incorporated into compounds of the present disclosure include, for example, isotopes of hydrogen.

[0147] In addition, the incorporation of certain isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages caused by higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvement of therapeutic index or tolerability. It should be understood that deuterium is considered to be a substituent of the compounds of the present disclosure in this context. The concentration of deuterium can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of the present disclosure is indicated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation on 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.

[0148] For example, formula (I) is deuterated, as shown in formula (II):

[0149]

[0150] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and A are as defined in formula (I); R D1 To R D8 Each independently is H or D.

[0151] Other examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P.35 S. 36 Cl, 123 I. 124 I. 125 I. Thus, it should be understood that the present disclosure includes incorporation of one or more of any of the foregoing isotopes (including, for example, radioactive isotopes, such as 3 H and 14 C) or compounds in which non-radioactive isotopes such as 2 H and 13 C. Such isotope-labeled compounds can be used for metabolic studies (using 14 C) reaction kinetics 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 radiotherapy for patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations, using an appropriate isotopically labeled reagent in place of the unlabeled previously used reagent.

[0152] Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present disclosure may exist in a racemic or enantiomerically enriched configuration, such as (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 (R)- or (S)-configuration. If possible, substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)-forms.

[0153] 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.

[0154] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the components, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0155] Any obtained compound of the present disclosure or the racemate of intermediate can be split into optical antipodes by known methods, for example, by separating its diastereomeric salt obtained with optically active acid or alkali, and releasing optically active acidic or basic compounds. In particular, the compound of the present disclosure can be split into its optical antipodes using an alkaline moiety, for example, by fractional crystallization with the following optically active acid formed salt, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, two-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. The racemic compound of the present disclosure or racemic intermediate can also be split by chiral chromatography (for example, using high pressure liquid chromatography (HPLC) of chiral adsorbent).

[0156] How to use

[0157] The compounds of the present disclosure in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, for example, Ca V 1.2 Activation properties, e.g. as shown in the in vitro and in vivo tests provided in the next section, and thus indicated for use in therapy or as a research chemical, e.g. as a tool compound.

[0158] The compounds of the present disclosure may be used to treat an indication selected from the following list: psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders;

[0159] Neurodevelopmental disorders, such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and autism spectrum disorder; and

[0160] Neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease, and

[0161] Cardiac disorders, 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.

[0162] Therefore, as another aspect, the present disclosure provides the use of the compound of the present disclosure or a pharmaceutically acceptable salt thereof in therapy. In another embodiment, the therapy is selected from the group consisting of: V 1.2 Diseases to be treated. In another embodiment, the disease is selected from the list of indications above.

[0163] Therefore, as another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in therapy. In another embodiment, the therapy is selected from the group consisting of: V 1.2 Diseases to be treated. In another embodiment, the disease is selected from the list of indications above.

[0164] In another aspect, the present disclosure provides for treating a disorder by activating Ca V 1.2 A method for treating a disease, the method comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In another embodiment, the disease is selected from the list of the above indications.

[0165] In another aspect, the present disclosure provides for treating a disorder by activating Ca V 1.2 A method for treating a disease comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In another embodiment, the disease is selected from the list of indications above.

[0166] Therefore, as another aspect, the present disclosure provides the use of the compound of the present disclosure or its pharmaceutically acceptable salt for the manufacture of a medicament. In another embodiment, the medicament is used to treat a disease caused by activating Ca V 1.2 Diseases to be treated. In another embodiment, the disease is selected from the list of indications above.

[0167] In another aspect, the present disclosure provides for treating a disorder caused by activation of Ca V 1.2 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, the method comprising administering a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0168] In another aspect, the present disclosure provides for treating a disorder caused by activation of Ca V 1.2 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, the method comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0169] Therefore, as a further aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a disease selected from the group consisting 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.

[0170] Therefore, as a further aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease selected from the group consisting 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.

[0171] In another aspect, the disclosure provides 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, the method comprising administering a therapeutically effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0172] In another aspect, the disclosure provides 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, the method comprising administering a compound of the disclosure or a pharmaceutically acceptable salt thereof.

[0173] Therefore, as a further aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the manufacture of a medicament 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.

[0174] Pharmaceutical composition

[0175] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers (such as those described herein). The pharmaceutical composition can be formulated for a specific route of administration, such as oral administration, parenteral administration (such as by injection, infusion, percutaneous or topical administration) and rectal administration. Topical application may also involve inhalation or intranasal application. The pharmaceutical composition of the disclosure may be 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 added with film coatings or enteric coatings according to methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule comprising an active ingredient and one or more of the following:

[0176] a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0177] b) lubricants, for example silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0178] c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone; if desired

[0179] d) disintegrants, for example starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and

[0180] e) Adsorbents, colorants, flavoring agents and sweeteners.

[0181] For a subject of about 50-70kg, the pharmaceutical composition or combination of the present disclosure can be a unit dose of one or more active ingredients of about 1-1000mg, or a unit dose of an active ingredient of about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or about 1-50mg. The therapeutically effective dose of a compound, pharmaceutical composition, or a combination thereof depends on the species, body weight, age, and individual symptoms, disorders, or diseases or their severity in the treatment of the subject. A physician, clinician, or veterinarian with ordinary skills can easily determine the effective amount of each active ingredient necessary for preventing, treating, or inhibiting disorder or disease progression.

[0182] The above dosage characteristics are demonstrated in in vitro and in vivo tests using advantageous mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues and preparations. The compounds disclosed herein can be applied in vitro in the form of solutions (e.g., aqueous solutions) and can be applied enterally, parenterally, advantageously intravenously, for example as a suspension or in aqueous solution. In vitro doses can be about 10 -3 Molar concentration and 10 -9 Depending on the route of administration, the in vivo therapeutically effective amount may be in the range of between about 0.1-500 mg / kg, or between about 1-100 mg / kg.

[0183] Crystalline form

[0184] 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 to a method for preparing the same. In addition, the present disclosure relates to a pharmaceutical composition comprising a crystalline form of the 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 pharmaceutically acceptable excipient in a preferably predetermined amount and / or effective amount. The pharmaceutical compositions disclosed herein can be used as medicaments, particularly 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.

[0185] Different solid forms of active pharmaceutical ingredients usually have different characteristics. The difference in the physicochemical properties of solid forms can play a key role in the improvement of pharmaceutical compositions, for example, due to the improvement of the solid form of active pharmaceutical ingredients, pharmaceutical formulations with improved dissolution curves or improved stability or shelf life can become easily available. The processing or handling of active pharmaceutical ingredients can also be improved during formulation. The new solid form of active pharmaceutical ingredients can therefore have the processing characteristics of hope. Compared with previously known solid forms, they are easier to handle, more suitable for storage and / or allow better purification.

[0186] 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 can 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 measurement system). These forms can be characterized by one of the aforementioned analytical methods or by combining two or more of them.

[0187] The 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 referred to herein as being characterized by graphical data "as shown in the figure." Such data include, for example, powder X-ray diffraction, FTIR, and Raman spectroscopy. Those skilled in the art understand that factors such as variations in instrument type, response, and variations in sample orientation, sample concentration, and sample purity may result in small variations in such data when presented in graphical form, such as variations relating to precise 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 two sets of graphical data relate to the same crystalline form are well within the knowledge of those skilled in the art.

[0188] As used herein, the term "reflection" with respect to powder X-ray diffraction means a peak in an X-ray diffraction pattern which, at certain diffraction angles (Bragg angles), is caused by constructive interference of X-rays scattered by parallel planes of atoms in a solid material which is distributed in a sequential and repeating pattern in a long-range positional order. Such solid materials are classified as crystalline materials, while amorphous materials are defined as solid materials which lack long-range order and only show short-range order, thus resulting in broad scattering. According to the literature, long-range order, for example, extends over about 100 to 1000 atoms, while short-range order only exceeds 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, p. 3).

[0189] The term "substantially the same" with respect to powder X-ray diffraction means that the variability of the positions and relative intensities of the reflections needs to be taken into account. For example, a typical accuracy of the 2-theta values ​​is within ±0.2° 2-theta, preferably within ±0.1° 2-theta.

[0190] Furthermore, one skilled in the art will appreciate that relative reflection intensity will show device-to-device variability as well as variability due to crystallinity, preferred orientation, particle size, sample preparation and other factors known to those skilled in the art, and should be taken only as a qualitative measurement.

[0191]

[0046] The terms "solid form" or "solid state form" as used interchangeably herein refer to any crystalline and / or amorphous phase of a compound.

[0192] As used herein, the term "amorphous" refers to a solid form of a compound that is not crystalline. An amorphous compound has no long-range order and does not display a definitive X-ray diffraction pattern with reflections.

[0193] As used herein, the term "polymorph" refers to crystalline forms having the same chemical composition but differing in the spatial arrangement of the molecules, atoms and / or ions forming the crystals.

[0194] As used herein, the term "eutectic material" refers to a crystalline material comprising two or more different molecules and / or ionic compounds associated by non-ionic and non-covalent bonds within the same crystal lattice, wherein at least two of the individual molecules and / or ionic compounds are solid at room temperature.

[0195] As used herein, the term "hydrate" refers to a crystalline solid in which water is incorporated into or contained in the crystal structure (e.g., as part of the crystal structure) or trapped in the crystal (water inclusions). Thus, water can be present in stoichiometric amounts or in non-stoichiometric amounts. When water is present in stoichiometric amounts, hydrates can be referred to by adding a Greek numeral prefix. For example, a hydrate may be referred to as a hemihydrate or as a monohydrate, depending on the stoichiometry of the water / compound. Water content can be measured, for example, by Karl-Fischer-Coulometry.

[0196] As used herein, the term "dehydrating" or "dehydration" describes the at least partial removal of water from the crystal structure of a host molecule.

[0197] As used herein, the term "solvate" refers to a crystalline solid in which one or more organic solvents are incorporated into or contained in a crystal structure (e.g., as part of a crystal structure) or trapped in a crystal (water inclusions). Therefore, one or more organic solvents can be present in a stoichiometric amount or a non-stoichiometric amount. When one or more organic solvents are present in one or more stoichiometric amounts, a solvate can be referred to by adding a Greek numeral prefix. For example, depending on the stoichiometry of one or more solvents / compounds, a solvate can be referred to as a semisolvate or a monosolvate. Solvent content can be measured, for example, by GC, NMR, SXRD and / or TGA / MS.

[0198] As used herein, the term "non-hygroscopic" refers to compounds that show up to 2 w-% water uptake based on the weight of the compound in an adsorption cycle at a relative humidity ranging from 0 to 95% RH and at a temperature of (25.0±0.1)°C when measured by GMS.

[0199] As used herein, the term "about" means within a range of statistically significant values. Such ranges may be within an order of magnitude of the indicated value or range, typically within 10%, more typically within 5%, even more typically within 1%, and most typically within 0.1%. Sometimes, such ranges may be within the experimental error range, which is a typical value for a standard method used to measure and / or determine a given value or range.

[0200] As used herein, with respect to a composition comprising a specific 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, the term "substantially free of any other solid form" means that the composition comprises at most 20 w-%, preferably at most 10 w-%, more preferably at most 5 w-%, even more preferably at most 2 w-%, and most preferably at most 1 w-% 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.

[0201] As used herein, "substantially pure" when used with respect to a form means a compound having a purity of greater than 90 w-%, including greater than 90 w-%, 91 w-%, 92 w-%, 93 w-%, 94 w-%, 95 w-%, 96 w-%, 97 w-%, 98 w-%, and 99 w-%, 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, based on the weight of the compound. The remaining material comprises one or more other forms of the compound, and / or reaction impurities and / or processing 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 can be considered to be substantially pure in that it has a purity of greater than 90 w-% as measured by means known and generally accepted at this time in the art, with the remaining less than 10 w-% of material comprising one or more other forms of [Compound ABC] and / or reaction impurities and / or processing impurities.

[0202] Crystalline Form A

[0203] In a further aspect, the present disclosure provides a 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. Table 1 shows the most prominent X-ray powder diffraction peaks of 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.

[0204] Table 1. Most prominent X-ray powder diffraction peaks of Form A

[0205]

[0206] One embodiment of the present disclosure 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, which Form A is characterized in that when subjected to a temperature in the range of 20° C. to 30° C. and with a Cu-Kα wavelength of 0.15419 nm, 1,2 When measured radiometrically, an XRPD pattern having reflections at the following 2-theta angles:

[0207] (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)° and (22.4±0.2)° .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)°. 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)°, (1 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)°.

[0208] In yet 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 in that when subjected to a temperature in the range of 20° C. to 30° C. with a Cu-Kα ion having a wavelength of 0.15418 nm, the crystalline form is ... 1,2 When measuring radiation, it is consistent with the disclosure of Figure 1 Essentially the same XRPD pattern is shown.

[0209] 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), which is characterized by having a melting onset temperature of 98°C ± 5°C when measured by DSC at a heating rate of 10K / min.

[0210] 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), which is characterized by having a melting point peak maximum temperature of 104°C ± 5°C when measured by DSC at a heating rate of 10K / min.

[0211] Crystalline Form B

[0212] In a further aspect, the present disclosure 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. Table 2 shows the most prominent X-ray powder diffraction peaks of 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.

[0213] Table 2. Most prominent X-ray powder diffraction peaks of Form B

[0214]

[0215] In one embodiment, the present disclosure 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 in that when subjected to a temperature in the range of 20° C. to 30° C. and with a Cu-Kα ion having a wavelength of 0.15419 nm, the 1,2 When measured radiometrically, an XRPD pattern having reflections at the following 2-theta angles:

[0216] (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)° 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)°.

[0217] In yet 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 in that when subjected to a temperature in the range of 20° C. to 30° C. with a Cu-Kα ion having a wavelength of 0.15418 nm, the crystalline form is characterized in that the crystalline form is subjected to a temperature in the range of 20° C. to 30° C. with a Cu-Kα ion having a wavelength of 0.15418 nm. 1,2 When measuring radiation, it has the same Figure 2 Essentially the same XRPD pattern is shown.

[0218] 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 in that it has a melting onset temperature of 184°C ± 5°C when measured by DSC at a heating rate of 10K / min.

[0219] 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), which is characterized by having a melting point peak maximum temperature of 185°C ± 5°C when measured by DSC at a heating rate of 10K / min.

[0220] Crystalline Form C

[0221] In further embodiments, the present disclosure 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. Table 3 shows the most prominent X-ray powder diffraction peaks of 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.

[0222] Table 3. Most prominent X-ray powder diffraction peaks of Form C

[0223]

[0224] In one embodiment, the present disclosure 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 in that when subjected to a temperature in the range of 20° C. to 30° C. and with a Cu-Kα ion having a wavelength of 0.15419 nm, the 1,2 When measured radiometrically, an XRPD pattern having reflections at the following 2-theta angles:

[0225] (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)° 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)° and (22.7±0.2)° 5.5±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)°, (2 2.0±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)°. .

[0226] In yet 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 in that when subjected to a temperature in the range of 20° C. to 30° C. with a Cu-Kα ion having a wavelength of 0.15418 nm, the crystalline form is characterized in that the crystalline form is subjected to a temperature in the range of 20° C. to 30° C. with a Cu-Kα ion having a wavelength of 0.15418 nm. 1,2 When measuring radiation, it has the same Figure 3 Essentially the same XRPD pattern is shown.

[0227] 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), which is characterized by having a melting onset temperature of 178°C ± 5°C when measured by DSC at a heating rate of 10K / min.

[0228] 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), which is characterized by having a melting point peak maximum temperature of 178°C ± 5°C when measured by DSC at a heating rate of 10K / min.

[0229] Hydrate A

[0230] In another 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. Table 4 shows the most prominent X-ray powder diffraction peaks of 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.

[0231] Table 4. Most prominent X-ray powder diffraction peaks of Hydrate A

[0232]

[0233] In one embodiment, the present disclosure provides Hydrate A 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 Hydrate A being characterized by having an XPRD pattern comprising reflections at the following 2-θ angles:

[0234] (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)°, (23.5±0.2)° and (25.0±0.2)°. 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)°; (when at a temperature in the range of 20°C to 30°C, using a Cu-Kα 1,2 Radiation measurement).

[0235] In yet 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 in that when subjected to a temperature in the range of 20° C. to 30° C., the crystalline form is subjected to a temperature in the range of 100° C. to 30 ...1,2 When measuring radiation, it has the same Figure 4 Essentially the same XRPD pattern is shown.

[0236] 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), which is characterized by a broad endothermic event with a peak maximum temperature of 109±10°C when measured by DSC at a heating rate of 10K / min.

[0237] Hydrate B

[0238] In another 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. Table 5 shows the most prominent X-ray powder diffraction peaks of 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.

[0239] Table 5. Most prominent X-ray powder diffraction peaks of Hydrate B

[0240]

[0241] In one embodiment, the present disclosure 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 in that when subjected to a temperature in the range of 20° C. to 30° C., a Cu-Kα ion having a wavelength of 0.15419 nm is used. 1,2 When measured radiometrically, an XRPD pattern having reflections at the following 2-theta angles:

[0242] (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)°, (19.6±0.2)°, and (20.6±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)°;

[0243] In yet 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 in that when subjected to a temperature in the range of 20° C. to 30° C., the crystalline form is ... 1,2 When measuring radiation, it has the same Figure 5 Essentially the same XRPD pattern is shown.

[0244] 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), which is characterized by a broad endothermic event with a peak maximum temperature of 93±10°C when measured by DSC at a heating rate of 10K / min.

[0245] 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 substantially 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, the composition of the present disclosure 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 comprises up to 20 w-%, preferably up to 10 w-%, more preferably up to 5 w-%, 4 w-%, 3 w-%, 2 w-% or 1 w-% 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.

[0246] Ca V 1.2-HEK293 (AUX) cell line

[0247] In one aspect, the disclosure relates to a cell comprising a human CaV1.2α1C (alpha1C) subunit (encoded by human CACNA1C transcript variant 14; GenBank ID: NM_001129840), an α2Δ (alpha2delta, α2Δ2) auxiliary subunit (encoded by human CACNA2D2 transcript variant 3; GenBank ID: NM_001174051), and a β2 (beta2) 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 having biological activity. In one aspect, the cell is contained in a stable cell line (e.g., HEK293) that constitutively expresses the α1C subunit and doxycycline-inducible expression of the α2Δ2 subunit and the β2 subunit. In another aspect, the stable cell line is produced by DNA transfection or viral transduction, e.g., via a lentivirus or baculovirus. In one aspect, the cell is contained in a cell line (e.g., HEK293) from transient DNA transfection that constitutively expresses the α1C subunit and doxycycline-inducible expression of the α2Δ2 subunit and the β2 subunit. In another aspect of the present disclosure, the compound is Ca V 1.2 Activators. In another aspect, the disclosure relates to cells for use in methods of identifying an agent for treating, preventing, and / or diagnosing a disease or disorder (e.g., 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 aspects, the agent is Ca V 1.2 Activator.

[0248] Intermediates and Examples

[0249] The following examples are intended to illustrate the present disclosure and should not be construed as limiting thereof.

[0250] Each of these examples was separated into their single enantiomers and tested in the Sophion Qpatch assay described in the Biological Data section below. However, the stereochemistry of each enantiomer has not yet been determined. The stereochemistry of the active enantiomers of 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) and Example 9 (methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate) was analyzed using single crystal x-ray crystallography and it was determined that the active enantiomer was the R-enantiomer. Therefore, it is assumed that the R-enantiomer 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 depicted below is the active enantiomer.

[0251]

[0252] Methyl (R)-2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0253]

[0254] Methyl (R)-2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0255] All active enantiomers assumed to have the R configuration are given example numbers (Examples 1, 2, 3, etc.). All other isomers isolated from the synthesis are given example numbers with letters (Examples 1b, 2b, 3b, etc.). Although there is strong evidence that the R configuration is the desired stereochemistry, it is still possible that the S-enantiomer is the active enantiomer.

[0256] Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of final products, intermediates and starting materials are confirmed by standard analytical methods (e.g., microanalysis and spectroscopic characteristics (e.g., MS, IR, NMR)).

[0257] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds disclosed herein are commercially available or can be prepared by organic synthesis methods known to those of ordinary skill in the art. In addition, the compounds disclosed herein can be prepared by organic synthesis methods known to those of ordinary skill in the art, as shown in the following examples. The abbreviations used are conventional abbreviations in the art or the following abbreviations:

[0258] 1 H NMR Proton nuclear magnetic resonance

[0259] AUTO Ca V 1.2 Auxiliary subunits of the channel

[0260] C degrees Celsius

[0261] CD3OD Methanol-d4

[0262] CDCl3 Chloroform-d

[0263] CHO Chinese Hamster Ovary Cells

[0264] Ct threshold cycle in quantitative polymerase chain reaction assay

[0265] d Doublet

[0266] DAST Diethylaminosulfur trifluoride

[0267] DCM Dichloromethane

[0268] dd double doublet

[0269] DME 1,4-dimethoxyethane

[0270] DMEM Dulbecco's Modified Eagle's Medium

[0271] DMF N,N-Dimethylformamide

[0272] DMSO Dimethyl sulfoxide

[0273] DMSO-d6 Dimethyl sulfoxide-d6

[0274] D-PBS Dulbecco's phosphate buffered saline

[0275] EC50 half maximal effective concentration

[0276] EDTA Ethylenediaminetetraacetic acid

[0277] EGTA Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

[0278] Eq equivalent

[0279] EtOAc Ethyl acetate

[0280] FAM 6-Carboxyfluorescein

[0281] FCS furin cleavage site

[0282] FRT flippase recognition target site

[0283] g

[0284] h hour

[0285] H2O water

[0286] HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid

[0287] HOBt 1-Hydroxy-7-azabenzotriazole

[0288] HPLC High Pressure Liquid Chromatography

[0289] HRMS High Resolution Mass Spectrometry

[0290] Hrs Hours

[0291] Hz Hertz

[0292] IACUC Institutional Animal Care and Use Committee

[0293] IPA Isopropyl Alcohol

[0294] kg kilogram

[0295] L Liter

[0296] LCMS Liquid chromatography mass spectrometry

[0297] M Moore

[0298] m multiplet

[0299] m / z mass-to-charge ratio

[0300] mg milligram

[0301] MHz Megahertz

[0302] min

[0303] mL milliliters

[0304] ml milliliters

[0305] mL / min milliliters / minute

[0306] mm Millimeters

[0307] mM millimole

[0308] mmol millimole

[0309] mRNA messenger RNA

[0310] MS mass spectrometry

[0311] mV millivolt μl

[0312] N equivalent concentration

[0313] n-BuLi n-butyllithium

[0314] NMR Nuclear Magnetic Resonance

[0315] NOESY Nuclear Overhauser Effect Spectrum

[0316] pCMV Cytomegalovirus promoter

[0317] P2A is derived from the peptide self-cleavage sequence of porcine teschovirus-1

[0318] PdCl2(dppf) Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[0319] PD Pharmacodynamics

[0320] PK Pharmacokinetics

[0321] ppm parts per million

[0322] PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[0323] QT The time interval between the Q wave and the T wave of the electrocardiograph

[0324] rac racemic

[0325] rpm revolutions per minute

[0326] RNA Ribonucleic acid

[0327] RT Room temperature

[0328] Rt retention time

[0329] RT-PCR Reverse transcription-polymerase chain reaction

[0330] s Single peak

[0331] SFC Supercritical Fluid Chromatography

[0332] SFM serum-free medium

[0333] SNP Single Nucleotide Polymorphism

[0334] t Triplet

[0335] TFA Trifluoroacetic acid

[0336] THF Tetrahydrofuran

[0337] uL microliter

[0338] Um micrometer

[0339] UPLC Ultra-Performance Liquid Chromatography

[0340] UV

[0341] VIC 2′-Chloro-7′phenyl-1,4-dichloro-6-carboxy-fluorescein

[0342] v / v volume / volume percentage

[0343] Small molecule X-ray crystallography

[0344] Data Collection

[0345] Intensity data were collected at 100 K on a Bruker AXS three-circle diffractometer with monochromatic Cu (Kα)-radiation, a microfocus rotating anode generator, and a Smart 6000CCD detector using SMART software (Bruker AXS (2003)). 16ω scans were performed at different φ-positions to ensure appropriate data redundancy. Data processing and global cell refinement were performed using Saint (Bruker AXS (2012)). A semi-empirical absorption correction was applied, which was based on the intensity of symmetry-related reflections measured at different angle settings using SADABS version 2016 / 2 (Krause L (2015)). The extinction coefficient was accurate to 0.00048 (11). Crystal data, data collection parameters, and convergence results are listed.

[0346] Structural solutions and refinement

[0347] The structure was solved by a two-dimensional recycling method and subsequent DF synthesis and refined based on full-matrix least squares fit on F2 using the SHELXTL program suite (Sheldrick GM (2001)) together with SHELXL-2013 / 4.

[0348] References:

[0349] 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.

[0350] Bruker AXS (2005) SMART V5.632. Bruker AXS Inc., Madison, WI, USA.

[0351] Bruker AXS (2012) SAINT V7.36A. Bruker AXS Inc., Madison, WI, USA.

[0352] 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.

[0353] Spek AL (2003) Single-crystal structure validation with the program PLATON. J. Appl.

[0354] Cryst.; 36:7 - 13.

[0355] Sheldrick GM (2001) SHELXTL V6.12. Bruker AXS Inc.. Madison, WI, USA.

[0356] LCMS Method 1:

[0357] Instrument: Waters Acquity UPLC, photodiode array detector; Column: Acquity UPLC BEH C 181.7 μm, 21x30 mm; 2 min run time, 2% solvent B from 0 to 0.1 min, 2% → 98% solvent B: solvent A from 0.1 to 1.8 min, 98% solvent B for 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.

[0358] LCMS method 2:

[0359] Instrument: Waters Acquity UPLC, photodiode array detector; Column: Acquity UPLC BEH C 18 1.7 μm 21x50 mm; 2 min run time, 2% solvent B from 0 to 0.1 min, 2% → 98% solvent B: solvent A from 0.1 to 1.8 min, 98% solvent B for 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.

[0360] LCMS method 3:

[0361] Instrument: Waters Acquity UPLC, photodiode array detector; column: Acquity UPLC BEH C 18 1.7 μm 21x30 mm; 5.2 min run time, 2% → 98% solvent B: solvent A from 0 to 5.15 min, 98% solvent B from 5.15 to 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.

[0362] LCMS Method 4:

[0363] Instrument: Waters Acquity UPLC, photodiode array detector; column: Acquity UPLC BEH C 181.7 μm 21x30 mm; 5.2 min run time, 2% → 98% solvent B: solvent A from 0 to 5.15 min, 98% solvent B from 5.15 to 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.

[0364] LCMS Method 5:

[0365] Instrument: Agilent 1200LC / G1956A, diode array detector; column: Chromolith Flash C 18 , 1.6 micron 2x25mm; 1.5 minute run time, 5%→95% solvent B: solvent A (from 0→1.2 minutes) and then 95% solvent B (from 1.21→1.5 minutes). Solvents: solvent A=0.0375% TFA (v / v) in water, solvent B=0.01875% TFA (v / v) in acetonitrile. 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.

[0366] LCMS Method 6:

[0367] Instrument: SHIMADZU LCMS-2020, photodiode array detector; column: Kinetex EVO C 18 , 5uM, 1x30mm; 1.55 min run time, 5%→95% solvent B: solvent A (from 0→1.20 min) and then 95% solvent B (from 1.21 min to 1.55 min). Solvents: solvent A=0.025% NH4OH (v / v) in water, solvent B=acetonitrile. Injection volume 2-5μL; UV detection 220 and 254nM, mass detection 100-1000 (electrospray ionization); column, at 40°C; flow rate 1.5mL / min.

[0368] LCMS Method 7:

[0369] Instrument: API2000, column: Mercury MS Synergi 2μm, 20X4.0mm, 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 2.0mL / min; UV detection array 190-400, mass detection 100-1000 (electrospray ionization); column temperature 30°C.

[0370] LCMS Method 8:

[0371] Instrument: API3000, column: Synergi 2.5μm MAX-RP, 20X4.0mm 100A Mercury; gradient: 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 2.0mL / min; UV detection array 190-400 (total wavelength chromatogram), mass detection 100-1000 (electrospray ionization); column temperature 30°C.

[0372] LCMS Method 9:

[0373] Instrument: API3000, column: Synergi 2.5μm, 50x4.6mm, MAX-RP 100A; Gradient: 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 1.2mL / min; UV detection array 190-400 (total wavelength chromatogram), mass detection 100-1000 (electrospray ionization); column temperature 30°C.

[0374] LCMS Method 10:

[0375] Shimadzu, column: Mercury MS Synergi 2.5μm, 20X4.0mm, 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 2.0mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ionization); column temperature 40°C.

[0376] LCMS Method 11:

[0377] Shimadzu, column: Kinetex 5μm EVO C18 100A, (100x2.1mm); 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 1.4mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ionization); column temperature 40°C.

[0378] LCMS Method 12:

[0379] Shimadzu, column: Synergi 2.5μm MAX-RP 100A, (20X4.0mm) 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 2.0mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ionization); column temperature 40°C.

[0380] LCMS Method 13:

[0381] Acquity, column: UPLC BEH C18 1.7 μm 2.1x50 mm; gradient: A-0.1% formic acid in water / B-acetonitrile: 2.2 min run time, 2%→98% solvent B: solvent A (from 0→1.76 min) and then 95% solvent B (from 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

[0382] Preparative HPLC method for purification:

[0383] Method 1: HPLC column: XBRIDGE-C18 (19.0x150mm, 5 microns), mobile phase-A: 0.1% TFA in H2O, B: CH3CN, gradient (time / %B): 0 / 20, 2 / 20, 8 / 50) flow rate: [19mL / min].

[0384] Method 2: HPLC column: ZORBAX ECLIPSE XDB C18 (21.2X150 mm, 5 microns), mobile phase-A: 0.1% TFA in H2O, B: CH3CN, gradient (time / %B): 0 / 10, 2 / 20, 10 / 40, flow rate: [20 mL / min].

[0385] Method 3: HPLC [column: XBRIDGE C18 (21.2x150mm, 5 micron), mobile phase-A: 10mM NH4HCO3 in water, B: CH3CN, gradient (time / %B): 0 / 10, 2 / 20, 8 / 50, flow rate: [18mL / min].

[0386] 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)

[0387] Method 5: HPLC column: KINETEX EVO 5μC18 (21.2X150mm), mobile phase: water (A) CH3CN (B), gradient (time / %B): 0 / 20, 2 / 30, 7 / 70, and flow rate: [18mL / min].

[0388] Method 6: HPLC column: KINETEX C18, (21.2x150 mm), mobile phase: A: water, B: CH3CN:MeOH, gradient (time / %B): 0 / 20, 2 / 30, 7 / 70, flow rate: 18 mL / min].

[0389] Method 7: HPLC column: KINETEX (21.2 x 150 mm, 5 microns), mobile phase: A = 0.05% TFA in water, B = CH3CN, gradient (time / %B): 0 / 20, 2 / 30, 10 / 60, flow rate: 20 mL / min].

[0390] Chiral preparative HPLC method for separation of isomers:

[0391] Method 1: Column: CHIRALPAK IC (10x250mm, 5 microns), mobile phase: hexane (A) IPA:MeOH, 1:1 (B); flow rate: 8 mL / min; isocratic: 96:04 (A:B).

[0392] Method 2: Column: REGIS WELKO (250x10 mm, 5 microns), mobile phase: hexane (A): EtOH, 1:1 (B); flow rate: 9 mL / min; isocratic: 85:15 (A:B).

[0393] Method 3: Column: CHIRALPAC IG (250x10 mm, 5 microns), mobile phase: IPA (A): MeOH, 1:1 (B); flow rate: 6 mL / min; isocratic: 98:2 (A:B).

[0394] Method 4: Column: LUX cellulose-4 (10x250mm, 5 microns), mobile phase: hexane (A) EtOH:IPA 1:1 (B); flow rate: 8 mL / min; isocratic: 90:10 (A:B).

[0395] Method 5: Column: LUX cellulose-4 (10x250mm, 5 microns), mobile phase: hexane (A) EtOH: 1:1 (B); flow rate: 8 mL / min; isocratic: 90:10 (A:B).

[0396] Method 6: Column: LUX cellulose-4 (10x250mm, 5 microns), mobile phase: hexane (A); EtOH:MeOH 1:1 (B); flow rate: 18 mL / min; isocratic: 90:10 (A:B).

[0397] Method 7: Column: LUX cellulose-4 (21.2x250 mm, 5 microns), mobile phase: hexane (A); EtOH:MeOH 1:1 (B); flow rate: 19 mL / min; isocratic: 80:20 (A:B).

[0398] Method 8: Column: REGIS (10X250mm, 5 microns), mobile phase: CO2 (A) MeOH:EtOH 1:1 (B); flow rate: 13mL / min, isocratic: 80:20 (A:B).

[0399] Method 9: Column: LUX cellulose-4 (10x250 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).

[0400] Chiral analytical HPLC method for analysis of separated isomers:

[0401] Method 1: Column: Lux, cellulose-4 (250X4.6mm, 5 microns); Mobile phase: A = n-hexane, B = 0.1% TFA in ethanol; 1 mL / min; Isocratic: 70:30 (A:B)

[0402] Method 2: Column: LUX cellulose-4 (4.6x250mm, 5 microns); Mobile phase: Hexane (A) EtOH: 1:1 (B); Flow rate: 1 mL / min; Isocratic: 50:50 (A:B).

[0403] Method 3: Column: REGIS, (S,S) WHELK-01 (250X4.6mm, 5 microns); Mobile phase: A = n-hexane, B = ethanol; Flow rate: 1 mL / min; Isocratic: 70:30 (A:B).

[0404] Intermediate A: Formation of ethyl 4-acetoxy-3-oxobutyrate

[0405]

[0406] 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 hours. The solvent was dissolved in water (2 L) and extracted into ethyl acetate (1 L x 4 times). The EtOAc phase was combined and washed with saturated NaHCO3 solution (2 L), brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica flash chromatography ((0 → 15%) ethyl acetate in petroleum ether) to give the title compound ethyl 4-acetoxy-3-oxobutanoate (152 g) as a light brown liquid.

[0407] 1 H NMR (400MHz, CDCl3) δ4.78 (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).

[0408] Intermediate B: Formation of methyl (Z)-3-amino-4-fluorobut-2-enoate

[0409] Method 1:

[0410]

[0411] Under nitrogen atmosphere, a solution of methyl acetate (36.5 g, 492.71 mmol) in tetrahydrofuran (200 mL) was cooled to -78 ° C, lithium diisopropylamide (246.44 mL, 2.0 M, 492.71 mmol) in THF was slowly added to the reaction over a period of 20 min, the resulting mixture was stirred at -78 ° C for 1 h, and then 2-fluoroacetonitrile (19.4 g, 328.9 mmol) in tetrahydrofuran (150 mL) solution was added dropwise. The reaction mixture was stirred at -78 ° C for another 1 h, then saturated ammonium chloride solution (200 mL) was added, and the product was extracted into ethyl acetate (5 L). EtOAc was washed with saturated brine solution (500 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography ((0→10%) ethyl acetate in petroleum ether) to give the title compound methyl (Z)-3-amino-4-fluorobut-2-enoate (16 g) as a white crystalline solid.

[0412] Method 2:

[0413]

[0414] Step 1: Under nitrogen atmosphere, a solution of methyl acetate (83.78g, 1131.0mmol) in tetrahydrofuran (800mL) was cooled to -78°C, then lithium diisopropylamide (565.5mL, 2.0M, 1131.0mmol) in THF was slowly added to the reaction over a 20min period. The resulting mixture was stirred for 1h at -78°C, then ethyl 2-fluoroacetate (100g, 942.5mmol) was added dropwise in tetrahydrofuran (200mL) solution, and the reaction mixture was stirred for another 1h at -78°C. Saturated ammonium chloride solution (200mL) was added to the reaction mixture, and the product was extracted into ethyl acetate (5L). EtOAc was washed with saturated brine solution (500mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give yellow crystals of methyl 4-fluoro-3-oxobutanoate (60 g).

[0415] 1 H NMR (400MHz, CDCl3) δ4.97 (s, 1H), 4.85 (s, 1H), 3.76 (d, J = 2.3Hz, 3H), 3.62 (d, J = 3.7Hz, 2H).

[0416] Step 2: In a sealed tube at room temperature, methyl 4-fluoro-3-oxobutanoate (from step 1, 60 g) was added a saturated ammonia solution in methanol (300 mL). The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to give the title compound methyl (Z)-3-amino-4-fluorobut-2-enoate (51 g) as a white solid.

[0417] 1 H NMR (300MHz, DMSO-d6) δ4.98(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).

[0418] General Program I

[0419]

[0420] 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 hours. The solvent was removed under reduced pressure to give the title compound (crude).

[0421] Step 2: Add potassium carbonate (5mmol) to the crude intermediate from step 1 in methanol (10mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and added to water. The product was extracted into ethyl acetate (100mL), 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.

[0422] General Program II

[0423]

[0424] 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) were added to a solution of aldehyde (1 mmol) in MeOH (10 mL). The resulting solution was stirred at 75 ° C for 16-48 hours. The solvent was removed under reduced pressure, and the product was purified using silica flash chromatography.

[0425] 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

[0426]

[0427] Step 1: 2-(2-Bromo-3-fluorophenyl)-1,3-dioxolane

[0428]

[0429] To a solution of 2-bromo-3-fluorobenzaldehyde (60g, 295.56mmol) and ethylene glycol (65.4mL, 1182.2mmol) in toluene (600mL) was added p-toluenesulfonic acid monohydrate (28.11g, 147.78mmol). The resulting solution was stirred at 120°C using a dean-stark apparatus for 24 hours. The reaction mixture was poured into water (2L) and extracted into ethyl acetate (3L). EtOAc was washed with saturated NaHCO3 solution (1L), brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (60g) as a colorless liquid.

[0430] 1 H NMR (400MHz, CDCl3) δ7.42-7.37(m,1H),7.34-7.29(m,1H),7.16-7.10(m,1H),6.10(s,1H),4.19-4.09(m,4H).

[0431] Step 2: 2-(3-Fluoro-2-vinylphenyl)-1,3-dioxolane

[0432]

[0433] To a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, 15 g, 60.72 mmol) and potassium vinyl trifluoroborate (16.26 g, 121.45 mmol) in isopropanol (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 for 10 min and stirred at 80° C. for 16 hours. 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 the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane (7.5 g) as a colorless liquid.

[0434] 1H NMR (400MHz, CDCl3) δ7.45-7.41(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).

[0435] Step 3: 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3-dioxolane

[0436]

[0437] 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 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). This was washed with water (50 mL), brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3-dioxolane (8 g) as a colorless liquid.

[0438] 1 H NMR (400MHz, CDCl3) δ7.42 (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).

[0439] Step 4: 2-(2,2-difluorocyclopropyl)-3-fluorobenzaldehyde

[0440]

[0441] 6N HCl (10 mL) was added to a solution of 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 8 g, 32.76 mmol) and in diethyl ether (80 mL). The resulting solution was stirred at room temperature for 2 hours. This was washed with water (50 mL), saturated NaHCO3 solution (100 mL), brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2,2-difluorocyclopropyl)-3-fluorobenzaldehyde (3.8 g) as a colorless liquid.

[0442] 1 H NMR (400MHz, CDCl3) δ10.28 (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).

[0443] Step 5: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0444]

[0445] 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 is in the next step without further purification and analysis.

[0446] 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

[0447]

[0448] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 5, 1.4 g, 2.884 mmol). The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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 chirally separated into two products using chiral SFC: column: Lux-cellulose-2 21x250mm 5um; flow rate: 80 g / min; co-solvent: 20% 1:1 MeOH:IPA; detection: 344 nm; BPR set point: 125 bar.

[0449] The previously separated peaks 1 and 2 were separated into 4 isomers using chiral SFC: Column: WO1 SS 21x250 mm; Flow rate: 80 g / min; Co-solvent: 15% IPA; Detection: 344 nm; BPR set point: 150 bar.

[0450] Example 1

[0451] 20 mg of the title compound as the second eluting stereoisomer as a white solid (61%)

[0452] SFC Rt = 2.49; Mobile phase: 5%-55% (1:1) MeOH IPA w / 10 mM NH4OH in CO2, 5 mL / min; Column: Lux Cellulose-2 4.6x100 mm 5 μm

[0453] LCMS Rt=2.12min;MS m / z 398.3[M+H]+;[Method 3]

[0454] 1 H NMR (400MHz, DMSO-d6) δ10.13(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),5.03-4.73(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).

[0455] Example 1b

[0456] 15 mg of the first eluting stereoisomer as a white solid (46%)

[0457] SFC Rt = 2.42; Mobile phase: 5%-55% (1:1) MeOH IPA w / 10 mM NH4OH in CO2, 5 mL / min; Column: Lux Cellulose-2 4.6x100 mm 5 μm

[0458] LCMS Rt=2.15min;MS m / z 398.2[M+H]+;[Method 3]

[0459] 1 H NMR(400MHz, DMSO-d6)δ10.08(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),5.2 7(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).

[0460] Example 1c

[0461] 24 mg of the third eluting stereoisomer as a white solid (73%)

[0462] SFC Rt = 2.73 min; Mobile phase: 5%-55% (1:1) MeOH IPA w / 10 mM NH4OH in CO2, 5 mL / min; Column: Lux Cellulose-2 4.6x100 mm 5 μm

[0463] LCMS Rt=2.16min;MS m / z 398.3[M+H]+;[Method 3]

[0464] 1 H NMR (400MHz, DMSO-d6) δ10.13(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).

[0465] Example 1d

[0466] 15 mg of the fourth eluting stereoisomer as a white solid (46%)

[0467] SFC Rt = 2.78 min; Mobile phase: 5%-55% (1:1) MeOH IPA w / 10 mM NH4OH in CO2, 5 mL / min; Column: Lux Cellulose-2 4.6x100 mm 5 μm

[0468] LCMS Rt=2.11min;MS m / z 398.1[M+H]+;[Method 3]

[0469] 1 H NMR: (400MHz, DMSO-d6) δ10.08(d,J=3.3Hz,1H),7.33(td,J=8.0,5.6Hz,1H),7.14-6.94(m,2H),5.72(dd,J=47.8,4.8 Hz, 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).

[0470] Example 2: Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0471]

[0472] Step 1: 2-Cyclopropyl-3-fluorobenzaldehyde

[0473]

[0474] 2N KCO (25.5 mL, 182.16 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were added 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). DCM (6.03 g, 7.38 mmol) was used. The resulting solution was degassed with argon for 10 min and stirred at 100 ° C for 4 hours. 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 NaSO. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→1%) ethyl acetate in petroleum ether) to give the title compound 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane (11.2 g) as a colorless liquid.

[0475] 1 H NMR (300MHz, CDCl3) δ10.70 (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).

[0476] Step 2: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclopropyl-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0477]

[0478] The title compound was synthesized using Step 1 of General Procedure I (using 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).

[0479] LCMS Rt=1.806min;MS m / z 450.3[M+H]+;[Method 7]

[0480] Step 3: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0481]

[0482] The title compound was synthesized using Step 2 of General Procedure I (using the intermediate from Step 2, 7.0 g, 15.57 mmol). The crude product was purified by silica flash chromatography ((0→50%) ethyl acetate in petroleum ether) to afford 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.

[0483] 150 mg of the racemic mixture were separated into its enantiomers using chiral preparative HPLC [Method 6].

[0484] Example 2

[0485] 50 mg of the first eluting enantiomer was obtained as a white solid.

[0486] Chiral HPLC Rt=6.129min[Chiral analysis method 1]

[0487] LCMS Rt = 1.538 min; MS m / z 360.0 [MH]-; [Method 7]

[0488] 1 H NMR (400MHz,CDCl3)δ7.15-7.05(m,1H),6.92(ddd,J=7.8,1.2,0.6Hz,1H),6.82(ddd,J=10.8,8.2,1.3Hz,1H),5.78(d,J=0.9Hz,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.

[0489] 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

[0490] 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

[0491]

[0492] Step 1: 2-(2-Bromo-3,5-difluorophenyl)-1,3-dioxolane

[0493]

[0494] The title compound was synthesized according to a procedure similar to step 1 of Example 1 using 10 g of 2-bromo-3,5-difluorobenzaldehyde to obtain 11.5 g of the desired product 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane.

[0495] 1 H NMR (300MHz, CDCl3) δ7.20-7.15(m,1H),6.49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H).

[0496] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane

[0497]

[0498] 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).

[0499] 1 H NMR (300MHz, CDCl3) δ7.20-7.16(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).

[0500] Step 3: 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-1,3-dioxolane

[0501]

[0502] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (from step 2, 2.4g, 11.31mmol) and trifluoromethyltrimethylsilane (16.1g, 113.1mmol) in tetrahydrofuran (15mL) was added sodium iodide (850mg, 5.65mmol). The resulting solution was stirred at 65°C for 24 hours. The reaction mixture was cooled to room temperature, and trifluoromethyltrimethylsilane (16.1g, 113.1mmol) and sodium iodide (850mg, 5.65mmol) were added, and the resulting solution was stirred at 65°C for 24 hours. The reaction mixture was then distributed between ethyl acetate and water, the organic phase was washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compound 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-1,3-dioxolane (1.5g) as a brown liquid.

[0503] 1 H NMR (400MHz, CDCl3) δ7.26-7.14(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).

[0504] Step 4: 2-(2,2-difluorocyclopropyl)-3,5-difluorobenzaldehyde

[0505]

[0506] 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 hours. This 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 the crude product was purified by flash chromatography on silica ((0→5%) ethyl acetate in hexanes) to give the title compound 2-(2,2-difluorocyclopropyl)-3,5-difluorobenzaldehyde (1.25 g) as a colorless liquid.

[0507] 1 H NMR (300MHz, CDCl3) δ10.22(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).

[0508] Step 5: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0509]

[0510] The title compound was synthesized using general procedure 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).

[0511] LCMS Rt=1.683min;MS m / z 504[M+H]+;[Method 7]

[0512] 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

[0513]

[0514] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 5, 2.5 g, 4.97 mmol). The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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-O1 SS 21x250 mm; instrument: Thar80_SN4740).

[0515] Example 3

[0516] 20.9 mg of the first eluting stereoisomer as a white solid (68.8%).

[0517] SFC Rt = 2.40 min ((SS) Whelk-O1 4.6 x 100 mm, 5 μm, 5% → 55% IPA in CO2).

[0518] LCMS Rt=2.27min;MS m / z 416.2[M+H]+;[Method 4]

[0519] 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).

[0520] Example 4

[0521] 20.6 mg of the second eluting stereoisomer as a white solid (67.8%).

[0522] SFC Rt = 2.43 min ((SS) Whelk-O1 4.6 x 100 mm, 5 μm, 5% → 55% IPA in CO2).

[0523] LCMS Rt=2.21min;MS m / z 416.4[M+H]+;[Method 4]

[0524] 1 H NMR (400 MHz, methanol-d4) δ 6.93 -6.72 (m, 2H), 5.74 (d, J = 3.6 Hz, 1H), 5.62 (d, J = 4.1 Hz, 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, 5.9 Hz, 1H).

[0525] The remaining stereoisomers were isolated as Examples 3b and 4b

[0526] Example 3b

[0527] 21.6 mg of the third eluting stereoisomer as a white solid (74.1%).

[0528] SFC Rt = 2.68 min ((SS) Whelk-O1 4.6 x 100 mm, 5 μm, 5% → 55% IPA in CO2).

[0529] LCMS Rt=2.22min;MS m / z 416.6[M+H]+;[Method 4]

[0530] 1 H 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).

[0531] Example 4b

[0532] 20.6 mg of the fourth eluting stereoisomer as a white solid (70.7%).

[0533] SFC Rt = 2.79 min ((SS) Whelk-O1 4.6 x 100 mm, 5 μm, 5% → 55% IPA in CO2).

[0534] LCMS Rt=2.21min;MS m / z 416.3[M+H]+;[Method 4]

[0535] 1H 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).

[0536] 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

[0537]

[0538] Step 1: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde

[0539]

[0540] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (prepared in Example 4 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 diacetoxy iodobenzene (11.4 g, 35.37 mmol). The resulting solution was stirred at 30 ° C for 2 hours. 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 the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (3 g) as a colorless liquid.

[0541] 1 H NMR (300MHz, CDCl3) δ10.41 (s, 1H), 7.35 (d, J = 9.6Hz, 1H), 6.95-6.85 (m, 1H), 6.53 (s, 1H), 4.08 (s, 4H).

[0542] Step 2: 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethan-1-ol

[0543]

[0544] At 0 ° C, 2- (1,3-dioxolane -2- bases) -4,6-difluorobenzaldehyde (from step 1, 1.0g, 4.67mmol) in a solution of dry tetrahydrofuran (10mL) was added with methylmagnesium bromide (2.33mL, 3M in ether, 4.67mmol). The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (10mL) at 0 ° C and diluted with ethyl acetate (100mL). The organic phase was separated, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to obtain the title compound 1- (2- (1,3-dioxolane -2- bases) -4,6-difluorophenyl) second -1- alcohol (950mg) as a colorless liquid. The crude compound was used in the next step without further purification.

[0545] 1 H NMR (300MHz, CDCl3) δ7.17 (dd, J=2.4, 6.3Hz, 1H), 6.89-6.72 (m, 1H), 6.17 (s, 1H), 5.3 1(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).

[0546] Step 3: 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane

[0547]

[0548] At -78 ° C, diethylamino sulfur trifluoride (1.0 g, 6.13 mmol) was added to a solution of 1-(2-(1,3-dioxolane-2-yl)-4,6-difluorophenyl)ethane-1-ol (from step 2, 950 mg, 4.13 mmol) in dichloromethane (10 mL). The resulting solution was stirred at room temperature for 1 hour. 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 obtain 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 used in the next step without further purification.

[0549] 1H NMR (300MHz, CDCl3) δ7.20 (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).

[0550] Step 4: 3,5-difluoro-2-(1-fluoroethyl)benzaldehyde

[0551]

[0552] 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 hours. This was washed with water (50 mL), saturated NaHCO3 solution (100 mL), brine, 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 aldehyde obtained is volatile in nature)

[0553] 1 H NMR (300MHz, CDCl3) δ10.44(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).

[0554] Step 5: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0555]

[0556] 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 used in the next step without purification.

[0557] LCMS Rt = 2.272 min; MS m / z 472.3 [MH]-; [Method 7]

[0558] 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

[0559]

[0560] The title compound was synthesized using step 2 of general procedure 1 (using 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.

[0561] The diastereomeric mixture was separated into its two isomers using combi-flash 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.

[0562] Peak-1: 100 mg and Peak-2: 80 mg were further separated into their enantiomers using preparative chiral HPLC [Method 7] to obtain four isomers.

[0563] Example 5

[0564] 21 mg of the first eluting enantiomer was obtained as a white solid.

[0565] Chiral HPLC Rt = 4.418min; [Chiral analysis method 2]

[0566] LCMS Rt = 1.514 min; MS m / z 384.0 [MH]-; [Method 7]

[0567] 1 H NMR: (400MHz, CD3OD) δ6.87-6.74(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).

[0568] Example 5b

[0569] 22 mg of the second eluting enantiomer was obtained as a white solid.

[0570] Chiral HPLC Rt = 4.792min; [Chiral analysis method 2]

[0571] LCMS Rt = 1.513 min; MS m / z 384.0 [MH]-; [Method 7]

[0572] 1 H NMR (400MHz, CD3OD) δ6.87-6.74(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).

[0573] Example 5c

[0574] 18 mg of the third eluting enantiomer was obtained as a white solid.

[0575] Chiral HPLC Rt = 6.777min; [Chiral analysis method 2]

[0576] LCMS Rt = 1.476 min; MS m / z 384.1 [MH]-; [Method 7]

[0577] 1 H NMR: (400MHz, CDCl3) δ6.77-6.63(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).

[0578] Example 5d

[0579] Chiral HPLC Method 7 obtained 16 mg of the fourth eluting enantiomer as a white solid.

[0580] Chiral HPLC Rt = 7.475min; [Chiral analysis method 2]

[0581] LCMS Rt = 2.00 min; MS m / z 384.2 [MH]-; [Method 9]

[0582] 1H NMR (400MHz, CDCl3) δ6.77-6.63(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).

[0583] 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

[0584]

[0585] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethane-1-one

[0586]

[0587] Under nitrogen atmosphere, a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, example 1, 26g, 105.23mmol) in THF (250mL) was cooled to -78 °C. Then n-butyl lithium (44.19mL, 2.5M, 110.49mmol) in n-hexane solution was added and the reaction was stirred for 30min at -78 °C. Then ethyl 2-fluoroacetate (22.33g, 210.47mmol) was added to the reaction, and the resulting mixture was stirred for another 60min at -78 °C. The reaction mixture was quenched with saturated ammonium chloride solution (100mL) and extracted with ethyl acetate (2x250mL). The combined organic phase was washed with water (250mL), brine (250mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethane-1-one (16.2 g) as a colorless liquid.

[0588] 1 H NMR (400MHz, CDCl3) δ7.45(m,1H),7.37(d,J=7.8,1H),7.13(dd,J=9.3,8.2Hz,1 H), 6.02 (s, 1H), 5.23 (d, J = 1.4Hz, 1H), 5.11 (d, J = 1.3Hz, 1H), 4.08-3.87 (m, 4H).

[0589] Step 2: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoroethane-1-ol

[0590]

[0591] Under nitrogen atmosphere at 0 ° C, sodium borohydride (3.9 g, 103.07 mmol) was added to a stirred solution of 1-(2-(1,3-dioxolane-2-yl)-6-fluorophenyl)-2-fluoroethane-1-one (from step 1, 19.6 g, 85.89 mmol) in methanol (100 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2x250 mL). The combined organic phases were washed with water (250 mL), then washed with brine (250 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→30%) ethyl acetate in petroleum ether) to give the title compound 1-(2-(1,3-dioxolane-2-yl)-6-fluorophenyl)-2-fluoroethane-1-ol (18 g) as a colorless liquid.

[0592] 1 H NMR (400MHz, CDCl3) δ7.44 (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).

[0593] Step 3: 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane

[0594]

[0595] A solution of 1-(2-(1,3-dioxolane-2-yl)-6-fluorophenyl)-2-fluoroethane-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 it was stirred for another 1 h. Water (150 mL) was added, and the product was extracted with dichloromethane (2x200 mL). The combined organic phases were combined, washed with saturated sodium bicarbonate solution (2x200 mL), water (200 mL), brine (200 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (12.4 g) as a colorless liquid.

[0596] 1 H NMR(400MHz, CDCl3)δ7.45(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).

[0597] Step 4: 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde

[0598]

[0599] 2N HCl (100 mL) was added 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) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was extracted with diethyl ether (200 mL), washed with water (2x100 mL), brine (100 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde (10 g) as a colorless liquid.

[0600] 1H NMR (400MHz, CDCl3) δ10.30(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)

[0601] Step 5: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0602]

[0603] The title compound was synthesized using Step 1 of General Procedure I (using aldehyde from Step 4, 9 g, 47.83 mmol) to afford the title compound 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (25.0 g, crude) as a mixture of diastereomers as an off-white solid.

[0604] The crude product was used in the next step without further purification and analysis.

[0605] 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

[0606]

[0607] The title compound was synthesized using Step 2 of General Procedure I (using a mixture of intermediates from Step 5, 25 g, 52.8 mmol) to afford 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 flash chromatography on silica (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.

[0608] The previously separated diastereomers Peak-1: 200 mg and Peak-2: 200 mg were further separated into their enantiomers using preparative chiral HPLC [Method 7] to obtain four isomers.

[0609] Example 6

[0610] 56 mg of the first eluting enantiomer was obtained as a white solid.

[0611] Chiral HPLC Rt = 7.623min; [Chiral analysis method 2]

[0612] LCMS Rt = 1.445 min; MS m / z 384.0 [MH]-; [Method 7]

[0613] 1 H NMR (400MHz, CD3OD) δ7.41-7.35(m,1H),7.17(dt,J=7.9,1.3Hz,1H),6.98(dd,J=11.4,8.1Hz,1H),6.66-6.3 3(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).

[0614] The stereochemistry 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 crystallographic analysis and the active enantiomer was confirmed to be the R-enantiomer ( Figure 7 ).

[0615] Example 6b

[0616] 54 mg of the second eluting enantiomer was obtained as a white solid.

[0617] Chiral HPLC Rt = 8.757min; [Chiral analysis method 2]

[0618] LCMS Rt=1.443min;MS m / z 386.3[M+H]+;[Method 7]

[0619] 1 H NMR: (400MHz, CD3OD) δ7.41-7.35(m,1H),7.17(dt,J=7.9,1.3,1.3Hz,1H),7.10-6.88(m,1H),6.67-6.26(m,1 H),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).

[0620] Example 6c

[0621] 67 mg of the third eluting enantiomer was obtained as a white solid.

[0622] Chiral HPLC = Rt = 10.574 min; [Chiral analysis method 2]

[0623] LCMS Rt = 1.379 min; MS m / z 384.0 [MH]-; [Method 7]

[0624] 1 H NMR (400MHz, CD3OD) δ7.41-7.35(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).

[0625] Example 6d

[0626] 69 mg of the fourth eluting enantiomer was obtained as a white solid.

[0627] Chiral HPLC Rt = 13.93min [Chiral analysis method 2]

[0628] LCMS Rt = 1.379 min; MS m / z 384.0 [MH]-; [Method 7]

[0629] 1 H NMR (400MHz, CD3OD) δ7.41-7.35(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,1 H),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).

[0630] 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

[0631]

[0632] Step 1: 3-Ethoxycyclopent-2-en-1-one

[0633]

[0634] pTSA (193 mg, 1.019 mmol) and EtOH (22.61 ml, 387.35 mmol) were added to a stirred solution of cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene (70 mL) at room temperature. The resulting mixture was stirred for 10 hours at 120 ° C using a Dean-Stark apparatus. The solvent was removed under reduced pressure to give a crude compound. The crude product was purified by flash chromatography on silica ((0 → 50%) ethyl acetate in petroleum ether) to give the title compound 3-ethoxycyclopent-2-ene-1-one (4.3 g) as a brown solid.

[0635] 1 H NMR (400MHz, CDCl3) δ5.26 (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).

[0636] Step 2: 3-Aminocyclopent-2-en-1-one

[0637]

[0638] 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 hours. The solvent was removed under reduced pressure to give the title compound 3-aminocyclopent-2-en-1-one (3.2 g) as a brown solid.

[0639] LCMS Rt=0.114min;MS m / z 98.2[M+H]+;[Method 1]

[0640] 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

[0641]

[0642] 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 tert-butanol (25 mL) were added to a solution of aldehyde (from Example 6, step 4, 3.0 g, 15.944 mmol). The reaction mixture was stirred at 80 ° C for 48 hours. The solvent was removed under reduced pressure to give a crude compound. The crude product was purified by flash chromatography on silica ((0 → 70%) ethyl acetate in petroleum ether) 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 as a mixture of diastereomers. The diastereomeric mixture was separated into its two isomers using flash chromatography on silica (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.

[0643] The first separated diastereomers Peak-1: 12 mg and Peak-2: 15 mg were further separated into their enantiomers using preparative chiral HPLC [Method 7] to obtain four isomers.

[0644] Example 7

[0645] 2 mg of the first eluting enantiomer was obtained as a white solid.

[0646] Chiral HPLC Rt = 9.084min; [Chiral analysis method 4]

[0647] LCMS Rt=1.477min;MS m / z 384.05[M+H]+;[Method 2]

[0648] 1 H NMR (400 MHz, methanol-d4) δ 7.36-7.24 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.92 (dd, J = 11.4, 8.2 Hz, 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, 10.8 Hz, 2H), 3.54 (s, 3H), 2.70 (t, J = 5.0 Hz, 2H), 2.43-2.29 (m, 2H).

[0649] Example 7b

[0650] 4 mg of the second eluting enantiomer was obtained as a white solid.

[0651] Chiral HPLC Rt = 10.439min; [Chiral analysis method 4]

[0652] LCMS Rt=1.477min;MS m / z 384.2[M+H]+;[Method 2]

[0653] 1 H NMR (400 MHz, methanol-d4) δ 7.37-7.23 (m, 1H), 7.10-7.02 (m, 1H), 6.92 (dd, J = 11.4, 8.1 Hz, 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, 11.1 Hz, 2H), 3.54 (s, 3H), 2.76-2.66 (m, 2H), 2.42-2.27 (m, 2H).

[0654] Example 7c

[0655] 4 mg of the third eluting enantiomer was obtained as a white solid.

[0656] Chiral HPLC Rt = 12.453min; [Chiral analysis method 4]

[0657] LCMS Rt=1.327min;MS m / z 384.2[M+H]+;[Method 2]

[0658] 1 H NMR (400 MHz, methanol-d4) δ 7.32 (tdd, J = 8.1, 5.6, 1.5 Hz, 1H), 7.08 (dt, J = 7.8, 1.3 Hz, 1H), 6.93 (dd, J = 11.5, 8.1 Hz, 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).

[0659] Example 7d

[0660] 4 mg of the fourth eluting enantiomer was obtained as a white solid.

[0661] Chiral HPLC Rt = 13.173min; [Chiral analysis method 4]

[0662] LCMS Rt=1.33min;MS m / z 384.2[M+H]+;[Method 2]

[0663] 1 H NMR (400 MHz, methanol-d4) δ 7.40-7.25 (m, 1H), 7.14-7.05 (m, 1H), 6.93 (dd, J = 11.4, 8.2 Hz, 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 = 4.8 Hz, 2H), 2.44-2.21 (m, 2H).

[0664] 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

[0665]

[0666] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol

[0667]

[0668] Under nitrogen atmosphere, a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, example 1, 30g, 121.42mmol) in THF (300mL) was cooled to -78 ° C. Then n-butyl lithium (58.3mL, 2.5M, 147.71mmol) in n-hexane solution was added over 10min, and the resulting mixture was stirred at -78 ° C for 1 hour. Acetaldehyde (6.42g, 145.71mmol) was added, and the resulting mixture was stirred at -78 ° C for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (50mL), and extracted with ethyl acetate (2x100mL). The combined organic phase was washed with water (50mL), brine (50mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol (15 g) as a colorless liquid.

[0669] 1H NMR (400MHz, CDCl3) δ7.38 (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).

[0670] Step 2: 2-(3-Fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane

[0671]

[0672] To a solution of 1-(2-(1,3-dioxolane-2-yl)-6-fluorophenyl)ethan-1-ol (from step 1, 15g, 70.68mmol) in dichloromethane (150mL) was added diethylaminosulfur trifluoride (19.3mL, 141.37mmol) at -78°C. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride (20mL) at 0°C and diluted with ethyl acetate (100mL). The organic phase was separated, 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 ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (8.5g) as a colorless liquid.

[0673] 1 H NMR(300MHz, CDCl3)δ7.38(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).

[0674] Step 3: 3-Fluoro-2-(1-fluoroethyl)benzaldehyde

[0675]

[0676] To a solution of 2-(3-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (from step 2, 8.5 g, 69.38 mmol) and in diethyl ether (150 mL) was added 4N HCl (85 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours. This 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 aldehyde obtained is volatile in nature).

[0677] 1 H NMR (300MHz, CDCl3) δ10.44(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).

[0678] Step 4: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0679]

[0680] 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 (13 g, crude) as a mixture of diastereomers.

[0681] LCMS Rt = 1.795 min; MS m / z 454.2 [MH]-; [Method 9]

[0682] 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

[0683]

[0684] The title compound was synthesized using Step 2 of General Procedure I (using a mixture of intermediates from Step 4 (13.0 g, 28.54 mmol)) to afford 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 ((0→80%) ethyl acetate in hexanes) to give 1.04 g of the first diastereomer and 1.45 g of the second diastereomer.

[0685] 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

[0686] Example 8

[0687] 37 mg of the title compound as the first eluting stereoisomer

[0688] LCMS Rt = 1.95 min; MS m / z 366.3 [MH]-; [Method 4]

[0689] 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

[0690] 1 H NMR (400MHz, DMSO-d6) δ10.12(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).

[0691] Example 8b

[0692] 38 mg as the second eluting stereoisomer

[0693] LCMS Rt = 1.95 min; MS m / z 366.3 [MH]-; [Method 4]

[0694] 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

[0695] 1 H NMR: (400MHz, DMSO-d6) δ10.12(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).

[0696] Example 8c

[0697] 42 mg as the third eluting stereoisomer

[0698] LCMS Rt = 1.88 min; MS m / z 366.3 [MH]-; [Method 4]

[0699] 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

[0700] 1 H NMR (400MHz, DMSO-d6) δ10.13(d,J=3.3Hz,1H),7.33(td,J=8.0,5.4Hz,1H),7.23-6.92(m,2H),6.49(dd,J=4 4.7, 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).

[0701] Example 8d

[0702] 40 mg: as the fourth eluting stereoisomer

[0703] LCMS Rt = 1.88 min; MS m / z 366.3 [MH]-; [Method 4]

[0704] 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

[0705] 1 H NMR: (400MHz, DMSO-d6) δ10.13(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).

[0706] The stereochemistry 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 and the active enantiomer was confirmed to be the R-enantiomer ( Figure 8 ).

[0707] Example 9: Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0708]

[0709] Step 1: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethoxy)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0710]

[0711] 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). It was used in the next step without analysis.

[0712] Step 2: Methyl 4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0713]

[0714] Potassium hydroxide (293.44 mg, 5.22 mmol) was added to the crude intermediate (600 mg, 1.30 mmol) from step 1 in methanol (20 mL). The resulting solution was stirred at 65 ° C for 30 min. Water was added to the reaction mixture, and the solid was precipitated and filtered. The solid was washed with diethyl ether, and the solid was collected and dried under reduced pressure to obtain the title compound methyl 4- (2- (difluoromethoxy) phenyl) -2- (fluoromethyl) -5- oxo -1,4,5,7- tetrahydrofuran [3,4-b] pyridine -3- carboxylate (100 mg).

[0715] Using chiral HPLC [Method 4], 90 mg of the racemic mixture were separated into its enantiomers.

[0716] Example 9

[0717] 40 mg of the first eluting enantiomer as a white solid, 44% yield.

[0718] Chiral HPLC Rt = 6.481min; [Chiral analysis method 1]

[0719] LCMS Rt=1.473min;MS m / z 370[M+H]+;[Method 7]

[0720] 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 were observed.

[0721] The stereochemistry 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 and the active enantiomer was confirmed to be the R-enantiomer ( Fig. 9 ).

[0722] Example 9b

[0723] 38 mg of the second eluting enantiomer as a white solid, 42% yield.

[0724] Chiral HPLC Rt = 10.303min; [Chiral analysis method 1]

[0725] LCMS Rt=1.475min;MS m / z 370.1[M+H]+;[Method 7]

[0726] 1 H NMR: (400MHz, CDCl3) δ7.30 (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).

[0727] 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

[0728]

[0729] Step 1: 1-Bromo-3,5-difluoro-2-(trifluoromethyl)benzene

[0730]

[0731] A solution of 3,5-difluoro-2-(trifluoromethyl)aniline (10g, 50.735mmol) in 48% HBr / H2O aqueous solution (80mL / 80mL) was cooled to -5°C, then NaNO2 (8.74g in 100mL H2O, 126.83mmol) was slowly added over a period of 5min, and the resulting mixture was then stirred at -5°C for 1h. At -5°C, the reaction mixture was treated in batches with CuBr (10.92g, 76.103mmol). The reaction mixture was slowly raised to room temperature and stirred for 4 hours. The reaction mixture was extracted with hexane (3X200mL). The organic phases were combined, washed with saturated saline solution (100mL), and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica (in petroleum ether) to give the title compound 1-bromo-3,5-difluoro-2-(trifluoromethyl)benzene (8g) as a colorless liquid.

[0732] 1 H NMR (400MHz, CDCl3) δ7.31 (dt, J = 7.6, 2.2Hz, 1H), 6.95-6.88 (m, 1H).

[0733] Step 2: 1,5-Difluoro-2-(trifluoromethyl)-3-vinylbenzene

[0734]

[0735] 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 isopropanol (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, followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (3.75 g, 4.599 mmol). The reaction mixture was stirred at 80° C. for 6 hours. 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 the crude product was purified by flash chromatography on silica in petroleum ether to give the title compound 1,5-difluoro-2-(trifluoromethyl)-3-vinylbenzene (6.5 g) as a colorless liquid.

[0736] 1 H NMR (300MHz, CDCl3) δ7.16-6.97 (m, 2H), 6.85-6.80 (m, 1H), 5.67 (d, J = 17.2Hz, 1H), 5.49 (d, J = 10.9Hz, 1H).

[0737] Step 3: 3,5-Difluoro-2-(trifluoromethyl)benzaldehyde

[0738]

[0739] 1,5-difluoro-2-(trifluoromethyl)-3-vinylbenzene (from step 2, 6.5 g, 31.23 mmol) and RuCl 3.XH2O (647mg, 3.123mmol) is added to a solution of diacetoxy iodobenzene (20g, 62.46mmol) in dichloromethane:H2O (130mL:30mL). The resulting solution is stirred at room temperature for 2h. The reaction mixture is filtered through a celite pad and washed with dichloromethane (200mL) and dried over Na2SO4. The solvent is removed under reduced pressure, and the crude product is purified by flash chromatography on silica ((0→5%) ethyl acetate in petroleum ether) to give the title compound 3,5-difluoro-2-(trifluoromethyl)benzaldehyde (3.0g) as a colorless liquid. 1 H NMR (300MHz, CDCl3) δ10.34(m,1H),7.82-7.52(m,1H),7.22-7.07(m,1H).

[0740] Step 4: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0741]

[0742] 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).

[0743] LCMS Rt=1.76min;MS m / z 496.0[M+H]+;[Method 7]

[0744] 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

[0745]

[0746] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 4 (900 mg, 1.8 mmol)). The crude product was flash chromatographed on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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].

[0747] Example 10

[0748] 30 mg of the first eluting enantiomer was obtained as a white solid.

[0749] Chiral HPLC Rt = 5.502min; [Chiral analysis method 2]

[0750] LCMS Rt = 1.542 min; MS m / z 406 [MH]-; [Method 7]

[0751] 1 H NMR: (400MHz, CDCl3) δ7.30(d,J=7.2Hz,1H),6.87(d,J=9.5Hz,1H),6.856.75(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).

[0752] Example 10b

[0753] 30 mg of the second eluting enantiomer was obtained as a white solid.

[0754] Chiral HPLC Rt = 6.935min; [Chiral analysis method 1]

[0755] LCMS Rt = 1.542 min; MS m / z 406 [MH]-; [Method 7]

[0756] 1 H NMR: (400MHz, CDCl3) δ7.30(d,J=7.2Hz,1H),6.87(d,J=9.5Hz,1H),6.856.75(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).

[0757] 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

[0758]

[0759] Step 1: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde

[0760]

[0761] Under nitrogen atmosphere, a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, example 1, 7g, 28.45mmol) in THF (70mL) was cooled to -78 ° C. Then n-butyl lithium (13.66mL, 2.5M, 58.5mmol) in n-hexane solution was added over 10min, and the resulting mixture was stirred at -78 ° C for 45min. DMF (2.5g, 34.15mmol) was added, and the resulting mixture was stirred at -78 ° C for 1.15h. The reaction mixture was quenched with saturated ammonium chloride solution (50mL), and extracted with ethyl acetate (2x100mL). The combined organic phase was washed with water (50mL), then washed with brine (50mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to give the title compound 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5 g) as a colorless liquid.

[0762] 1 H NMR (300MHz, CDCl3) δ10.52(s,1H),7.67-7.53(m,2H),7.22-7.12(m,1H),6.50(s,1H),4.27-3.99(m,4H).

[0763] Step 2: 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane

[0764]

[0765] 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-dioxolane-2-yl)-6-fluorobenzaldehyde (from step 1, 7 g, 35.7 mmol) was heated to 70 ° C under a nitrogen atmosphere and stirred for 30 min. Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (12 g, 62.4 mmol) was slowly added over a period of 10 min (mass color turned yellow). The resulting mixture was stirred at 70 ° C for another 3 hours, 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 the crude product was purified by silica flash chromatography ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (6.9 g) as a light yellow liquid.

[0766] 1 H NMR: (300MHz, CDCl3) δ7.39 (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).

[0767] Step 3: 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane

[0768]

[0769] 10% Pd-C (1 g) is added to a solution of 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from step 2, 3g, 13.04mmol) in ethyl acetate (60mL). At room temperature under a hydrogen atmosphere, the resulting reaction mixture is stored in a Parr-Shaker for 48 hours under a pressure of 60psi. The reaction mixture is filtered on a diatomaceous earth pad and washed with ethyl acetate (30mL). The filtrate is concentrated under reduced pressure, and the crude product is purified by flash chromatography on silica ((0→30%) ethyl acetate in petroleum ether) to obtain the title compound 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (3 g) as a colorless liquid.

[0770] 1H NMR (300MHz, CDCl3) δ7.42-7.35(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).

[0771] Step 4: 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde

[0772]

[0773] 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 hours. This was washed with water (50 mL), saturated NaHCO3 solution (100 mL), brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1.9 g) as a colorless liquid.

[0774] 1 H NMR (400MHz, CDCl3) δ10.14(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).

[0775] Step 5: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0776]

[0777] 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).

[0778] LCMS Rt=1.764min;MS m / z 473.4[M+H]+;[Method 7]

[0779] 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

[0780]

[0781] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 5, 1 g, 2.11 mmol). The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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].

[0782] Example 11

[0783] 30 mg of the first eluting enantiomer was obtained as a white solid.

[0784] Chiral HPLC Rt = 6.325min; [Chiral analysis method 2]

[0785] LCMS Rt=1.508min;MS m / z 386.0[M+H]+;[Method 7]

[0786] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(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).

[0787] Example 11b

[0788] 30 mg of the first eluting enantiomer was obtained as a white solid.

[0789] Chiral HPLC Rt = 8.402min; [Chiral analysis method 2]

[0790] LCMS Rt=1.508min;MS m / z 386.4[M+H]+;[Method 7]

[0791] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(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).

[0792] 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

[0793]

[0794] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane

[0795]

[0796] A solution of 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane (from step 1, example 3, 5g, 18.94mmol) and potassium trifluoroborate (5.8g, 37.89mmol), triethylamine (7.91mL, 56.82mmol) in isopropanol (50mL) was degassed with argon for 10min, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added. DCM (1.55g, 1.89mmol). The resulting solution was degassed with argon again for 10min, and stirred at 80°C for 5 hours. The reaction mixture was filtered and washed with ethyl acetate (100mL). The filtrate was dissolved in water (1L) and extracted into ethyl acetate (2L). 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 ((0→10%) ethyl acetate in petroleum ether) to afford the title compound 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (3.45 g) as a colorless liquid. Note: The compound is volatile in nature, hexanes are present in the compound.

[0797] 1H NMR (300MHz, CDCl3) δ7.20-7.16(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).

[0798] Step 3: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde

[0799]

[0800] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (from step 2, 5g, 23.58mmol) and ruthenium chloride .XH2O (490mg, 2.35mmol) in dichloromethane (50mL) and water (10mL) was added (diacetoxyiodo)benzene (11.4g, 35.37mmol). The resulting solution was stirred at 30°C for 2 hours. The reaction mixture was filtered and washed with ethyl acetate (200mL). The filtrate was dissolved in water (200mL) and the product was extracted into ethyl acetate (500mL). The organic matter 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 ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(1,3-dioxolane-2-yl)-4,6-difluorobenzaldehyde (3g) as a colorless liquid. Note: Compound is volatile in nature and hexane is present in the compound.

[0801] 1 H NMR (300MHz, CDCl3) δ10.41 (s, 1H), 7.35 (d, J = 9.6Hz, 1H), 6.95-6.85 (m, 1H), 6.53 (s, 1H), 4.08 (s, 4H).

[0802] Step 4: 2-(2-(2,2-difluorovinyl)-3,5-difluorophenyl)-1,3-dioxolane

[0803]

[0804] Under nitrogen atmosphere, triphenylphosphine (1.83g, 7.0mmol), potassium iodide (775mg, 4.66mmol) and 2-1,3-dioxolane-2-yl)-6-fluorobenzaldehyde (from step 3, 500mg, 2.33mmol) were added to acetonitrile (4.5mL). The reaction was stirred at 70°C for 30min. Then 2-(1,3-dioxolane-2-yl)-4,6-difluorobenzaldehyde (783mg, 4.07mmol) was slowly added over a period of 10min (the color of the material turned yellow during addition), and the resulting mixture was stirred at 70°C for another 3 hours. The reaction mixture was then cooled to room temperature and diluted with diethyl ether, the precipitated solid was filtered, and washed with diethyl ether (100mL). The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2-(2,2-difluorovinyl)-3,5-difluorophenyl)-1,3-dioxolane (400 mg) as a light yellow liquid.

[0805] 1 H NMR (300MHz, CDCl3) δ7.19-7.12(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).

[0806] Step 5: 2-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-1,3-dioxolane

[0807]

[0808] 10% Pd-C (180 mg) was added 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). The resulting reaction mixture was stored in a Parr shaker under a pressure of 60 psi for 48 hours at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth pad and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→30%) ethyl acetate in petroleum ether) to give the title compound 2-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-1,3-dioxolane (400 mg) as a colorless liquid.

[0809] 1H NMR (300MHz, CDCl3) δ7.22-7.12(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).

[0810] Step 6: 2-(2,2-difluoroethyl)-3,5-difluorobenzaldehyde

[0811]

[0812] 5N HCl (1 mL) was added 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). The resulting solution was stirred at room temperature for 3 hours. This 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 the crude product was purified by flash chromatography on silica ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2,2-difluoroethyl)-3,5-difluorobenzaldehyde (250 mg) as a colorless liquid.

[0813] 1 H NMR (300MHz, CDCl3) δ10.11 (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).

[0814] Step 7: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0815]

[0816] 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).

[0817] LCMS Rt=1.77min;MS m / z 491.0[M+]+;[Method 7]

[0818] 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

[0819]

[0820] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 7, 800 mg, 1.62 mmol). The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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].

[0821] Example 12

[0822] 11 mg of the first eluting enantiomer was obtained as a white solid.

[0823] Chiral HPLC Rt = 5.674min; [Chiral analysis method 2]

[0824] LCMS Rt=1.561min;MS m / z 403.9[M+]+;[Method 7]

[0825] 1 H NMR(400MHz,CD3OD)δ6.87-6.76(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).

[0826] Example 12b

[0827] 10 mg of the second eluting enantiomer was obtained as a white solid.

[0828] Chiral HPLC Rt = 7.215min; [Chiral analysis method 2]

[0829] LCMS Rt=1.557min;MS m / z 403.9[M+]+;[Method 7]

[0830] 1H NMR(400MHz,CD3OD)δ6.87-6.76(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).

[0831] 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

[0832]

[0833] Step 1: 2-Cyclopropyl-3,5-difluorobenzaldehyde

[0834]

[0835] 2N KCO (102 mL, 204 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) were added 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). DCM (3.17 g, 3.88 mmol) was used to degas the resulting solution with argon for 10 min and stirred at 100 ° C for 4 hours. 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 NaSO. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→1%) ethyl acetate in petroleum ether) to give the title compound 2-cyclopropyl-3,5-difluorobenzaldehyde (8 g) as a colorless liquid.

[0836] 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).

[0837] Step 2: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-cyclopropyl-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0838]

[0839] 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).

[0840] LCMS Rt=1.586min;MS m / z 477.0[M+H]+;[Method 10]

[0841] Step 3: Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0842]

[0843] The title compound was synthesized using Step 2 of General Procedure I (using the intermediate from Step 2, 4.61 g, 9.871 mmol). The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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.

[0844] The racemic mixture was separated into its enantiomers using chiral preparative HPLC [Method 9].

[0845] Example 13

[0846] 135 mg of the first eluting enantiomer was obtained as a white solid.

[0847] Chiral HPLC Rt = 5.33min; [Chiral analysis method 2]

[0848] LCMS Rt=1.591min;MS m / z 380.2[M+H]+;[Method 7]

[0849] 1H NMR (300MHz, CD3OD) δ6.78-6.70(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).

[0850] 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

[0851]

[0852] Step 2: Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[0853]

[0854] 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) in ethanol (5 mL) were added to a solution of aldehyde (from step 1, example 13, 300 mg, 1.64 mmol). The reaction mixture was stirred at 80 ° C for 16 hours. The solvent was removed under reduced pressure to give a crude compound. The crude product was purified by silica flash chromatography ((0 → 70%) ethyl acetate in petroleum ether) 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].

[0855] Example 14

[0856] 17 mg of the first eluting enantiomer was obtained as a white solid.

[0857] Chiral HPLC Rt = 8.588min; [Chiral analysis method 3]

[0858] LCMS Rt=1.548min;MS m / z 378.0[M+H]+;[Method 7]

[0859] 1H NMR (400MHz, CDCl3) δ7.21(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).

[0860] Example 14b

[0861] 17 mg of the second eluting enantiomer was obtained as a white solid.

[0862] Chiral HPLC Rt = 11.651 min; [Chiral analysis method 3]

[0863] LCMS Rt=1.548min;MS m / z 378.0[M+H]+;[Method 7]

[0864] 1 H NMR (400MHz, CDCl3) δ7.21(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).

[0865] Example 15: Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0866]

[0867] Step 1: 2-(Difluoromethyl)-1-fluoro-3-vinylbenzene

[0868]

[0869] To a solution of 1-bromo-2-(difluoromethyl)-3-fluorobenzene (2.0 g, 8.889 mmol), potassium vinyl trifluoroborate (2.38 g, 17.78 mmol) and triethylamine (3.7 mL, 26.66 mmol) in isopropanol (20 mL) were added. The resulting solution was purged with argon for 10 min, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added. DCM (725 mg, 0.889 mmol). The reaction mixture was stirred at 80° C. for 6 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica (in petroleum ether) to give the title compound 2-(difluoromethyl)-1-fluoro-3-vinylbenzene (1.2 g) as a colorless liquid.

[0870] 1 H NMR (400MHz, CDCl3) δ7.48-7.40(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).

[0871] Step 2: 2-(Difluoromethyl)-3-fluorobenzaldehyde

[0872]

[0873] To a solution of 2-(difluoromethyl)-1-fluoro-3-vinylbenzene (from step 1, 1.2 g, 6.970 mmol) was added RuCl in dichloromethane:H2O (20 mL:6 mL). 3. XH2O (145 mg, 0.697 mmol) and diacetoxy iodobenzene (6.73 g, 20.91 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was filtered through a celite pad and washed with dichloromethane (200 mL) and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0 → 5%) ethyl acetate in petroleum ether) to give the title compound 2-(difluoromethyl)-3-fluorobenzaldehyde (500 mg) as a colorless liquid.

[0874] 1H NMR (400MHz, CDCl3) δ10.42(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).

[0875] Step 3: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0876]

[0877] 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).

[0878] LCMS Rt=1.716min;MS m / z 460.1[M+H]+;[Method 7]

[0879] Step 4: Methyl 4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0880]

[0881] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 3, 1.0 g, 2.177 mmol). The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to afford 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].

[0882] Example 15

[0883] 90 mg of the first eluting enantiomer was obtained as a white solid.

[0884] Chiral HPLC Rt = 10.05min; [Chiral analysis method 2]

[0885] LCMS Rt=1.947min;MS m / z 372.2[M+H]+;[Method 9]

[0886] 1 H NMR (400 MHz, CDCl3) δ7.44-7.28 (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.

[0887] Example 15b

[0888] 90 mg of the second eluting enantiomer was obtained as a white solid.

[0889] Chiral HPLC Rt = 12.05min; [Chiral analysis method 2]

[0890] LCMS Rt=2.09min;MS m / z 372.2[M+H]+;[Method 9]

[0891] 1 H NMR (400MHz, CDCl3) δ7.43-7.33(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).

[0892] 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

[0893]

[0894] Step 1: 2-(2-Bromo-3,5-difluorophenyl)-1,3-dioxolane

[0895]

[0896] The title compound was synthesized according to a procedure similar to step 1 of Example 1 using 15 g of 2-bromo-3,5-difluorobenzaldehyde to obtain 15 g of the desired product 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane.

[0897] 1H NMR (300MHz, CDCl3) δ7.23-7.18(m,1H), 6.95-6.90(m,1H), 6.08(t,J=1.1Hz,1H), 4.24-3.99(m,4H).

[0898] Step 2: (3-Bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane

[0899]

[0900] At -78 ° C, under an inert atmosphere, 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), diisopropylamide lithium (31.1 mL, 2.0 M in hexane, 62.25 mmol) was added 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 × 500 mL). The combined EtOAc phases were washed with brine solution (250 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica in petroleum ether (100%) to give the title compound (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane (9.0 g) as a colorless liquid.

[0901] 1 H NMR (300MHz, CDCl3) δ7.08 (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).

[0902] Step 3: 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethane-1-one

[0903]

[0904] At -78 ° C, under an inert atmosphere, to a solution of (3-bromo-4-(1,3-dioxolane-2-yl)-2,6-difluorophenyl)trimethylsilane (from step 2, 5.0 g, 14.961 mmol) in freshly distilled THF (50 mL) was slowly added n-butyl lithium (6.0 mL, 2.5 M in hexanes, 14.961 mmol). 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 phases were washed with brine solution (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethane-1-one (2.5 g) as a colorless liquid.

[0905] 1 H NMR (300MHz, CDCl3) δ7.04 (dt, J = 8.9, 0.8 Hz, 1H), 6.02 (s, 1H), 5.22 (d, J = 1.6 Hz, 1H), 5.07 (d, J = 1.6 Hz, 1H), 4.03-3.79 (m, 4H), 0.37 (s, 9H).

[0906] Step 4: 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethane-1-ol

[0907]

[0908] To a solution of 1-(6-(1,3-dioxolane-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethane-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 allowed to rise slowly to room temperature over 1 hour, and stirred at room temperature for an additional 2 hours. 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 the crude product was purified by flash chromatography on silica ((0→30%) ethyl acetate in petroleum ether) to give the title compound 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethane-1-ol (2.5 g) as a colorless liquid.

[0909] 1 H NMR (400MHz, CDCl3) δ7.12 (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).

[0910] Step 5: (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane

[0911]

[0912] To a solution of 1-(6-(1,3-dioxolane-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethane-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 and washed with saturated NaHCO solution (50 mL), brine, and dried over NaSO. The solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography ((0→2%) ethyl acetate in petroleum ether) to give the title compound (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl)trimethylsilane (1.1 g) as a colorless liquid.

[0913] 1 H NMR (400MHz, CDCl3) δ7.23-7.04(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).

[0914] Step 6: 2-(1,2-difluoroethyl)-3,5-difluoro-4-(trimethylsilyl)benzaldehyde

[0915]

[0916] To a solution of (3-(1,2-difluoroethyl)-4-(1,3-dioxolane-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 hours. This 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 in the next step without further purification and analysis.

[0917] Step 7: 2-(1,2-difluoroethyl)-3,5-difluorobenzaldehyde

[0918]

[0919] 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), and this 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 the crude product was purified by flash chromatography on silica ((5%→10%) ethyl acetate in petroleum ether) to give the title compound 2-(1,2-difluoroethyl)-3,5-difluorobenzaldehyde (400 mg) as a colorless liquid.

[0920] 1H NMR (600MHz, CDCl3) δ10.41-10.14(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).

[0921] Step 8: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0922]

[0923] 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 in the next step without further purification and analysis.

[0924] 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

[0925]

[0926] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 8, 1.0 g, 2.03 mmol). The crude product was purified by silica flash chromatography ((0→50%) ethyl acetate in petroleum ether) to give 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 Peak-1: 70 mg and Peak-2: 50 mg were further separated into their enantiomers using preparative chiral SFC [Method 8] to obtain four isomers.

[0927] Example 16

[0928] 25 mg of the second eluting enantiomer was obtained as a white solid

[0929] Chiral HPLC Rt = 12.95min; [Chiral analysis method 3]

[0930] LCMS Rt = 1.52 min; MS m / z 402.2 [MH]-; [Method 7]

[0931] 1 H NMR (600MHz, CDCl3) δ7.29 (d, J=6.8Hz, 1H), 6.80-6.69 (m, 2H), 6.41 (dd, J=4 8.5,17.2Hz,1H),5.80(s,1H),5.72(s,1H),5.36-4.69(m,5H),3.59(s,3H).

[0932] Example 16b

[0933] 25 mg of the first eluting enantiomer was obtained as a white solid

[0934] Chiral HPLC RT 10.54min; [Chiral analysis method 3]

[0935] LCMS Rt = 1.52 min; MS m / z 402.0 [MH]-; [Method 7]

[0936] 1 H NMR (600MHz, CDCl3) δ7.29 (d, J=6.8Hz, 1H), 6.80-6.69 (m, 2H), 6.41 (dd, J=4 8.5,17.2Hz,1H),5.80(s,1H),5.72(s,1H),5.36-4.69(m,5H),3.59(s,3H).

[0937] Example 16c

[0938] 15 mg of the third eluting enantiomer as a white solid

[0939] Chiral HPLC Rt = 14.54min; [Chiral analysis method 3]

[0940] LCMS Rt = 1.472 min; MS m / z 402.0 [MH]-; [Method 7]

[0941] 1H NMR (400MHz, CD3OD) δ6.92-6.80(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).

[0942] Example 16d

[0943] 15 mg of the fourth eluting enantiomer as a white solid

[0944] Chiral HPLC Rt = 18.97min; [Chiral analysis method 3]

[0945] LCMS Rt = 1.466 min; MS m / z 402.2 [MH]-; [Method 7]

[0946] 1 H NMR (400MHz, CD3OD) δ6.92-6.80(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).

[0947] 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

[0948]

[0949] Step 1: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0950]

[0951] 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 in the next step without further purification and analysis.

[0952] Step 2: Methyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0953]

[0954] The title compound (from step 2, 2 g, 4.18 mmol) was synthesized using step 2 of general procedure I. The crude product was purified by flash chromatography on silica ((0→70%) ethyl acetate in petroleum ether) to afford 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].

[0955] Example 17

[0956] 80 mg of the first eluting enantiomer as a white solid, 33% yield.

[0957] Chiral HPLC Rt = 7.549 min; [Chiral analysis method 1]

[0958] LCMS Rt=1.485min;MS m / z 390.1[M+H]+;[Method 7]

[0959] 1 H NMR(600MHz,CD3OD)δ7.62-7.46(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).

[0960] 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

[0961]

[0962] Step 1: 2-(2-Bromo-3,5-difluorophenyl)-1,3-dioxolane

[0963]

[0964] The title compound was synthesized according to a procedure similar to Step 1 of Example 1 using 15 g of 2-bromo-3,5-difluorobenzaldehyde to obtain 15.4 g of 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane.

[0965] 1 H NMR (300MHz, CDCl3) δ7.20-7.15(m,1H),6.49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H).

[0966] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane

[0967]

[0968] The title compound was synthesized according to a similar procedure 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).

[0969] 1 H NMR (300MHz, CDCl3) δ7.20-7.16(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).

[0970] Step 3: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde

[0971]

[0972] The title compound was synthesized according to a similar procedure to step 1 of Example 5 to give 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (1.0 g).

[0973] 1 H NMR (300MHz, CDCl3) δ10.41 (s, 1H), 7.35 (d, J = 9.6Hz, 1H), 6.95-6.85 (m, 1H), 6.53 (s, 1H), 4.08 (s, 4H).

[0974] Step 4: 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxolane

[0975]

[0976] The title compound was synthesized according to a procedure similar to step 3 of Example 5 to give 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxolane (570 mg)

[0977] 1 H NMR (300MHz, CDCl3) δ7.29-7.25(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).

[0978] Step 5: 2-(Difluoromethyl)-3,5-difluorobenzaldehyde

[0979]

[0980] 6N HCl (10 mL) was added 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) at 0 ° C. The resulting reaction mixture was stirred at room temperature for 6 hours. 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 give the crude compound 2-(difluoromethyl)-3,5-difluorobenzaldehyde (360 mg) as a colorless liquid.

[0981] 1 H NMR (300MHz, CDCl3) δ10.42 (s, 1H), 7.74-7.54 (m, 1H), 7.25 (dd, J = 46.8, 10.4Hz, 1H), 7.15 -7.10 (m, 1H).

[0982] Step 6: 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate

[0983]

[0984] 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).

[0985] LCMS Rt = 1.698 min; MS m / z 476.1 [MH]-; [Method 7]

[0986] Step 7: Methyl 4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[0987]

[0988] The title compound was synthesized using step 2 of general procedure I (using the intermediate from step 6, 720 mg, 1.50 mmol). The crude product was purified by flash chromatography on silica ((0→70%) ethyl acetate in petroleum ether) to afford 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].

[0989] Example 18

[0990] 30 mg of the first eluting enantiomer was obtained as a white solid, 25% yield.

[0991] Chiral HPLC Rt = 17.629min; [Chiral analysis method 1]

[0992] LCMS Rt = 1.454 min; MS m / z 388.2 [MH]-; [Method 7]

[0993] 1 H NMR (400MHz, CD3OD) δ7.40-7.38 (m, 1H), 6.93 (dd, J=10.3, 7.6Hz, 2H), 5.77 (d, J=0.8 Hz, 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).

[0994] Example 18b

[0995] 36 mg of the second eluting enantiomer was obtained as a white solid, 30% yield.

[0996] Chiral HPLC Rt = 19.634min; [Chiral analysis method 1]

[0997] LCMS Rt = 1.454 min; MS m / z 388.0 [MH]-; [Method 7]

[0998] 1 H NMR (400MHz, CD3OD) δ7.40-7.38 (m, 1H), 6.93 (dd, J=10.3, 7.6Hz, 2H), 5.77 (d, J=0.8 Hz, 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).

[0999] Example 19: Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1000]

[1001] The title compound was prepared using General Procedure II using commercially available 2-(difluoromethoxy)-3-fluorobenzaldehyde (249 mg, 1.311 mmol). The crude product was purified by automated flash column chromatography eluting with EtOAc in heptane (gradient 0-100%) on a 24 g Si-column and further purified by mass directed reverse phase preparative chromatography; conditions: Xbridge C18 OBD 30x50mm 5um column ACN / H2O w / NH3OH 5mL / min injection 1.5mL. The racemate was separated into its individual enantiomers using chiral SFC (mobile phase: 5%-25% MeOH in C02 80g / min; column: (RR) Whelk-O1 21x250mm).

[1002] Example 19

[1003] 8.6 mg of the second eluting enantiomer (4%)

[1004] Chiral SFC Rt = 2.61 min (mobile phase: 5%-55% MeOH column: (RR) Whelk-O1 4.6x100mm 5um column, 6 min run)

[1005] LCMS Rt=1.94min;MS m / z 388.2[M+H]+;[Method 4]

[1006] 1H NMR (400 MHz, dichloromethane-d2) δ 7.46 (d, J = 6.8 Hz, 1H), 7.29-7.05 (m, 3H), 6.93 (t, J = 74.16 Hz, 1H), 5.88-5.56 (m, 2H), 5.23 (s, 1H), 4.81 (s, 2H), 3.57 (s, 3H).

[1007] Example 19b

[1008] 9.5 mg of the first eluting enantiomer (4%)

[1009] Chiral SFC Rt = 2.41 min (mobile phase: 5%-55% MeOH column: (RR) Whelk-O1 4.6x100mm 5um column, 6 min run)

[1010] LCMS Rt=1.90min;MS m / z 388.2[M+H]+;[Method 4]

[1011] 1 H NMR (400 MHz, dichloromethane-d2) δ 7.46 (d, J = 6.8 Hz, 1H), 7.29-7.05 (m, 3H), 6.93 (t, J = 74.16 Hz, 1H), 5.88-5.56 (m, 2H), 5.23 (s, 1H), 4.81 (s, 2H), 3.57 (s, 3H).

[1012] Example 20: Methyl (R)-4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1013]

[1014] The title compound was prepared using General Procedure II using commercially available 2-(difluoromethoxy)-5-fluorobenzaldehyde (229 mg, 1.206 mmol). The crude product was purified by automated flash column chromatography eluting with EtOAc in heptane (gradient 0-100%) on a 24 g Si-column and further purified by mass directed reverse phase preparative chromatography; Conditions: Xbridge C18 OBD 30x50mm 5um column ACN / H2O w / NH3OH 5mL / min injection 1.5mL. The racemate was separated into its individual enantiomers using chiral SFC (mobile phase: 5%-25% MeOH in C02 80g / min; column: (RR) Whelk-O1 21x250mm).

[1015] Example 20

[1016] 10 mg of the second eluting enantiomer

[1017] Chiral SFC Rt = 2.51 min (mobile phase: 5%-55% MeOH column: (RR) Whelk-O1 4.6x100mm 5um column, 6 min run)

[1018] LCMS Rt=1.91min;MS m / z 388.1[M+H]+;[Method 4]

[1019] 1 H NMR (400MHz, DMSO-d6) δ10.11(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).

[1020] Example 20b

[1021] 12 mg of the first eluting enantiomer

[1022] Chiral SFC Rt = 2.31 min (mobile phase: 5%-55% MeOH column: (RR) Whelk-O1 4.6x100mm 5um column, 6 min run)

[1023] LCMS Rt=1.91min;MS m / z 388.0[M+H]+;[Method 4]

[1024] 1 H NMR (400MHz, DMSO-d6) δ10.11(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).

[1025] Example 21: Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1026]

[1027] Step 1: 2-Cyclopropyl-5-fluorobenzaldehyde

[1028]

[1029] 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 K2CO3 aqueous solution (10.00 mL, 20.00 mmol) was stirred and heated to 80 ° C. After completion, the reaction mixture was cooled to room temperature and then distributed between water and ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica [0-20% ethyl acetate in heptane] to provide 800 mg of the title compound, 49% yield. The crude product was used without further purification.

[1030] Step 2: Methyl 4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1031]

[1032] The title compound was prepared according to 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 (containing 0.2% NH4OH / CO2) at 80 g / min; column: (SS) Whelk-O1 4.6x100 mm).

[1033] Example 21

[1034] 21.4 mg of the first eluting enantiomer as a white solid (5.6%).

[1035] 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).

[1036] LCMS Rt = 0.95 min; MS m / z 362.5 [M+H]+; [Method 4].

[1037] 1 H NMR (400 MHz, DMSO-d6) δppm 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 group is hidden under the DMSO peak.

[1038] Example 21b

[1039] 10.3 mg of the second eluting enantiomer as a white solid (2.7%).

[1040] 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).

[1041] LCMS Rt = 0.95 min; MS m / z 362.5 [M+H]+; [Method 4].

[1042] 1 H NMR(400MHz,DMSO-d6)δppm 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).

[1043] Example 22: Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1044]

[1045] Step 1: 2-Cyclopropylbenzaldehyde

[1046]

[1047] A degassed solution of 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 K2CO3 aqueous solution (5.40 mL, 10.81 mmol) was stirred and heated to 80°C. After completion, the reaction mixture was cooled to room temperature and then distributed between water and ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica [0-20% ethyl acetate in heptane] to provide 420 mg mg of the title compound, 53% yield. The crude product was used without further purification.

[1048] Step 2: Methyl 4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1049]

[1050] The title compound was prepared according to 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 was separated into its enantiomers using chiral SFC (mobile phase: 5%-55% methanol (containing 10 mM NH4OH / CO2) at 3 mL / min; column: (SS) WHO; 1 4.6x100 mm).

[1051] Example 22

[1052] 7.9 mg of the first eluting enantiomer as a white solid (3.0%).

[1053] Chiral SFC Rt=2.77min

[1054] LCMS Rt = 0.93 min; MS m / z 344.5 [M+H]+; [Method 4].

[1055] 1H NMR (400MHz, methanol-d4) δppm 6.91-7.23(m,4H),5.73(d,J=1.96Hz,1H),5.61(d,J=2.93Hz,1H),5.48(s,1H),4.8 2(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).

[1056] Example 22b

[1057] 7.5 mg of the second eluting enantiomer as a white solid (2.9%).

[1058] Chiral SFC Rt=3.19min

[1059] LCMS Rt = 0.93 min; MS m / z 344.5 [M+H]+; [Method 4].

[1060] 1 H NMR (400MHz, methanol-d4) δppm 6.91-7.23(m,4H),5.73(d,J=1.96Hz,1H),5.61(d,J=2.93Hz,1H),5.48(s,1H),4.8 2(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).

[1061] 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

[1062]

[1063] The title compound was prepared according to 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 at 80 g / min; column: 2.0 x 25.0 cm Chromega Chiral CC4).

[1064] Example 23

[1065] 12.2 mg of the first eluting enantiomer as a white solid (2.7%).

[1066] Chiral SFC Rt = 1.29 min (column: 4.6 x 100 mm Chiralcel OZ-H; isocratic 15% methanol and 0.1% isopropylamine; 125 bar

[1067] LCMS Rt = 0.92 min; MS m / z 390.0 [M+H]+; [Method 4].

[1068] 1 H NMR(400MHz,DMSO-d6)δppm 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).

[1069] Example 23b

[1070] 14.0 mg of the second eluting enantiomer as a white solid (3.0%).

[1071] Chiral SFC Rt = 1.74 min (column: 4.6 x 100 mm Chiralcel OZ-H; isocratic 15% methanol (containing 0.1% isopropylamine); 125 bar)

[1072] LCMS Rt = 0.92 min; MS m / z 390.0 [M+H]+; [Method 4].

[1073] 1H NMR(400MHz,DMSO-d6)δppm 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).

[1074] Example 24: Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1075]

[1076] The title compound was prepared according to General Procedure II 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). 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 at 80 g / min; column: 2.0 x 25.0 cm Chromega Chiral CC4).

[1077] Example 24

[1078] 7.9 mg of the first eluting enantiomer as a white solid (2.0%).

[1079] Chiral SFC Rt = 1.19 min (mobile phase: 20% methanol (containing 0.1% isopropylamine / CO2) at 4 mL / min; column: Chiralcel OZ-H; 1 4.6 x 100 mm).

[1080] LCMS Rt = 0.91 min; MS m / z 370.0 [M+H]+; [Method 4].

[1081] 1H NMR(400MHz,DMSO-d6)δppm 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).

[1082] Example 24b

[1083] 9.3 mg of the second eluting enantiomer as a white solid (2.4%).

[1084] Chiral SFC Rt = 1.72 min (mobile phase: 20% methanol (containing 0.1% isopropylamine / CO2) at 4 mL / min; column: Chiralcel OZ-H; 1 4.6 x 100 mm).

[1085] LCMS Rt = 0.91 min; MS m / z 370.0 [M+H]+; [Method 4].

[1086] 1 H NMR(400MHz,DMSO-d6)δppm 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).

[1087] 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

[1088]

[1089] Step 1: 2-(2-Bromo-3-fluorophenyl)-1,3-dioxolane

[1090]

[1091] 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 using a Dean-Stark apparatus for 24 hours. The solvent was added to water (2 L) and extracted into EtOAc (3 L). EtOAc was washed with saturated NaHCO3 solution (1 L), brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0 → 10%) ethyl acetate in petroleum ether) to give the title compound 2- (2-bromo-3-fluorophenyl) -1,3-dioxolane (60 g) as a colorless liquid.

[1092] 1 H NMR (400MHz, CDCl3) δ7.42-7.37(m,1H),7.34-7.29(m,1H),7.16-7.10(m,1H),6.10(s,1H),4.19-4.09(m,4H).

[1093] Step 2: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde

[1094]

[1095] Under nitrogen atmosphere, a solution of 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1, 7g, 28.45mmol) in THF (70mL) was cooled to -78 °C. Then n-butyllithium (13.66mL, 2.5M, 58.5mmol) in n-hexane solution was added over 10min. The resulting mixture was stirred at -78 °C for 45min, then DMF (2.5g, 34.15mmol) was added, and the resulting mixture was stirred at -78 °C for 1.15h. The reaction mixture was quenched with saturated ammonium chloride solution (50mL), and extracted with ethyl acetate (2x100mL). The combined organic phase was washed with water (50mL), then washed with brine (50mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to give the title compound 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5 g) as a colorless liquid.

[1096] 1H 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).

[1097] Step 3: 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane

[1098]

[1099] Under nitrogen atmosphere, 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) were added to a solution of acetonitrile (65 mL). The reaction was stirred at 70 ° C for 30 min, and then methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (12 g, 62.4 mmol) was slowly added over a period of 10 min (the color of the material turned yellow when added). The resulting mixture was stirred at 70 ° C for another 3 hours, then cooled to room temperature, diluted with diethyl ether, the precipitated solid was removed by filtration, and washed with diethyl ether (100 mL). The resulting solvent was removed under reduced pressure and the crude product was purified by silica flash chromatography ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (6.9 g) as a light yellow liquid.

[1100] 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).

[1101] Step 4: 2-(3-Fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane

[1102]

[1103] A solution of 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from step 3, 2.7 g, 11.73 mmol) and tetrabutylammonium fluoride in THF (13.7 g, 1 M, 13.7 mmol) was heated to 70 ° C in a closed system for 2 hours. The reaction was allowed to cool, diluted with diethyl ether, and washed with water (50 mL), saturated NaHCO3 solution (100 mL) and brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica flash chromatography ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane (1.2 g) as a colorless liquid.

[1104] 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).

[1105] Step 5: 3-Fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde

[1106]

[1107] 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 hours. This was washed with water (50 mL), saturated NaHCO3 solution (100 mL), brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica flash chromatography ((0→5%) ethyl acetate in petroleum ether) to give the title compound 3-fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde (1.2 g) as a colorless liquid. The crude product was used as is in the next step without further purification.

[1108] Step 6: 3-Ethoxycyclopent-2-en-1-one

[1109]

[1110] pTSA (193 mg, 1.019 mmol) and EtOH (22.61 ml, 387.35 mmol) were added to a stirred solution of cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene (70 mL) at room temperature. The resulting mixture was stirred at 120 ° C using a Dean-Stark apparatus for 10 hours. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) to give the title compound 3-ethoxycyclopent-2-ene-1-one (4.3 g) as a brown solid.

[1111] 1 H NMR (400MHz, CDCl3) δ5.26 (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).

[1112] Step 7: 3-Aminocyclopent-2-en-1-one

[1113]

[1114] 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 hours. The solvent was removed under reduced pressure to give the title compound 3-aminocyclopent-2-en-1-one (3.2 g) as a brown solid.

[1115] LCMS Rt=0.114min;MS m / z 98.2[M+H]+;[Method 7]

[1116] 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

[1117]

[1118] 3-aminocyclopent-2-ene-1-one (from step 7, 94 mg, 0.9708 mmol) was added to a solution of aldehyde (from step 5, 200 mg, 0.9708 mmol), methyl 4-fluoro-3-oxobutyrate (method 2, step 1 of intermediate B, 130 mg, 0.9708 mmol) in EtOH (2 mL). The reaction mixture was stirred at 80 ° C for 18 hours. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica ((0 → 70%) ethyl acetate in petroleum ether) to give the title compound as an off-white solid. The racemic mixture was separated into its enantiomers using chiral preparative HPLC [method 6].

[1119] Example 25

[1120] The second eluting enantiomer was obtained as a white solid (25 mg).

[1121] Chiral HPLC Rt = 7.610min; [Chiral analysis method 4]

[1122] LCMS Rt=1.533min;MS m / z 401.75[M+]+;[Method 12]

[1123] 1 H NMR (400MHz, CD3OD) δ7.31-7.25(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).

[1124] Example 25b

[1125] First eluting enantiomer as a white solid (24 mg).

[1126] Chiral HPLC Rt 7.103min; [Chiral analysis method 4]

[1127] LCMS Rt=1.533min;MS m / z 401.75[M+]+;[Method 12]

[1128] 1H NMR (400MHz, CD3OD) δ7.31-7.25(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).

[1129] 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

[1130]

[1131] Step 1: 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane

[1132]

[1133] 10% Pd-C (1 g) was added to a solution of 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (from Example 25, Step 3, 3g, 13.04mmol) in ethyl acetate (60mL). The resulting reaction mixture was stored in a Parr shaker at room temperature under a hydrogen atmosphere at a pressure of 60psi for 48 hours. The reaction mixture was filtered through a diatomaceous earth pad and washed with ethyl acetate (30mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→30%) ethyl acetate in petroleum ether) to give the title compound 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (3 g) as a colorless liquid.

[1134] 1 H NMR (300MHz, CDCl3) δ7.42-7.35(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).

[1135] Step 2: 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde

[1136]

[1137] 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 hours. This 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 the crude product was purified by flash chromatography on silica ((0→5%) ethyl acetate in petroleum ether) to give the title compound 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1.9 g) as a colorless liquid.

[1138] 1 H NMR (400MHz, CDCl3) δ10.14(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).

[1139] 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

[1140]

[1141] 3-aminocyclopent-2-ene-1-one (Example 25, Step 7, 103 mg, 1.063 mmol) is added to a solution of aldehyde (from step 2, 200 mg, 1.063 mmol), methyl 4-fluoro-3-oxobutyrate (Method 2, Step 1 of Intermediate B, 142 mg, 1.063 mmol) in EtOH (2 mL). The reaction mixture is stirred at 80 ° C for 18 hours. The solvent is removed under reduced pressure to give a crude compound. The crude product is purified by flash chromatography on silica ((0 → 70%) ethyl acetate in petroleum ether) to give the title compound (100 mg) as an off-white solid. Using chiral preparative HPLC [Method 6], the racemic mixture is separated into its enantiomers.

[1142] Example 26

[1143] The first eluting enantiomer was obtained as a white solid (25 mg).

[1144] Chiral HPLC Rt 7.341min; [Chiral analysis method 4]

[1145] LCMS Rt=1.505min;MS m / z 384.2[M+1]+;[Method 12]

[1146] 1 H NMR (400MHz, CD3OD) δ7.25-7.17(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).

[1147] Example 26b

[1148] The second eluting enantiomer was obtained as a white solid (26 mg).

[1149] Chiral HPLC Rt 9.044min; [Chiral analysis method 4]

[1150] LCMS Rt=1.505min;MS m / z 384.2[M+1]+;[Method 12]

[1151] 1 H NMR (400MHz, CD3OD) δ7.25-7.17(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).

[1152] 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

[1153]

[1154] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol

[1155]

[1156] At -78 ° C under nitrogen atmosphere, to 2- (2- bromo -3- fluorophenyl) -1,3- dioxolane (from Example 25, step 1, 30g, 121.42mmol) in THF (300mL) solution in n-BuLi (58.3mL, 2.5M, 147.71mmol) was added dropwise over 10min in n-hexane solution. The resulting mixture was stirred at -78 ° C for 1h, then acetaldehyde (6.42g, 145.71mmol) was added, and the reaction was stirred at -78 ° C for 1h. The reaction mixture was quenched with saturated ammonium chloride solution (50mL) and extracted with ethyl acetate (2x100mL). The combined organic phase was washed with water (50mL), washed with brine (50mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol (15 g) as a colorless liquid.

[1157] 1 H NMR (400MHz, CDCl3) δ7.38 (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).

[1158] Step-2: 2-(3-Fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane

[1159]

[1160] At -78 ° C, diethylaminosulfur trifluoride (19.3 mL, 141.37 mmol) was added to a solution of 1-(2-(1,3-dioxolane-2-yl)-6-fluorophenyl)ethan-1-ol (from step 1, 15 g, 70.68 mmol) in dichloromethane (150 mL). The resulting solution was allowed to warm to RT and stirred for 1 hour. 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 the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (8.5 g) as a colorless liquid.

[1161] 1 H NMR(300MHz, CDCl3)δ7.38(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).

[1162] Step-3: 3-Fluoro-2-(1-fluoroethyl)benzaldehyde

[1163]

[1164] 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 hours. This 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 aldehyde obtained is volatile in nature).

[1165] 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

[1166]

[1167] 3-aminocyclopent-2-ene-1-one (Example 25, Step 7, 570 mg, 5.876 mmol) was added to a solution of aldehyde (from step 3, 1 g, 5.876 mmol), methyl 4-fluoro-3-oxobutyrate (Method 2, Step 1 of Intermediate B, 780 mg, 5.876 mmol) in EtOH (10 mL). The reaction mixture was stirred at 80 ° C for 18 hours. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0 → 70%) ethyl acetate in petroleum ether) to give the title compound (220 mg) as a diastereoisomer 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 as an off-white solid.

[1168] Using chiral preparative purification [Method 2], the diastereomeric mixture was separated into its two isomers.

[1169] Using chiral preparative purification [Method 5], the first peak of diastereoisomeric separation was separated into its enantiomers Peak 1 and Peak 2.

[1170] Example 27

[1171] The second eluting enantiomer obtained as a white solid (55 mg)

[1172] Chiral HPLC Rt = 5.729min; [Chiral analysis method 2]

[1173] LCMS Rt = 2.25 min; MS m / z 364.1 [MH]-; [Method 7]

[1174] 1 H NMR (400MHz, CDCl3) δ7.25-7.15(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).

[1175] Example 27b

[1176] The first eluting enantiomer was obtained as a white solid (55 mg).

[1177] Chiral HPLC Rt = 5.678min; [Chiral analysis method 2]

[1178] LCMS Rt = 2.25 min; MS m / z 364.1 [MH]-; [Method 7]

[1179] 1 H NMR (400MHz, CDCl3) δ7.25-7.15(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).

[1180] Using chiral preparative purification [Method 10], the second peak of the diastereoisomeric separation was separated into its enantiomers Peak 3 and Peak 4.

[1181] Example 27c

[1182] The third eluting enantiomer was a white solid (10 mg).

[1183] Chiral HPLC Rt = 8.702min; [Chiral analysis method 2]

[1184] LCMS Rt = 2.22 min; MS m / z 364.1 [MH]-; [Method 7]

[1185] 1 H NMR (400MHz, CDCl3) δ7.25-7.15(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).

[1186] Example 27d

[1187] The fourth eluting enantiomer was a white solid (10 mg).

[1188] Chiral HPLC Rt = 9.851min; [Chiral analysis method 2]

[1189] LCMS Rt = 2.22 min; MS m / z 364.1 [MH]-; [Method 7]

[1190] 1H NMR (400MHz, CDCl3) δ7.25-7.15(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).

[1191] Example 28: Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[1192]

[1193] Step 1: 2-Cyclopropyl-3-fluorobenzaldehyde

[1194]

[1195] 2N KCO (25.5 mL, 182.16 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) were added 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). The resulting solution was degassed with argon for 10 min and stirred at 100 ° C for 4 hours. 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 NaSO. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica ((0→1%) ethyl acetate in petroleum ether) to give the title compound 2-cyclopropyl-3-fluorobenzaldehyde (11.2 g) as a colorless liquid.

[1196] 1 H NMR (300MHz, CDCl3) δ10.70 (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).

[1197] Step 2: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate

[1198]

[1199] Cyclopentane-1,3-dione (875.68161 mg, 5.481 mmol) was added to a solution of 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). The reaction mixture was stirred at 80 ° C for 16 hours. The solvent was removed under reduced pressure, and the crude product was purified by silica flash chromatography ((0 → 70%) ethyl acetate in petroleum ether) 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].

[1200] Example 28

[1201] The first eluting enantiomer was obtained as a white solid (46 mg).

[1202] Chiral HPLC Rt = 10.37min; [Chiral analysis method 3]

[1203] LCMS Rt=1.47min;MS m / z 360.2[M+H]+;[Method 7]

[1204] 1 H NMR (400MHz, CDCl3) δ7.10-7.01(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).

[1205] Example 28b

[1206] The second eluting enantiomer was obtained as a white solid (48 mg).

[1207] Chiral HPLC Rt = 15.216min; [Chiral analysis method 3]

[1208] LCMS Rt=1.47min;MS m / z 360.2[M+H]+;[Method 7]

[1209] 1 H NMR (400MHz, CDCl3) δ7.10-7.01(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).

[1210] 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

[1211]

[1212] Step 1: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde

[1213]

[1214] To a solution of 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (from step 2 of 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 diacetoxy iodobenzene (11.4 g, 35.37 mmol). The resulting solution was stirred at 30 ° C for 2 hours. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The filtrate was dissolved in water (200 mL) and extracted into ethyl acetate (500 mL), and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica ((0→10%) ethyl acetate in petroleum ether) to give the title compound 2-(1,3-dioxolane-2-yl)-4,6-difluorobenzaldehyde (3 g) as a colorless liquid.

[1215] 1 H NMR (300MHz, CDCl3) δ10.41 (s, 1H), 7.35 (d, J = 9.6Hz, 1H), 6.95-6.85 (m, 1H), 6.53 (s, 1H), 4.08 (s, 4H).

[1216] Step 2: 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethan-1-ol

[1217]

[1218] At 0 ° C, methylmagnesium bromide (2.33 mL, 3M in ether, 4.67 mmol) was added to a solution of 2- (1,3-dioxolane-2-yl) -4,6-difluorobenzaldehyde (from step 1, 1.0 g, 4.67 mmol) in dry tetrahydrofuran (10 mL). The resulting solution was stirred at room temperature for 1 hour. 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-dioxolane-2-yl) -4,6-difluorophenyl) 1-ol (950 mg) as a colorless liquid. The crude compound was carried out to the next step without further purification.

[1219] 1 H NMR (300MHz, CDCl3) δ7.17 (dd, J=2.4, 6.3Hz, 1H), 6.89-6.72 (m, 1H), 6.17 (s, 1H), 5.3 1(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).

[1220] Step 3: 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane

[1221]

[1222] Diethylaminosulfur trifluoride (1.0 g, 6.13 mmol) was added to a solution of 1-(2-(1,3-dioxolane-2-yl)-4,6-difluorophenyl)ethan-1-ol (from step 2, 950 mg, 4.13 mmol) in dichloromethane (10 mL) at -78 ° C. The resulting solution was stirred at room temperature for 1 hour. 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 out to the next step without further purification.

[1223] 1H NMR (300MHz, CDCl3) δ7.20 (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).

[1224] Step 4: 3,5-difluoro-2-(1-fluoroethyl)benzaldehyde

[1225]

[1226] 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 hours. This 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 aldehyde obtained is volatile in nature)

[1227] 1 H NMR (300MHz, CDCl3) δ10.44(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).

[1228] Step 5: 3-Ethoxycyclopent-2-en-1-one

[1229]

[1230] pTSA (193 mg, 1.019 mmol) and EtOH (22.61 ml, 387.35 mmol) were added to a stirred solution of cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene (70 mL) at room temperature. The resulting mixture was stirred for 10 hours at 120 ° C using a Dean-Stark apparatus. The solvent was removed under reduced pressure to give a crude compound. The crude product was purified by flash chromatography on silica ((0 → 50%) ethyl acetate in petroleum ether) to give the title compound 3-ethoxycyclopent-2-ene-1-one (4.3 g) as a brown solid.

[1231] 1H NMR (400MHz, CDCl3) δ5.26 (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).

[1232] Step 6: 3-Aminocyclopent-2-en-1-one

[1233]

[1234] 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 hours. The solvent was removed under reduced pressure to give the title compound 3-aminocyclopent-2-en-1-one (3.2 g) as a brown solid.

[1235] LCMS RT = 0.114 min; MS m / z 98.2 [M+H]+; [Method 7]

[1236] 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

[1237]

[1238] To a solution of aldehyde (from step 4, 700 mg, 3.7204 mmol), methyl 4-fluoro-3-oxobutyrate (step 1; Method 2 of Intermediate B, 598.73 mg, 4.4645 mmol) and 3-aminocyclopent-2-en-1-one (step 6, 361.32 mg, 3.7204 mmol) in tert-butanol (15 mL). The reaction mixture was stirred at 80° C. for 48 hours. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by flash chromatography on silica ((0→50%) ethyl acetate in petroleum ether) 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 an off-white solid first diastereomer (320 mg, peak-1). The mixture (580 mg) was further purified by preparative HPLC purification (method 8) to give an off-white solid second diastereomer (80 mg, peak-2).

[1239] Peak-1: 160 mg and Peak-2: 80 mg were further separated into their enantiomers using preparative chiral HPLC [Method 11] to obtain four isomers of Example 29.

[1240] Example 29

[1241] 50 mg of the first eluting enantiomer were obtained as a white solid using chiral HPLC [Method 11].

[1242] LCMS RT = 1.445 min; MS m / z 382.1 [MH]-; [Method 7]

[1243] This was further purified by preparative HPLC purification [Method 9] to give an off-white solid (25 mg).

[1244] Chiral HPLC: RT: 8.905min; [Chiral analysis method 3]

[1245] LCMS RT = 1.445 min; MS m / z 382.1 [MH]-; [Method 13]

[1246] 1 H NMR(400MHz, DMSO-d6)δ10.10(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).

[1247] Example 29b

[1248] Chiral HPLC [Method 11] was used to obtain 55 mg of the second eluting enantiomer as a white solid.

[1249] Chiral HPLC: RT: 10.197min; [Chiral analysis method 3]

[1250] LCMS RT = 1.510 min; MS m / z 382.1 [MH]-; [Method 13]

[1251] 1H NMR(400MHz, DMSO-d6)δ10.10(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).

[1252] Example 29c

[1253] Chiral HPLC [Method 11] was used to obtain 24.2 mg of the third eluting enantiomer as a white solid.

[1254] Chiral HPLC: RT: 14.455min; [Chiral analysis method 3]

[1255] LCMS RT = 1.504 min; MS m / z 382.0 [MH]-; [Method 10]

[1256] 1 H NMR (400MHz, DMSO-d6) δ10.13(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).

[1257] Example 29d

[1258] Chiral HPLC [Method 11] was used to obtain 32.4 mg of the fourth eluting enantiomer as a white solid.

[1259] Chiral HPLC: RT: 18.561min [Chiral analysis method 3]

[1260] LCMS RT = 1.514 min; MS m / z 382.0 [MH]-; [Method 10]

[1261] 1H NMR (400MHz, DMSO-d6) δ10.13(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).

[1262] Example 30: Methyl (R)-4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1263]

[1264] Step 1: Methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate

[1265]

[1266] 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) to give the title compound, methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (0.165 g, 43%) as a cream solid. LCMS Rt = 1.506 min; MS m / z 331.85 [M+H]+; [Method 10]

[1267] The racemic sample was separated into its enantiomers by chiral HPLC (column: LUX cellulose-4 (250MM X 21.2MM X 5 microns); mobile phase: n-hexane (A) EtOH:MeOH, 1:1 (B), flow rate: 15 mL).

[1268] Example 30

[1269] First eluting enantiomer as a pale yellow solid (30 mg).

[1270] Chiral HPLC Rt=5.952 min (column: LUX cellulose-4 (150X4.6mmX5μ); mobile phase: A=n-hexane, B: ethanol:methanol (50:50); flow rate: 1.0 mL / min).

[1271] LCMS Rt=1.53min;MS m / z 332.0[M+H]+;[Method 7]

[1272] 1 H NMR(400MHz,DMSO-d6)δ10.03(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).

[1273] Example 30b

[1274] The second eluting enantiomer was a pale yellow solid (29 mg).

[1275] Chiral HPLC Rt=7.581 min (column: LUX cellulose-4 (150X4.6mmX5μ); mobile phase: A=n-hexane, B: ethanol:methanol (50:50); flow rate: 1.0 ml / min).

[1276] LCMS Rt=1.528min;MS m / z 332.0[M+H]+;[Method 7]

[1277] 1 H NMR(400MHz,DMSO-d6)δ10.03(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).

[1278] 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

[1279]

[1280] Step 1: 5-ethyl 3-methyl 2-(dimethoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

[1281]

[1282] A stirred solution of methyl 4,4-dimethoxy-3-oxobutyrate (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 h. The reaction mixture was concentrated under reduced pressure to give a crude compound as a brown liquid. The crude compound was purified by silica flash chromatography ((9% → 10%) ethyl acetate in hexane) to give the title compound as a yellow viscous 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%).

[1283] The compounds were used crude without further analysis.

[1284] Step 2: 3-ethyl 5-methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylate

[1285]

[1286] 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. At 0 ° C, 6N aqueous hydrochloric acid solution (15.0 mL) was added, 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 saturated sodium bicarbonate solution, 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 hexane) to give diastereomer 1 (400 mg, 26%) and diastereomer 2 (300 mg, 20%) of the title compound as a yellow viscous liquid.

[1287] Diastereomer 1

[1288] LCMS Rt = 1.606 min; MS m / z 392.0 [MH]-; [Method 10]

[1289] 1H NMR (300MHz, DMSO-d6) δ10.13(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)

[1290] Diastereomer 2

[1291] LCMS Rt = 1.461 min; MS m / z 392.0 [MH]-; [Method 14]

[1292] 1 H NMR (300MHz, DMSO-d6) δ10.12(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).

[1293] Step 3: 5-ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

[1294]

[1295] 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 (diastereomer 1 from 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 in portions at -78 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by 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).

[1296] LCMS Rt = 1.632 min; MS m / z 414.0 [MH]-; [Method 10]

[1297] 1 H NMR(300MHz,DMSO-d6)δ9.38(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)

[1298] Step 4: 3-ethyl 5-methyl 2-(bromomethyl)-6-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate

[1299]

[1300] 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, 0.3g, 0.722mmol) in dichloromethane (5.0mL) was cooled to -78 °C. At -78 °C, pyridinium tribromide (0.254g, 0.794mmol) was added and stirred for 1h at the same temperature. The reaction mixture was then stirred at room temperature for 30 minutes. 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 hexane) to obtain the title compound as a yellow viscous 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%)

[1301] LCMS Rt = 1.653 min; MS m / z 491.95 [MH]-; [Method 10]

[1302] 1 H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.40-7.34(m,2H),7.11-7.02(m,2H),6.40-6.24(m,1H),5.16(s,1H),4 .73(dd,J=34,9.2Hz,2H),4.14-4.05(m,2H),3.58(s,3H),1.75(dd,J=22.4,6.4Hz,3H),1.18(t,J=7.4Hz,3H)

[1303] 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

[1304]

[1305] 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 h. 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 h. 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), 5.0 μ; mobile phase: A = water B = ACN; flow rate: 18 ml / min) to give the title compound (methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate) as a cream solid (20 mg, 26%).

[1306] LCMS Rt = 1.503 min; MS m / z 384.05 [MH]-; [Method 10]

[1307] 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).

[1308] Example 31:

[1309] First eluting peak by chiral HPLC as a cream solid (3.4 mg).

[1310] Chiral HPLC Rt = 6.393 min (column: CHIRAL PAK IJ (250X4.6mmX5μ); mobile phase: A: n-hexane B: ethanol; flow rate: 1.0 mL / min.

[1311] LCMS Rt=1.502min;MS m / z 384.05[MH]-[Method 10]

[1312] 1H NMR(300MHz,DMSO-d6)δ10.43(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)

[1313] Example 31b

[1314] Second eluting peak by chiral HPLC as a cream solid (3 mg).

[1315] Chiral HPLC Rt = 7.605 min (column: CHIRAL PAK IJ (250X4.6mmX5μ); mobile phase: A: n-hexane B: ethanol; flow rate: 1.0 mL / min.

[1316] LCMS Rt = 1.500 min; MS m / z 384.05 [MH] -. [Method 10]

[1317] 1 H NMR(300MHz,DMSO-d6)δ10.42(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).

[1318] Crystalline form

[1319] X-ray powder diffraction measurement (XRPD)

[1320] XRPD was performed with a Bruker D8 Advance diffractometer equipped with a nickel filter monochromator and a LYNXEYE (1D mode) detector with an opening angle of 2.948° using Cu-Kα 1,2The diffraction patterns were recorded at a tube voltage of 40 kV and a tube current of 40 mA, over an angular range of 2° to 40° 2-θ under ambient conditions, using a step size of 0.0164° (2-θ value) with 0.3 seconds per step. The scan time was 768 seconds. The typical accuracy of the 2-θ value is within the range of ±0.2° 2-θ, preferably ±0.1° 2-θ. Thus, for example, the diffraction peak 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 appearing at 10.4° 2-θ, for example, may appear in the range from (10.4-0.2)° to (10.4+0.2)° 2-θ, preferably from (10.4-0.1)° to (10.4+0.1)° 2-θ on most X-ray diffractometers under standard conditions.

[1321] Crystalline Form A

[1322] 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 diethyl ether (520 ml) at room temperature for 3 hours to obtain a suspension, which was filtered. The wet cake was then dried at 60° C. under vacuum for 72 hours to provide 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.

[1323] Crystalline Form B

[1324] Crystalline Form B was prepared by dissolving 100 mg of Form A in sufficient isopropyl acetate to obtain a solution. Sufficient heptane was then added at 55° C. until a turbid 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 to 4 hours. The solid portion was separated and analyzed by XRPD to confirm the presence of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofurano[3,4-b]pyridine-3-carboxylate (Form B).

[1325] Alternative synthesis: 400 mL of heptane was added to a 500 mL reactor and heated to 55 ° C. At room temperature, 20 g of Form A was added to 60 mL of isopropyl acetate. At 55 ° C, about 2 g of Form B was added to the reactor as a seed, and the resulting mixture was balanced at 55 ° C for 30 min. Then a syringe pump was used to add a solution of isopropyl acetate in the free form of Form A to the reactor dropwise over 2 hours. The resulting mixture was balanced at 55 ° C for 2 hours. The mixture was then cooled to 25 ° C within 6 hours and then rebalanced at 25 ° C for 10 hours. The suspension was then filtered, and the wet cake was dried under vacuum at 50 ° C for 4 hours. About 21 g of the final product was obtained, which was confirmed to be consistent with Form B by XRPD. The water content measured by KF was 0.3%.

[1326] Crystalline Form C

[1327] 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 was crystallized with various stoichiometric amounts of citric acid (base:acid ratios of 4:1, 3:1, 2:1, or 1:1) in tert-butyl methyl ether. The solid form obtained was consistent with 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).

[1328] Alternative synthesis: At 25 ° C, 40 mL of heptane was added to a 100 mL EasyMax reactor. At room temperature, 2 g of Form A was dissolved in 5 mL of isopropyl acetate. Then at 25 ° C, 20 mg of seeds of Form C were added to the reactor. The resulting mixture was balanced at 25 ° C for 30 min. An isopropyl acetate solution of Form A free form was added dropwise to the reactor over a 2 hour period using a syringe pump. The resulting mixture was balanced at 25 ° C for 2 hours. Process control shows 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. The XRPD of the final product was consistent with Form C. The water content measured by KF was 0.3%.

[1329] Crystalline Form Hydrate A

[1330] 1.97 g of Form A was weighed into a 100 mL EasyMax glass vial and dispersed in 35 mL of water, the suspension was stirred at 50° C. for 3 hours at 300 rpm with overhead stirring, then cooled to 25° C. at about 0.07° C. / min over 6 hours, then kept stirring at 25° C. for 24 hours. The solid material was isolated by filtration. The XRPD of the solid form was consistent with Hydrate A.

[1331] Alternative Synthesis: For example, hydrate A is obtained by evaporative crystallization of a clear saturated solution of crystalline form B in 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. At 25°C, the water absorption between 10% and 95% RH is about 0.2%.

[1332] Crystalline Form Hydrate B

[1333] 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 at 25° C. for 20 hours at 300 rpm with overhead stirring. The solid material was isolated by filtration, and the solid was exposed to 92% RH for 1 day. The solid material was consistent with Hydrate B as confirmed by XRPD.

[1334] Alternative Synthesis: Hydrate B was obtained by air drying crystalline Form B in methanol solvate. Hydrate B showed a mass loss of about 4.4% by TGA, which is also close to the monohydrate (calculated water content of 4.7%). Hydrate B began to dehydrate below 20% RH and lost about 4.4% of water by 0% RH. Upon subsequent increase in relative humidity, it absorbed only about 3% of water at 25°C.

[1335] Differential Scanning Calorimetry

[1336] Differential scanning calorimetry was performed using a TA Discovery DSC in the temperature range of 30°C to 300°C at a scan rate of 10°C / min under nitrogen at a flow rate of 25 mL / min. The sample mass used was approximately 2 mg.

[1337] Biological data

[1338] Many known calcium channel activators have been shown to activate Ca V These molecules not only increase peak currents, but also have additional mechanisms of increasing intracellular calcium concentrations, for example, by shifting the voltage sensitivity of the channel toward more negative membrane potentials. Figure 6The Ca2+ signal is expressed by plotting simulated cardiac action potentials from the epicardial environment and displaying the Ca2+ signal at potential (mV) versus time (ms). V These alternative mechanisms may be demonstrated by the effects of the voltage of activation of 1.2 toward a more negative membrane potential. These alternative mechanisms may drive or contribute to cardiovascular effects such as increased blood pressure, changes in heart rate or contractility, and / or arrhythmias resulting from QT prolongation. For example, the O'Hara-Rudy model is used to study the effects of Ca V 1.2 Effects of modulation on action potential duration and arrhythmogenic tendency. It has been determined that a hyperpolarizing shift of >12 mV in the activation curve can potentially lead to >15% QT prolongation and increased risk of arrhythmias. Therefore, minimizing any shift in voltage sensitivity may result in a compound with a reduced risk of QT prolongation and arrhythmias.

[1339] The compound of formula (I) is a highly effective Ca V 1.2 Activators, which have biophysical characteristics that minimize the above cardiovascular risks. First, compounds of formula (I) limit their effects on voltage sensitivity by minimizing hyperpolarization shifts to <9 mV, thereby reducing the potential for arrhythmias. Second, compounds of formula (I) V 1.2 The peak current does not increase more than 2.5 times, thereby limiting the over-activation of the channel. Third, the compound of formula (I) does not delay the Ca V 1.2 Channel inactivation (which is the underlying pathophysiological mechanism of the cardiac symptoms of Timothy syndrome) In addition, compounds of formula (I) are designed to maximize brain exposure by not showing significant efflux in the brain.

[1340] Ca V 1.2-Generation and maintenance of HEK293(AUX) cell line

[1341] Monoclonal Ca V 1.2-HEK293 (AUX) cell line constitutively expresses human Ca V1.2α1C (alpha1C) subunit (CACNA1C) and doxycycline-inducible expression of α2Δ (alpha2delta, α2Δ2) auxiliary subunit (CACNA2D2) and β2 (beta2) auxiliary subunit (CACNB2). To generate cell lines, expression vectors pcDNA5.0 / FRT-TO-CACNA2D2-FCS-P2A-CACNB2 and pCMV6-entry-CACNA1C were established by gene synthesis and cloning. Here, pcDNA5.0 / FRT-TO plasmid is from Invitrogen, pCMV6-entry is from Origene, FCS represents furin cleavage site, P2A is a peptide self-cleavage sequence derived from porcine teschovirus-1, and FRT is a flippase recognition target site. Next, the parental line Flp-In was transfected with pcDNA5.0 / FRT-TO-CACNA2D2-FCS-P2A-CACNB2 and the flippase vector pOG44 (Invitrogen). TM 293T-Rex (Invitrogen) was used to construct the CACNA2D2-FCS-P2A-CACNB2 expression cassette for Flp-In TM Targeted integration of the pre-engineered FRT site in 293T-Rex was performed. 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 current (see electrophysiological methods below) was selected for characterization of Ca V 1.2 Activator.

[1342] To maintain the cell line, cells were passaged twice a week. At each passage, the growth medium (Table 6) was completely removed and the cells were washed with 10 ml of D-PBS and 5 ml of warm TrypLE TM After washing, D-PBS and TrypLE were immediately removed. TM Express enzyme. The plate is then placed at room temperature for 3-5 minutes. Next, 10 mL of warm 37°C complete medium is added to rinse the cell growth surface and collect the dissociated cells. The cells are counted and seeded into a new flask with a target density of 2-3 × 10 6 cells / T175cm 2 Flask.

[1343] Table 6. HEK293-Ca V 1.2 (AUX) cell growth medium

[1344] Reagents concentration DMEM Heat-inactivated fetal bovine serum 10％ Hygromycin B 100ug / ml 30 Blasticidin 10ug / ml Geneticin (G418) 200ug / mL

[1345] Use Ca V 1.2-HEK293 (AUX) cell line and QPatch for Ca V 1.2 Electrophysiological characterization of activators

[1346] Doxycycline (1 μg / ml) was added to the growth medium (Table 6) 24 hours before electrophysiological experiments, and 25 μM verapamil was co-applied to prevent calcium influx-induced cell death. Just before the experiment, the cell confluence should reach 70%-80%.

[1347] To harvest cells (from T175cm as an example 2 flask), the growth medium was completely removed, and the cells were rinsed with 10 mL of D-PBS. The D-PBS was aspirated and 10 mL of Detachin (Genlantis) was added, and the plate was placed in a 37°C incubator for 10 minutes. The detached cells were placed in a 15 mL conical tube and spun at 1000 rpm for 2 minutes. The supernatant was removed and the cells were resuspended in QPatch complete medium (Table 7) to achieve the desired cell density of 1.5-3 million cells per QPatch run. 1.5 mL of cells were used for each experimental run.

[1348] The cell suspension was transferred to the Sophion QPatch platform, which uses whole-cell voltage clamp to measure Ca2+ in single-well QPlates. V 1.2 Conducted barium currents. The extracellular and intracellular patch clamp solutions are described in Tables 7 and 8, respectively. The dose response assay protocol was used to determine the peak inward current (Emax) and potency (EC 50 ). The protocol had eight liquid periods. The first liquid period was a steady current amplitude that was monitored using repeated 200-ms voltage pulses stepping from -80 mV to 0 mV. The second liquid period was a baseline current amplitude determined in the presence of vehicle control using a single 20-ms voltage pulse stepping from -80 mV to 0 mV. The third to eighth liquid periods also used a single 20-ms voltage pulse stepping from -80 mV to 0 mV to determine the 6 dose responses to compound treatment. EC was generated using the following equation 50 :I 浓度 =I 基线 +(I 完整 -I 基线 )*c n / (XC 50 n+c n ), where c is the concentration and n is the Hill coefficient constant. 完整 is the maximum achievable current, and I 基线 is 0. The channel biophysical assay protocol is used to determine the channel gating properties, including the current-voltage relationship (IV curve), the half-way channel activation voltage (V 1 / 2 ), channel inactivation rate (tau) and tail current amplitude. Among them, V 1 / 2 According to the fitting equation: G(V) = G Vmin +(G Vmax -G Vmin ) / (1+exp(-(V-V1 / 2) / V 斜率 )) is obtained, where G represents conductivity, G Vmin =0, G Vmax is the maximum conductance, and V slope is the slope factor. G(V) is pre-calculated by the equation G(V)=I(V) / (V-0.06), for each experimentally applied depolarizing potential (V) and corresponding current amplitude (I(V)), where 0.06 in the equation is the experimentally determined reversal potential in volts. The protocol has four liquid cycles. The first liquid cycle is a stable current amplitude that is monitored using repeated 200-ms voltage pulses that step from -80mV to 0mV. After the current amplitude stabilizes, the baseline value of inactivated tau is determined by fitting a single exponential to the inactivation phase of the current trajectory. The second liquid cycle is a measurement of the baseline value that constitutes the current-voltage relationship in the presence of a vehicle control, and the third liquid cycle is a measurement of the effect of the compound on the current-voltage relationship. During each of these two liquid cycles, ten 20-ms voltage pulses were given to the cell, each of which stepped from -80mV to an incremental value ranging from -55mV to +35mV (increment size of 10mV). During the fourth liquid cycle, a 200-ms voltage pulse from -80 mV to 0 mV was again delivered to measure the effect of the compound on inactivated tau.

[1349] Table 6. QPatch Complete Medium:

[1350] Reagents concentration CHO-Serum-Free Medium (SFM) 1M HEPES 25mM

[1351] Table 7. Extracellular solutions used in QPatch experiments

[1352]

[1353] Table 8. Intracellular solution for QPatch experiments. This solution is a mixture of 80% of the second part (stored at -80°C) and 20% of the first part:

[1354] Part I:

[1355]

[1356] Part II:

[1357]

[1358] Evaluation of compound exposure-cFos induction (PK-PD) relationships in wild-type mice

[1359] Animal maintenance and ethics. All animals were housed under regulated temperature and light cycles (22°C, 12 h light / 12 h dark cycle) with unrestricted access to food and water. All animal experiments were performed in accordance with the institutional guidelines for the care and use of laboratory animals approved by the Institutional Animal Care and Use Committee (IACUC) of the Novartis Institutes for BioMedical Research, Inc. (Cambridge, MA, USA).

[1360] Compound administration and brain tissue collection. Wild-type C57BL / 6J male mice were obtained from Jackson laboratories (Bar Harbor, ME). The Ca2+-dependent agonists of the present disclosure were evaluated in eight-week-old male mice. V 1.2 Acute single-dose effect of activators (each compound, n = 6 mice). Each compound was dissolved in 10% PEG300, 10% Solutol, 10% Cremophore EL and 70% phosphate buffered saline and administered intraperitoneally (ip) at a concentration of 1 mg / kg to 30 mg / kg, depending on the compound. The animals were euthanized by bleeding one hour after compound administration under deep anesthesia. Blood was collected in EDTA tubes for downstream analysis of drug levels. The brain was 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 maintain the integrity of RNA in the sample. The samples were kept in RNAlater at 4°C for at least 24 hours and then moved to -80°C for storage before processing.

[1361] cFos mRNA induction was quantified. Tissue homogenization was performed using a 96-well plate tissue grinder (TissueLyser) system (Qiagen). First, frozen cortical samples were thawed, taken out from RNAlater, and placed in a tissue grinder tube with buffer RLT containing 0.5% reagent DX and a 5mm tissue grinder metal bead. The tissue grinder tube was loaded into a tissue grinder II tissue homogenizer for 3 rounds of homogenization, each round of homogenization lasting 5 minutes at a 30Hz bead grinding frequency. Total RNA was purified from the homogenate using the RNeasy96Plus kit (Qiagen), RNA concentration and A260 / A280 ratio were quantified by Nanodrop (Thermo Fisher Scientific), and all samples were normalized relative to a 100ng / μL concentration. RNA was reverse transcribed into cDNA using the Superscript III First-strandsynthesis SuperMix Kit (Thermo Fisher Scientific). 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. Next, 10 μL of 2X first-strand reaction mixture and 2 μL of enzyme mixture were added to reach a total reaction volume of 20 uL. The sample was heated to 50°C for 50 minutes and then heated to 85°C for 5 minutes to complete cDNA synthesis.

[1362] Quantitect Multiplex RT-PCR kit (Qiagen) was used to carry out quantitative PCR on cDNA samples in 384-well assay format. Each PCR well contained 2 μl of cDNA (total 60 ng), 10 μl of RT-PCR premix, 1 μl of cFosFAM Taqman probe (Mm00487425_m1 (FAM) #4351368), 1 μl of GAPDH VIC Taqman probe (Mm99999915-g1 (VIC) #4448486), 0.2 μl of Multiplex RT mixture and 5.8 μl of RNase-free water. On ViiA7 real-time PCR system (Thermo Fisher Scientific), samples were heated to 95°C for 15 minutes, then cycled between 45 seconds at 94°C and 45 seconds at 60°C for 45 seconds, for 45 cycles. cFos Ct values ​​were exported, normalized to GAPDH Ct values, and converted to relative fold changes in expression using the delta-delta Ct relative quantification method. Fold changes in cFos between compound treatment and vehicle were analyzed by one-way ANOVA followed by Tukey post hoc comparisons.

[1363] Compound exposure was quantified. Cerebellar tissue samples were homogenized in 4 ml of 20% acetonitrile and 80% phosphate buffered saline for every 1 g of tissue (5x dilution). Tissues were homogenized using one of three methods, depending on tissue type: a hand-held probe system, a tissue grinder system with a 5 mm steel ball, at a frequency of 30 s -1 , for 4 min, or OMNI Bead Ruptor Elite homogenizer, for 30 sec to 1 min. Tissue samples were added to 96-well plates (12.5 uL sample) and processed for quantification by mass spectrometry.

[1364] result

[1365] Table 9: Compound data

[1366]

[1367]

[1368] Qpatch was performed as a 6-point dose response with 10 separate measurements at each concentration. Unless otherwise stated only one experimental replicate (n=1) was used.

[1369] *n=2

[1370] #n=3

[1371] nd = not determined

[1372] Comparative Examples

[1373] Other Ca V 1.2 Activators are known, however these compounds are not as potent and / or do not possess the desired biophysical properties required to activate the channel and do not have sufficient brain exposure while minimizing cardiovascular risks (such as increased blood pressure, changes in heart rate or contractility and / or arrhythmias resulting from QT prolongation).

[1374] Table 10. Comparison examples with other known CaV1.2 activators

[1375]

[1376]

Claims

1. A compound according to formula (I), or a pharmaceutically acceptable salt thereof in: A is O or CH2; R 1 is H or F; R 2 is H or F; and R 3 is OCHF2, methyl, ethyl, or cyclopropyl, each of which is optionally substituted with 1 to 3 F groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having formula (Ia):

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound having formula (Ib):

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

5. The compound as claimed in claim 4, wherein R 2 It's F.

6. The compound of claim 4, wherein R 2 It's H.

7. The compound of claim 4, wherein R 3 It's OCHF2.

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

9. The compound of claim 4, wherein R 3 It is CHF2 or CF3.

10. The compound of claim 4, wherein R 3 It is ethyl substituted by 1 or 2 F groups, or cyclopropyl which is unsubstituted or substituted by 2 F groups.

11. The compound of any one of claims 1-3, wherein A is CH2.

12. The compound of claim 11, wherein R 2 It's F.

13. The compound of claim 11 or claim 12, wherein R 3 It is ethyl substituted by 1 to 3 F groups.

14. The compound of claim 1, selected from the group consisting of: 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 pharmaceutically acceptable salt thereof.

15. The compound of claim 1, selected from the group consisting of: 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 pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein the compound is 17. 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.

18. The crystalline form of claim 17, wherein the form is Form A, characterized in that Having an X-ray powder diffraction pattern comprising reflections at the following 2-theta angles: 8.5°±0.2, 10.4°±0.2, and 10.8°±0.

2.

19. The crystalline form of claim 17, wherein the form is Form B, characterized in that Having an X-ray powder diffraction pattern comprising reflections at the following 2-theta angles: 12.0°±0.2, 13.7°±0.2, and 21.4°±0.

2.

20. The crystalline form of claim 17, wherein the form is Form C, characterized in that Having an X-ray powder diffraction pattern comprising reflections at the following 2-theta angles: 10.3°±0.2, 15.5°±0.2°, and 20.6°±0.

2.

21. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

22. A compound as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in the preparation of Ca V 1.2 Use of activators in 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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