Methyl 2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6,7-tetrahydro-1h-cyclopenta[b]pyridine-3-carboxylate and methyl 2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate as cav1.2 activators

Abstract

To provide CaV1.22 activators for 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.SOLUTION: The present disclosure provides a compound according to the formula (I) in the figure or a pharmaceutically acceptable salt thereof. (In the formula: A is O or CH2; R1 is H or F; R2 is H or F; and R3 is OCHF2, methyl, ethyl or cyclopropyl each of which is optionally substituted with one to three F atoms.)SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to methyl 2-(fluoromethyl)-5-oxo-4-phenyl-4,5,6, 7-Tetrahydro-1H-cyclopenta[b]pyridine-3-carboxylate and methyl 2-(fluoromethyl)-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuran Furo[3,4-b]pyridine-3-carboxylate compounds and pharmaceutical compositions containing them and mental disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders. neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and Autism spectrum disorders; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and and Alzheimer's disease; and cardiac conditions, e.g., Brugada syndrome, Short QT syndrome, and Calcium signaling defects and / or synaptic dysfunction in early repolarization syndrome and early repolarization syndrome Ca for treatment V 1.2 Concerning the use of such compounds as activators. [Background technology]

[0002] Advances in human genomics have shed light on the genetic basis of psychiatric disorders. Genome-wide association studies (GWAS) of Ca V 1.2, and Neuro The results are consistent with those of over 100 other diseases, including other genes involved in calcium signaling in mice. Cross-disorder GWAS analyses have identified genetic loci associated with schizophrenia, bipolar disorder, and It is strongly associated with polarizing disorders, major depressive disorder, ADHD, and autism spectrum disorders. TeCa V 1.2 and its channel-forming beta subunit (CACNB2) have been identified. In addition to evidence from GWAS, exome sequencing in patients with schizophrenia has The determination is Ca V 1.2, and the CACNA2D, CACNB, and CAMK2 genes Enrichment of disruptive mutations in other gene members of the calcium signaling pathway in the thymus Ca V 1.2 Neuronal differentiation and migration, neurite outgrowth, and synaptic signaling It has been shown to be important for brain development, gene expression, and brain plasticity. V 1.2 It has been shown to play a role in the brain's emotions, learning and memory, executive functions, and reward responses. It has been shown that:

[0003] Ca V 1.2 is widely expressed throughout the body and is involved in multiple organ systems, including the cardiovascular system. However, Ca in the cardiovascular system V 1.2 Physiological functions , which differs from its function in the brain. V 1.2 is a function of the action potential generation in the heart. while playing a significant role in the generation of action potentials in neurons. Studies have shown that ribosomal protein is a key driver of intracellular signaling and gene expression. In Timothy syndrome, Ca V 1.2 The mutation p.G406R is a marker for cardiomyocytes and Cardiovascular specific disorders (Brugada syndrome and Ca2+, which causes long QT syndrome type 8 V 1.2 mutation reduces Ca in the heart and brain V 1.2 This is further evidence of the diverse functions of

[0004] Calcium channel activators have been reported previously, but few have been used for the treatment of neuropsychiatric disorders. Further investigation into their use has been limited by their effects on the cardiovascular system. Indeed, many of these molecules are being investigated for their potential therapeutic use in heart failure. Initially investigated and developed for the purpose of identifying Ca related to psychiatric GWAS studies. V 1.2SN The majority of Ps are located in the introns of genes, and these risk SNPs are often This is associated with a reduction in mRNA expression leading to an overall reduction in calcium current amplitude. Therefore, small molecules that can increase the overall current amplitude may be useful in treating patients. This may be most beneficial for Summary of the Invention

[0005] The present disclosure provides a compound according to formula (I) or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony: A is O or CH2; R 1 is H or F; R 2 is H or F; R 3 is OCHF2, methyl, ethylene, each of which is optionally substituted with 1 to 3 F. cyclopropyl, cyclopropyl, or cyclopropyl.

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

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

[0008] In a fourth aspect, the present disclosure provides a method for treating, among other conditions, schizophrenia, bipolar disorder, major ataxia, Psychiatric disorders, including depression and substance use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder sexual disorders, Phelan-McDermid syndrome, and autism spectrum disorders; neurodegenerative disorders, For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, For example, in the treatment of Brugada syndrome, short QT syndrome, and early repolarization syndrome. The present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in treating a chronic inflammatory condition.

[0009] In a fifth aspect, the present disclosure provides a method for the administration of a compound of formula (I) to a patient in need of such treatment. The present invention relates to a method for treating schizophrenia, bipolar disorder, major depressive disorder, and depression, comprising administering a compound or a pharma- ceutical Psychiatric disorders, including depressive disorders, and substance use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder (ADHD); movement disorders, Phelan-McDermid syndrome, and autism spectrum disorders; neurodegenerative disorders , such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions. Methods for treating, e.g., Brugada syndrome, short QT syndrome, and early repolarization syndrome to provide.

[0010] In a sixth aspect, the present disclosure provides a method for treating schizophrenia, bipolar disorder, major depressive disorder, and substance abuse. Psychiatric disorders, including use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder, Ferran-Maslow Coudermid syndrome, and autism spectrum disorders; neurodegenerative disorders, e.g., multiple sclerosis , frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, such as Brugada syndrome. In the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease, short QT syndrome, and early repolarization syndrome, or a pharma- ceutically acceptable salt thereof.

[0011] In a seventh aspect, the present disclosure provides a method for administering a compound according to formula (I) to a patient in need of such treatment. The present invention relates to a method for treating schizophrenia, bipolar disorder, major depressive disorder, and the like, comprising administering to said patient a compound or a pharma- ceutical acceptable salt thereof. psychiatric disorders, including mental disorders, behavioral disorders, and substance use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder , Phelan-McDermid syndrome, and autism spectrum disorders; neurodegenerative disorders, e.g. , multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, e.g. The present invention provides methods for the treatment of Brugada syndrome, short QT syndrome, and early repolarization syndrome. do.

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

[0013] In a ninth aspect, the present disclosure provides a method for treating, in particular, schizophrenia, bipolar disorder, major ataxia, Psychiatric disorders, including depression and substance use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder sexual disorders, Phelan-McDermid syndrome, and autism spectrum disorders; neurodegenerative disorders, For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, For example, in the treatment of Brugada syndrome, short QT syndrome, and early repolarization syndrome. The present invention provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof for use in treating a chronic obstructive pulmonary disease (COPD) comprising:

[0014] In a tenth aspect, the present disclosure provides a method for administering to a patient in need of treatment thereof an effective amount of a compound of formula (I II) or a pharma- ceutical acceptable salt thereof, psychiatric disorders, including mental health problems, major depressive disorder, and substance use disorders; neurodevelopmental disorders, e.g., attention Deficit / hyperactivity disorder, Phelan-McDermid syndrome, and autism spectrum disorder; neurodegenerative disorders disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, such as Brugada syndrome, short QT syndrome, and early repolarization syndrome. The present invention provides a method for:

[0015] In an eleventh aspect, the present disclosure provides a method for treating schizophrenia, bipolar disorder, major depressive disorder, and depression. Psychiatric disorders, including quality of life disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder, psychiatric disorders, McDiarmid syndrome, and autism spectrum disorders; neurodegenerative disorders, such as multiple sclerosis dementia, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, such as Brugada syndrome. In the manufacture of a medicament for the treatment of pulmonary circulation disorders, short QT syndrome, and early repolarization syndrome, III) or a pharma- ceutically acceptable salt thereof.

[0016] In a twelfth aspect, the present disclosure provides a method for the treatment of a patient having a compound according to formula (III) The present invention relates to a method for treating schizophrenia, bipolar disorder, and ataxia, comprising administering a compound or a pharma- ceutical thereof or a pharma- ceutical acceptable salt thereof to a patient. Psychiatric disorders, including depression and substance use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder sexual disorders, Phelan-McDermid syndrome, and autism spectrum disorders; neurodegenerative disorders, For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and cardiac conditions, For example, methods for the treatment of Brugada syndrome, short QT syndrome, and early repolarization syndrome are provided. provide. [Brief description of the drawings]

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

[0018] 5.1.Definition Generally, the nomenclature used herein, as well as the organic chemical Laboratory procedures in pharmaceutical chemistry, medicinal chemistry, and pharmacology are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein are Terms generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. .

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

[0020] As used herein, "optionally substituted" means that the group to which it refers is: Any one or any combination of the groups listed thereafter at one or more positions This means that it can be replaced by

[0021] As used herein, "halo" or "halogen" refers to When present, it may be fluorine, chlorine, bromine or iodine.

[0022] As used herein, a "subject" refers to a subject of the pharmaceutical compositions described herein. A disease or disorder described herein that can be treated by administration of psychiatric disorders, including depression, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders; For example, attention deficit hyperactivity disorder, Phelan-McDiarmid syndrome, and other autism spectrum disorders. neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; -DISEASE; and cardiac conditions, such as Brugada syndrome, short QT syndrome, and early repolarization disorder. A living organism suffering from one or more of the following disorders: For example, humans and animals, such as dogs, cows, horses, monkeys, pigs, sheep, goats, and cats. , mice, rabbits, rats, and transgenic non-human animals). In embodiments, the subject is a human, e.g., a patient suffering from a disease described herein (e.g., integrative Psychiatric disorders, including ataxia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders Harm, e.g., attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; Immersion disease; and cardiac conditions, such as Brugada syndrome, short QT syndrome, and premature redistribution syndrome. Humans who suffer from, are at risk for, or are potentially susceptible to be.

[0023] Throughout this specification and in the claims that follow, unless the context requires otherwise, Except as provided herein, the word "include" or variations thereof, such as "included" or "including" , means to include a stated integer or step or group of integers or steps to the exclusion of any other integer or step or group of integers or steps. It should be understood that this does not mean

[0024] If there is a discrepancy between a shown structure and a chemical name given to that structure, the shown structure In addition, the configuration of a structure or part of a structure is weighted by, for example, a bold line or Unless indicated by dashed lines, the structure or part of the structure is shown in all three dimensions of the structure or part of the structure. It is intended to include isomers.

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

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

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

[0028] In another embodiment, A is O.

[0029] In another embodiment, A is CH2.

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

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

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

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

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

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

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

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

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

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

[0040] In another embodiment, R 3 is a cycloalkyl group that is unsubstituted or substituted with two Fs. It is propyl.

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

[0042] In another embodiment, A is O.

[0043] In another embodiment, A is CH2.

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

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

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

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

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

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

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

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

[0052] In another embodiment, R3 is ethyl substituted with one or two F.

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

[0054] In another embodiment, R 3 is a cycloalkyl group that is unsubstituted or substituted with two Fs. It is propyl.

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

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

[0057] The specific compound is Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluoro (2-(fluorophenyl)-5-oxo-1,4,5,7-tetrahydrofuran b[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluoro (2-(fluorophenyl)-5-oxo-1,4,5,7-tetrahydrofuran b[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-carbo xylates; Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-di Fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran Droflo[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-di Fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran Droflo[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl (fluoromethyl)-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 (fluoromethyl)-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 (fluoromethyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3, 4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl 2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-phenyl Chlopenta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl 2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-phenyl Chlopenta[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-carbo xylates; 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-(fluorophenyl) (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine -3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluorophenyl) (Oromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b] Pyridine-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoro (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine -3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3,5-difluoro Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran [3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3,5-difluoro Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran [3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoro (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridin ketone-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2- (Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pi Lysine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoro (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridin ketone-3-carboxylate; Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethoxy) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- carboxylate; Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- carboxylate; Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-phenyl 1,4,5,7-Tetrahydrofuro[3,4-b]pyridine-3-carboxylate to; Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoro (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridin ketone-3-carboxylate; Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl) )phenyl)-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbo xylates; (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2 -(Fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopentene ta[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-cyclopentadiene pent[b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)- 2-(Fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopentadiene pent[b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl (ethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin ketone-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl 2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-phenyl Chlopenta[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-phenyl Chlopenta[b]pyridine-3-carboxylate Includes.

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

[0059] Depending on the selection of starting materials and procedures, compounds can be produced with any of the possible stereoselective stereochemistry depending on the number of asymmetric carbon atoms. In the form of one of the isomers or as a mixture thereof, for example as a pure optical isomer, or as stereoisomeric mixtures, e.g. racemates and diastereoisomeric mixtures The present disclosure includes racemic mixtures, diastereomeric mixtures and optically pure mixtures. The term "stereoisomer" is intended to include all such possible stereoisomers, including optically active ( The (R) and (S) stereoisomers may be prepared using chiral synthons or chiral reagents. or may be resolved using conventional techniques. If the compound contains a double bond, the substituents may be When the compound contains a disubstituted cycloalkyl, the cycloalkyl may be in the E, E or Z configuration. Alkyl substituents may have cis or trans configurations. All tautomeric forms are also included. It is intended to be used in

[0060] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. The term "salt" specifically includes "a pharma- ceutically acceptable salt." "Salts that are suitable for use in the preparation of pharmaceutical compositions" are salts that retain the biological effectiveness and properties of the compounds disclosed herein and typically are biologically In many cases, the compounds of the present disclosure are referred to as salts that are not undesirably or otherwise undesirable. is formed into acid salts and / or salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Or a basic salt can be formed.

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

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

[0063] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, and the like. Acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid Aromatic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfo Contains salicylic acid.

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

[0065] Inorganic bases from which salts can be derived include, for example, ammonium salts and salts of the compounds of the periodic table. In certain embodiments, the salts include metals from groups I to XII. derived from calcium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; especially Suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts. nothing.

[0066] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary Amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins Certain organic amines include isopropylamine, benzathine, cholinate, etc. , diethanolamine, diethylamine, lysine, meglumine, piperazine and trometa Including Min.

[0067] In another aspect, the present disclosure provides an acetate, ascorbate, adipate, asparagine, Phosphate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, sulfate Salt / Sulfate, Camphorsulfonate, Caprate, Chloride / Hydrogen, Chlortheof Ilonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate phosphate, glucuronate, glutamate, glutarate, glycolate, hippurate, Hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate Salt, malate, maleate, malonate, mandelate, mesylate, methylsulfate , mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, Oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / phosphorus dihydrogen acetate, polygalacturonate, propionate, sebacate, stearate, Succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, Compounds of the present disclosure are provided in the form of a trifluoroacetate salt or a xinafoate salt.

[0068] Contains groups that can act as donors and / or acceptors for hydrogen bonds The compounds of the present disclosure, i.e., compounds of formula (I), can be co-crystallized with a suitable co-crystal former. These co-crystals can be prepared by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, etc. by co-melting, or by crystallizing the compound of formula (I) and the co-crystal former in solution under crystallization conditions. and isolating the co-crystal thereby formed. Suitable co-crystal formers are described in WO 2004 / 078163. Accordingly, the present disclosure further provides a co-crystal comprising a compound of formula (I).

[0069] Furthermore, the compounds of the present disclosure, including their salts, may also be obtained in the form of their hydrates. or other solvents used for their crystallization. , which inherently or intentionally forms solvates with pharma- ceutically acceptable solvents (including water) therefore, the disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a compound of the present disclosure with one or more solvent molecules. Such solvent molecules are used in the recipe. those commonly used in the pharmaceutical arts, known to be harmless to patients, e.g. , water, ethanol, etc. The term "hydrate" refers to the complex where the solvent molecule is water.

[0070] The present disclosure provides unlabeled and isotopically labeled forms of compounds of formula (I). Isotopically labeled compounds include those in which one or more atoms have a selected atomic mass or The formulas shown herein are used except that atoms having mass numbers are substituted. Isotopes that can be incorporated into the compounds of the present disclosure include, for example, , including isotopes of hydrogen.

[0071] Additionally, certain isotopes, particularly deuterium (i.e. 2 The incorporation of H or D) is more Greater metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements, or may confer certain therapeutic benefits due to improvements in therapeutic index or tolerability. It is understood that deuterium, in this context, is considered a substituent of the compounds of the present disclosure. The concentration of deuterium may be defined by the isotopic enrichment factor. As used herein, the term "abundance" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. Where a substituent in a compound of the present disclosure is indicated as being deuterium, such compound The material must have at least 3500 (52.5% deuterium at each designated deuterium atom) incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (6 7.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least At least 5500 (82.5% deuterium uptake) and at least 6000 (90% deuterium uptake) (95% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466. 7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or Each designated deuterium atom has at least 6633.3 (99.5% deuterium incorporation) The term "isotopic enrichment factor" describes deuterium. It should be understood that the present invention can be applied to any isotope in the same manner as described above.

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

[0073] Other examples of isotopes that can be incorporated into the compounds of the present disclosure include hydrogen, carbon, nitrogen, oxygen, and argon. , phosphorus, fluorine, and chlorine isotopes, e.g., 3 H, 11 C. 13 C. 14 C , 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 I Thus, the present disclosure includes, for example, radioisotopes, e.g. 3 H and 14 Including C Compounds incorporating one or more of any of the above isotopes or non-radioactive isotopes therein. Positions, for example, 2 H and 13 It should be understood that this includes compounds in which C is present. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques, e.g., drugs or substrate tissue Positron emission tomography (PET) or single photon emission computed tomography including distribution assays It is useful in spectroscopic computed tomography (SPECT) or in radioactive treatment of patients. To, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The disclosed isotopically labeled compounds are generally prepared by conventional techniques known to those of skill in the art or by methods previously known to those of skill in the art. Use the appropriate isotopically labeled reagents instead of the unlabeled reagents used in the accompanying procedure. It can be prepared by methods similar to those described in the examples and preparations.

[0074] Any asymmetric atoms (e.g., carbon, etc.) of the compounds of the present disclosure may be racemic or enantiomerically enriched. It can exist in condensed configurations, for example, in the (R), (S) or (R,S) configurations. In certain embodiments, each asymmetric atom is at least 50% mirror image in the (R) or (S) configuration. 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. Groups may be in the cis- (Z)- or trans- (E)-form, where such is possible.

[0075] Thus, as used herein, the compounds of the present disclosure include any of the possible stereoisomers. , rotamers, atropisomers, tautomers or mixtures thereof, e.g. , substantially pure geometric (cis or trans) stereoisomers, diastereomers, photoisomers The compound may be present as an optical isomer (enantiomer), a racemate or a mixture thereof.

[0076] Any resulting mixtures of stereoisomers can be purified by, for example, chromatography and / or By fractional crystallization, pure or substantially pure compounds can be obtained based on the physicochemical differences of the constituents. Can be separated into pure geometric or optical isomers, diastereomers, and racemates. Cut.

[0077] Any resulting racemates of the compounds or intermediates of the present disclosure may be purified by known methods. For example, the separation of diastereomeric salts thereof obtained with optically active acids or bases, and the separation of the diastereomeric salts thereof obtained with optically active acids or bases, The decomposition into optical antipodes can be achieved by liberation of optically active acidic or basic compounds. In this way, the basic moiety can be used to produce, for example, an optically active acid, such as tartaric acid, dibenzoyl Zoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, By fractional crystallization of the salt formed with malic acid or camphor-10-sulfonic acid, The disclosed compounds may be resolved into their optical antipodes. Intermediates may also be used to perform chiral chromatography, e.g., high pressure liquid chromatography. The compounds can be resolved by chromatography (HPLC).

[0078] How to use The compounds of the present disclosure, in free form or in the form of a pharma- ceutically acceptable salt, can be, for example, As shown in in vitro and in vivo tests such as those provided in this document, It has valuable pharmacological properties, e.g., Ca V 1.2 Showing activating properties and therefore therapeutic or as a research chemical, e.g., as a tool compound.

[0079] The compounds of the present disclosure may be useful in the treatment of an indication selected from the list below. : Psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders; Neurodevelopmental disorders, such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and autism dementia spectrum disorders; and Neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia and Alzheimer's disease, and Cardiac conditions, such as Brugada syndrome, Short QT syndrome, and Early Repolarization Syndrome. In the form, the indications are psychiatric disorders, such as schizophrenia, bipolar disorder, major depressive disorder, and and substance use disorder. In another embodiment, the indication is schizophrenia or bipolar disorder. .

[0080] Thus, in a further aspect, the present disclosure provides a compound or pharmaceutical composition of the present disclosure in therapy. In a further embodiment, the treatment is a method for treating Ca V 1.2 In another embodiment, the disease is selected from diseases that can be treated by activation of the The selection is made from the list of options described above.

[0081] Thus, in a further aspect, the present disclosure provides a compound of the present disclosure for use in therapy. In a further embodiment, the treatment comprises administering to the patient a therapeutically effective amount of Ca V 1 In another embodiment, the disease is selected from diseases that can be treated by activation of .2. The disease is selected from the above list of disorders.

[0082] In another aspect, the present disclosure provides a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable Ca, including administration of its salts V 1.2 is provided as a method for treating a disease that is treated by activation of In a further embodiment, the disease is selected from the above list of indications.

[0083] In another aspect, the present disclosure provides a method for administering a compound of the present disclosure or a pharma- ceutical acceptable salt thereof. Contains Ca V 1.2. In some embodiments, the disease is selected from the above list of indications.

[0084] Thus, in a further aspect, the present disclosure provides a method for the manufacture of a medicament comprising administering to a subject a compound of the present disclosure or In a further embodiment, the medicament is Ca V 1 In another embodiment, the disease is for the treatment of a disease that can be treated by activation of The indications are selected from the above list.

[0085] In another aspect, the present disclosure provides a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable Ca, including administration of its salts V 1.2 activation treats schizophrenia, bipolar disorder Harm, major depressive disorder, substance use disorder, ADHD, Phelan-McDiarmid syndrome, autism Spectrum disorders, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome The present invention provides methods for the treatment of short QT syndrome, or early repolarization syndrome.

[0086] In another aspect, the present disclosure provides a method for administering a compound of the present disclosure or a pharma- ceutical acceptable salt thereof. Including, schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, ferran- McDiarmid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, alopecia For the treatment of Zheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome A method is provided.

[0087] Thus, in a further aspect, the present disclosure provides a method for treating schizophrenia, bipolar disorder, major depressive disorder, Harm, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder , multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome A compound or drug of the present disclosure for treating a disease selected from the group consisting of: The present invention provides for the use of physiologically acceptable salts thereof.

[0088] Thus, in a further aspect, the present disclosure provides a method for treating schizophrenia, bipolar disorder, major depressive disorder, Harm, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder , multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome The compound of the present disclosure for use in treating a disease selected from the group consisting of cerebrovascular disease, cerebrovascular disease, and cerebrovascular disease. or a pharma- ceutically acceptable salt thereof.

[0089] In another aspect, the present disclosure provides a therapeutically effective amount of a compound of the present disclosure or a pharma- ceutically acceptable and the administration of its salts to treat schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADH. D, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome The present invention provides a method for the treatment of

[0090] In another aspect, the present disclosure provides a method for administering a compound of the present disclosure or a pharma- ceutical acceptable salt thereof. Including, schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, ferran- McDiarmid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, alopecia For the treatment of Zheimer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome A method is provided.

[0091] Thus, in a further aspect, the present disclosure provides a method for treating schizophrenia, bipolar disorder, major depressive disorder, Harm, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder , multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, short QT syndrome or a compound or pharmaceutical composition of the present disclosure for the manufacture of a medicament for the treatment of early repolarization syndrome. The present invention provides for the use of physiologically acceptable salts thereof.

[0092] Pharmaceutical Compositions In another aspect, the present disclosure provides a compound of the present disclosure or a pharma- ceutically acceptable salt thereof, and a drug. In a further embodiment, the composition comprises: At least two pharma- ceutically acceptable carriers, including those described herein, The pharmaceutical composition may be administered by a specific route, for example, oral administration, parenteral administration (e.g., injection, infusion, etc.). They can be formulated for oral, transdermal or topical administration, and rectal administration. Administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present disclosure may be in solid form (such as including, but not limited to, capsules, tablets, pills, granules, powders or suppositories), or The composition may be prepared in a liquid form (including, but not limited to, a solution, a suspension, or an emulsion). Tablets can be film coated by methods known in the art. Typically, the pharmaceutical composition comprises: a) excipients, such as lactose, dextrose, sucrose, mannitol, sorbitol, Thor, cellulose and / or glycine; b) For tablets also lubricants, e.g. silica, talcum, stearic acid, magnesium ium or calcium salts and / or polyethylene glycol; c) optionally, a binder, for example, magnesium aluminum silicate, starch paste, gel cellulose, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescents. Gender mixture; and e) Absorbents, colouring agents, flavouring agents and sweetening agents The active ingredient is preferably a tablet or gelatin capsule containing one or more of the following:

[0093] The pharmaceutical composition or combination of the present disclosure is administered in an amount of about 1 to 100 mg / kg for a subject weighing about 50 to 70 kg. 0 mg of active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-15 A unit dose of 0 mg or about 0.5 to 100 mg, or about 1 to 50 mg of active ingredient The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof may be administered to the subject. Depending on the species, weight, age and individual condition of the subject, the disorder or disease to be treated or its severity. A physician, clinician, or veterinarian of ordinary skill may determine whether or not to prevent, treat, or delay the progression of a disorder or disease. The effective amount of each of the active ingredients required for inhibition can be readily determined.

[0094] The above dosage characteristics are advantageously administered to a mammal, such as a mouse, rat, dog, monkey or Using isolated organs, tissues and preparations, in vitro and in vivo The compounds of the present disclosure can be demonstrated in vitro in solutions, e.g. , in the form of an aqueous solution, and in vivo enterally, parenterally, preferably intravenously, e.g. The dosage in vitro is: about 10 -3 Molar concentration ~ 10 -9 Therapeutic efficacy in vivo The effective dose is about 0.1 to 500 mg / kg or about 1 to 100 mg / kg depending on the administration route. The range may be:

[0095] Crystal morphology The present disclosure relates to methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran Crystalline forms of [3,4-b]pyridine-3-carboxylate and methods for the preparation thereof Further, the present disclosure relates to a method for treating a chronic inflammatory condition, comprising administering to a patient a predetermined and / or effective amount of methyl (R )-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoro (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine said crystalline form of .alpha.-3-carboxylate, and at least one pharma- ceutically acceptable additive. The pharmaceutical composition of the present disclosure is particularly useful for treating schizophrenia, bipolar disorder, Major depressive disorder, substance use disorder, ADHD, Phelan-McDiarmid syndrome, autism spectrum disorder Neuropsychiatric disorders, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, For use as a medicine for the treatment and / or prevention of short QT syndrome or early repolarization syndrome It is possible.

[0096] Different solid state forms of an active pharmaceutical ingredient often have different properties. Differences in physicochemical properties can play an important role for improving pharmaceutical compositions. , e.g., having an improved dissolution profile or improved stability or shelf life. Pharmaceutical formulations can be made available with improved solid state forms of active pharmaceutical ingredients. Also, the processing or handling of active pharmaceutical ingredients during the formulation process may be improved. The novel solid state forms of the ingredients can thus have desirable processing properties. They are easier to handle and better suited for storage compared to known solid forms. , and / or may allow for better purification.

[0097] Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] The crystalline form of pyridine-3-carboxylate is a useful pharmaceutical compound for characterizing solids. These may be characterized by analytical methods well known in the art. Including but not limited to, XRPD, SXRD, FTIR, Raman, DSC, TGA, and G The form may be determined by one of the analytical methods listed above, or by a combination of both. Or it may be characterized by combining more than one.

[0098] Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] The crystalline form of pyridine-3-carboxylate is shown herein in FIG. Such data may be referred to as being characterized by "graphical data as shown in FIG. 1." Examples include powder X-ray diffraction, FTIR, and Raman spectroscopy. Factors such as instrument type, Variations in response, as well as variations in sample orientation, sample concentration, and sample purity. The study shows little variation in such data when presented in graphical form. Note that the above analysis may result in variations in the exact peak positions and intensities. Those skilled in the art will understand, however, that the schematic data in the figures herein may differ from other or unrelated data. Comparison of the diagrams generated for the solid forms of the compound and whether the two sets of diagrams match the same crystal The determination of shape is well within the knowledge of one of ordinary skill in the art.

[0099] The term "reflection" as used herein with respect to powder X-ray diffraction means X-ray diffraction. means a peak in a tractogram, which corresponds to a parallel plane of atoms in a solid material. At a certain diffraction angle (Bragg angle), constructive interference from X-rays scattered by the This is caused by regular and repeating patterns in long-range positional order. Such solid materials are classified as crystalline materials, whereas amo Rufus materials lack long-range order and exhibit only short-range order and therefore have broad Long-range order is defined as a solid material that exhibits a wide range of scattering. According to the literature, long-range order is characterized by, for example, The short-range order spans roughly 100-1000 atoms, whereas the short-range order spans only a few atoms. ("Fundamentals of Powder Diffraction and Structural Characterization of Mate rials”by Vitalij K.Pecharsky and Peter Y .Zavalij, Kluwer Academic Publishers, 2003 ,see page 3).

[0100] The term "essentially the same" refers to the variability in the positions of reflections and the This means that relative intensities are taken into account. For example, a typical accuracy for 2-theta values ​​is ±0. A range of 2° 2-theta, preferably a range of ±0.1° 2-theta.

[0101] Furthermore, the relative reflection intensities are subject to variability between devices, as well as the degree of crystallinity, preferred orientation, These are qualitative measurements only and are subject to variability due to particle size, sample preparation, and other factors known to those skilled in the art. Those skilled in the art will recognize that the disclosure should be taken as given.

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

[0103] As used herein, the term "amorphous" refers to a solid form of a compound that is not crystalline. Amorphous compounds have no long-range order and do not show definitive X-ray diffraction patterns due to reflection. Does not show fold pattern.

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

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

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

[0107] The term "dehydrating" or "dehydration" as used herein refers to the dehydration of a host molecule. At least partial removal of water from the crystal structure is described.

[0108] The term "solvate" as used herein refers to a crystalline solid, wherein one The organic solvent or solvents interact with each other in the crystal structure or are converged by the crystal structure. are contained within the crystal structure or trapped within the crystal (hydrated) Thereby, the organic solvent or solvents may be present in stoichiometric or non-stoichiometric amounts. When one or more organic solvents are present in stoichiometric amounts, the solvate can be For example, solvates may be referred to by adding a Greek number prefix. Depending on the solvent / compound stoichiometry, it may be referred to as a hemisolvate or monosolvate. can be measured, for example, by GC, NMR, SXRD and / or TGA / MS. do.

[0109] The term "non-hygroscopic" as used herein refers to a relative humidity range of 0 to 95% RH. The weight of the compound was measured by GMS at a humidity of 25.0±0.1°C. Based on this, it refers to compounds that exhibit a maximum water uptake of 2% by weight in the sorption cycle.

[0110] As used herein, the term "about" means within a statistically significant range of a value. Such ranges are within an order of magnitude, typically within 10% of the stated value or range, more preferably within 10% of the stated value or range. Typically within 5%, even more typically within 1%, and most typically within 0.1%. Sometimes such ranges are used to refer to the extent possible for purposes of measuring and / or determining a given value or range. The results may be within experimental error that is inherent to the standard methods used for this purpose.

[0111] As used herein, the term "substantially free of any other solid form" is methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl )-2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4 -b] With respect to compositions comprising a particular solid form of pyridine-3-carboxylate, the composition at most 20% by weight, preferably at most 10% by weight, based on the weight of the composition; More preferably, at most 5% by weight, even more preferably at most 2% by weight, and most preferably Preferably, at most 1% by weight of methyl(R)-4-(3-fluoro-2-((R)-1- Fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7- Any other solid form of tetrahydrofuro[3,4-b]pyridine-3-carboxylate means that it contains

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

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

[0114] [Table 1]

[0115] One embodiment of the present disclosure has a wavelength of 0.15419 nm at a temperature in the range of 20 to 30° C. Cu-K Alpha 1,2 When measured by irradiation, (8.5±0.2)°, (10.4±0.2)°, and (10.8±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)° and (22. 4±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4 ±0.2)° and (22.4±0.2)°; or (8.5±0.2)°, (10.4±0.2)°, (10.8±0.2)°, (14.4 ±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8± 0.2)°, (14.4±0.2)°, (21.6±0.2)° and (22.4±0.2 )°; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8± 0.2)°, (14.4±0.2)°, (18.5±0.2)°, (21.6±0.2) ° and (22.4 ± 0.2) °; or (7.2±0.2)°, (8.5±0.2)°, (10.4±0.2)°, (10.8± 0.2)°, (14.4±0.2)°, (15.6±0.2)°, (18.5±0.2) 21.6±0.2°, (21.6±0.2)°, and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0 .2)°, (10.8±0.2)°, (14.4±0.2)°, (15.6±0.2)° , (18.5±0.2)°, (21.6±0.2)°, and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0 .2)°, (10.8±0.2)°, (13.5±0.2)°, (14.4±0.2)° , (15.6±0.2)°, (18.5±0.2)°, (21.6±0.2)° and (2 2.4±0.2)° and having an XRPD pattern including reflections at 2 theta angles of Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b ] provides form A of pyridine-3-carboxylate.

[0116] In yet another embodiment, the present disclosure provides a composition comprising a 0.15418n Cu-K alpha with wavelength of 1.0 m 1,2 When measured by irradiation, the 4. The method of claim 1, further comprising: (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-ethyl -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] Relating to a crystalline form of pyridine-3-carboxylate, Form A.

[0117] In another embodiment, the present disclosure provides a polymer having a molecular weight of 98±1000 when measured by DSC at a heating rate of 10 K / min. Methyl (R)-4-(3-phenylpropanediol) characterized by having a melting point onset of 5°C. Fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5 -Oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxy Rate, with respect to the crystalline form of Form A.

[0118] In another embodiment, the present disclosure provides a method for producing a 104 Methyl (R)-4 is characterized by having a melting point peak maximum temperature of ±5°C. -(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- Regarding the crystalline form of carboxylate form A.

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

[0120] [Table 2]

[0121] In one embodiment, the present disclosure provides a method for detecting a wavelength of 0.15419 nm at a temperature in the range of 20 to 30° C. Cu-K alpha with 1,2 When measured by irradiation, (12.0±0.2)°, (13.7±0.2)°, and (21.4±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)° and (21 0.4±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21. 4±0.2)° and (23.8±0.2)°; or (12.0±0.2)°, (13.7±0.2)°, (18.3±0.2)°, (21. (4±0.2)°, (23.0±0.2)° and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (18.3 ±0.2)°, (21.4±0.2)°, (23.0±0.2)° and (23.8±0. 2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (14.5 ±0.2)°, (18.3±0.2)°, (21.4±0.2)°, (23.0±0.2 )° and (23.8±0.2)°; or (9.1±0.2)°, (12.0±0.2)°, (13.7±0.2)°, (14.5 ±0.2)°, (15.7±0.2)°, (18.3±0.2)°, (21.4±0.2 )°, (23.0±0.2)° and (23.8±0.2)° and having an XRPD pattern including reflections at 2 theta angles of Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b ] provides form B of pyridine-3-carboxylate.

[0122] In yet another embodiment, the present disclosure provides a composition comprising a 0.15418n Cu-K alpha with wavelength of 1.0 m 1,2 When measured by irradiation, the 4. The method of claim 1, further comprising: (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-ethyl -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] Concerning the crystalline form of pyridine-3-carboxylate form B.

[0123] In another embodiment, the present disclosure provides a polymer having a molecular weight of 184 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 Concerning the crystalline form of sylate form B.

[0124] In another embodiment, the present disclosure provides a polymer having a molecular weight of 185 Methyl (R)-4 is characterized by having a melting point peak maximum temperature of ±5°C. -(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- Regarding the crystalline form of carboxylate form B.

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

[0126] [Table 3]

[0127] In one embodiment, the present disclosure provides a method for detecting a wavelength of 0.15419 nm at a temperature in the range of 20 to 30° C. Cu-K alpha with 1,2 When measured by irradiation, (10.3±0.2)°, (15.5±0.2)°, and (20.6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)° and (20 .6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (20. 6±0.2)° and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18. 2±0.2)°, (20.6±0.2)° and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18. 2±0.2)°, (20.6±0.2)°, (22.7±0.2)° and (22.0±0 .2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (16. 6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0. 2)° and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15. 5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0. 2)°, (22.7±0.2)°, and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15. 5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0. 2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)° or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12. 8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0. 2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and 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)° and having an XRPD pattern including reflections at 2 theta angles of Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b ] provides form C of pyridine-3-carboxylate.

[0128] In yet another embodiment, the present disclosure provides a composition comprising a 0.15418n Cu-K alpha with wavelength of 1.0 m 1,2 When measured by irradiation, the present invention shown in FIG. 4. The method of claim 1, further comprising: (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-ethyl -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] Regarding the crystalline form of pyridine-3-carboxylate form C.

[0129] In another embodiment, the present disclosure provides a polymer having a molecular weight of 178 or less when measured by DSC at a heating rate of 10 K / min. 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 Concerning the crystalline form of sylate form C.

[0130] In one embodiment, the present disclosure provides a polymer having a molecular weight of 178±1000, as measured by DSC at a heating rate of 10 K / min. 5° C., characterized by a melting point peak maximum temperature of methyl (R)-4- (3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl) (1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate The present invention relates to the crystalline morphology of carboxylate form C.

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

[0132] [Table 4]

[0133] In one embodiment, the present disclosure provides a method for detecting a wavelength of 0.15419 nm at a temperature in the range of 20 to 30° C. Cu-K alpha with 1,2 When measured by irradiation, (10.0±0.2)°, (10.6±0.2)°, and (23.5±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (23.5±0.2)° and (25 0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (14.4±0.2)°, (23. 5±0.2)° and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (14.4±0.2)°, (22. (9±0.2)°, (23.5±0.2)° and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14. 4±0.2)°, (22.9±0.2)°, (23.5±0.2)° and (25.0±0 .2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14. 4±0.2)°, (17.5±0.2)°, (22.9±0.2)°, (23.5±0. 2)° and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (12.8±0.2)°, (14. 4±0.2)°, (17.5±0.2)°, (18.1±0.2)°, (22.9±0. 2)°, (23.5±0.2)° and (25.0±0.2)°; or (10.0±0.2)°, (10.6±0.2)°, (11.1±0.2)°, (12. 8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0. 2)°, (22.9±0.2)°, (23.5±0.2)° and (25.0±0.2)° or (10.0±0.2)°, (10.6±0.2)°, (11.1±0.2)°, (12. 8±0.2)°, (14.4±0.2)°, (17.5±0.2)°, (18.1±0. 2)°, (20.0±0.2)°, (22.9±0.2)°, (23.5±0.2)° and (25.0±0.2)° and having an XPRD pattern including reflections at 2 theta angles of Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b ] to provide pyridine-3-carboxylate hydrate A.

[0134] In yet another embodiment, the present disclosure provides a composition comprising a 0.15418n Cu-K alpha with wavelength of 1.0 m 1,2 When measured by irradiation, the present invention shown in FIG. 4. The method of claim 1, further comprising: (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-ethyl -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] This relates to the crystalline form of pyridine-3-carboxylate hydrate A.

[0135] In another embodiment, the present disclosure provides a method for producing a 109 Characterized by having a broad endothermic event with peak maxima at temperatures of ±10°C. Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)fluoren-2-yl)phenyl (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[ 3,4-b]pyridine-3-carboxylate hydrate A in its crystalline form.

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

[0137] [Table 5]

[0138] In one embodiment, the present disclosure provides a method for detecting a wavelength of 0.15419 nm at a temperature in the range of 20 to 30° C. Cu-K alpha with 1,2 When measured by irradiation, (5.5±0.2)°, (8.4±0.2)°, and (13.0±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (13.0±0.2)° and (19.6 ±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0 .2)° and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0 .2)°, (16.5±0.2)° and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±0 .2)°, (16.5±0.2)°, (19.6±0.2)° and (20.6±0.2) ° or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0 .2)°, (13.0±0.2)°, (16.5±0.2)°, (19.6±0.2)° and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0 .2)°, (13.0±0.2)°, (16.5±0.2)°, (17.9±0.2)° , (19.6±0.2)° and (20.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (11.0±0 .2)°, (13.0±0.2)°, (16.5±0.2)°, (17.9±0.2)° , (19.6±0.2)°, (20.6±0.2)° and (24.0±0.2)° and having an XRPD pattern including reflections at 2 theta angles of Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b ] to provide pyridine-3-carboxylate hydrate B.

[0139] In yet another embodiment, the present disclosure provides a composition comprising a 0.15418n Cu-K alpha with wavelength of 1.0 m 1,2 When measured by irradiation, the present invention shown in FIG. 4. The method of claim 1, further comprising: (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-ethyl -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] This relates to the crystalline form of pyridine-3-carboxylate hydrate B.

[0140] In another embodiment, the present disclosure provides a polymer having a molecular weight of 93±1.001 when measured by DSC at a heating rate of 10 K / min. Characterized by having a broad endothermic event with a peak maximum at a temperature of 10° C. Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl) Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3 ,4-b]pyridine-3-carboxylate hydrate B in its crystalline form.

[0141] In another aspect, the present invention relates to a method for treating a pulmonary circulation comprising the steps of: Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] A composition comprising a crystalline form of pyridine-3-carboxylate, said composition comprising (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-ethyl -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] It is essentially free of any other solid form of pyridine-3-carboxylate. For example, The methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)fluorene of the present disclosure (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[ The composition comprising crystalline hydrate A of 3,4-b]pyridine-3-carboxylate is At most 20% by weight, preferably at most 10% by weight, more preferably at most or at most 5%, 4%, 3%, 2% or 1% by weight of methyl (R)- 4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoro Methyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3 -carboxylate] and any other solid form of the same.

[0142] Ca V 1.2-HEK293(AUX) cell line In one aspect, the present disclosure provides a method for the preparation of human Ca V 1.2 Alpha 1C (α1C) subunit ( Human CACNA1C transcript variant 14; GenBank ID: NM_001129840 ), alpha2delta (α2△2) auxiliary subunit (human C ACNA2D2 transcript variant 3; GenBank ID: NM_001174051 (encoded by the human CACNB2 transcript), and beta 2 (β2) auxiliary subunit (encoded by the human CACNB2 transcript). Mutant 2; encoded by GenBank ID: NM_201596 In a cell containing the α1C subunit, the α2Δ2 subunit is constitutively expressed. The β2 subunit and β3 subunit are expressed in a doxycycline-inducible manner. In accordance with the present disclosure, the present invention provides a method for screening compounds for biological activity. In one embodiment, the cell constitutively expresses the α1C subunit. and expresses the α2△2 and β2 subunits in a doxycycline-inducible manner. In another embodiment, the stably expressing Such cell lines can be transfected using DNA or other vectors, such as lentivirus or vaccinia. In one embodiment, the cells are produced by viral transduction via a human ovarian virus. Transient DNA transfection constitutively expresses the α1C subunit. and expressing the α2△2 and β2 subunits in a doxycycline-inducible manner. In another embodiment of the disclosure, the compound is Ca V 1.2 Activators. In another aspect, the present disclosure relates to a method for treating a disease or disorder, e.g., Schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Ferran-McDa idiopathic syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease

[0023] The present invention relates to a method for treating, preventing, and / or treating Cardiac Arrhythmia, ... or for use in a method for identifying an agent for diagnosis. In the embodiment, the agent is Ca V 1.2 It is an activator. EXAMPLES

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

[0144] All of the examples are resolved into their single enantiomers and are described in the Biological Data section below. The antibodies were tested in the Sophion Qpatch assay described in the section. The configuration of each enantiomer was not determined. -((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- carboxylate, and the methyl (R)-4-(2-(difluoromethoxy)furan of Example 9 (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[ Configuration of the active enantiomer for 3,4-b]pyridine-3-carboxylate was analyzed using single crystal X-ray crystallography and the active enantiomer was determined to be the R-enantiomer. Therefore, 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 The R-enantiomer of the rate compound is assumed to be the active enantiomer. [ka] [ka]

[0145] The example numbers (Examples 1, 2, 3, etc.) are all assumed to have the R configuration. All other isomers isolated from synthesis are given a lettered real number. Example numbers are given (Examples 1b, 2b, 3b, etc.). It has been shown that the R configuration is the desired configuration. There is strong evidence to suggest that the S-enantiomer is the active enantiomer. There is still a possibility to get it.

[0146] Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were performed under reduced pressure, typically at about The pressure is between 15mm Hg and 100mm Hg (=20 to 133 millibars). The structures of the products, intermediates and starting materials may be determined by standard analytical methods, e.g., microanalysis and spectroscopic characterization. The characteristics are confirmed by, for example, MS, IR, and NMR.

[0147] All starting materials, building blocks, reagents, acids, and the like used to synthesize the compounds of the present disclosure are , bases, dehydrating agents, solvents, and catalysts are either commercially available or can be prepared by methods of organic synthesis known to those skilled in the art. Further, the compounds of the present disclosure can be prepared by the methods shown in the Examples below. The compounds can be prepared by organic synthesis methods known to those skilled in the art, such as: Conventional in the art or the following: 1 H NMR Proton Nuclear Magnetic Resonance AUX Ca V 1.2 channel auxiliary subunit C Celsius CD3OD methanol-d4 CDCl3 Chloroform-d CHO Chinese hamster ovary cells Ct Threshold cycle in quantitative polymerase chain reaction assay d double line DAST Diethylaminosulfur trifluoride DCM Dichloromethane dd Double line double line DME 1,4-dimethoxyethane DMEM Dulbecco's Modified Eagle's Medium DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Dimethylsulfoxide-d6 D-PBS Dulbecco's Phosphate Buffered Saline EC50 50% effective concentration EDTA Ethylenediaminetetraacetic acid EGTA Ethylene glycol bis(β-aminoethyl ether)-N,N,N',N '-Tetraacetic acid Eq equivalent EtOAc Ethyl acetate FAM 6-Carboxyfluorescein FCS furin cleavage site FRT flippase recognition target site g grams h time H2O Water HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HOBt 1-Hydroxy-7-azabenzotriazole HPLC High Pressure Liquid Chromatography HRMS high-resolution mass spectrometry Hrs time Hz Hertz IACUC Animal Care and Use Committee IPA Isopropyl Alcohol kg Kilogram L Liter LCMS Liquid Chromatography Mass Spectrometry M mole m multiplet m / z mass-to-charge ratio mg milligram MHz Megahertz min mL Milliliters ml milliliter mL / min Milliliters per minute mm millimeters mM millimolar mmol mRNA Messenger Ribonucleic Acid MS mass spectrometry mV millivolt N Normal n-BuLi n-Butyl lithium NMR nuclear magnetic resonance NOESY Nuclear Overhauser Effect Spectroscopy pCMV cytomegalovirus promoter P2A Peptide self-cleavage sequence derived from porcine teschovirus-1 PdCl2(dppf) Dichloro[1,1'-bis(diphenylphosphino)ferrocene Palladium(II) PD Pharmacodynamics PK Pharmacokinetics ppm parts per million PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate Fluorophosphate QT: The time interval between the Q and T waves on an electrocardiogram rac Racemic rpm Revolutions per minute RNA Ribonucleic acid RT room temperature Rt retention time RT-PCR Reverse transcription polymerase chain reaction s single line SFC Supercritical Fluid Chromatography SFM Serum-free medium SNP Single nucleotide polymorphism t triple line TFA Trifluoroacetic acid THF Tetrahydrofuran uL microliter Um micrometer UPLC Ultra-Performance Liquid Chromatography UV ultraviolet light VIC 2'-chloro-7'phenyl-1,4-dichloro-6-carboxy-fluorescein in v / v volume / volume percent

[0148] Small molecule X-ray crystal structure analysis Data collection Intensity data was collected using SMART software (Bruker AXS (2003)). The monochromator-equipped Cu(Kα) radiation, the microfocus rotating anode source, and A Bruker AXS triple-axis diffractometer with a Smart6000 CCD detector and K. Sixteen ω-scans at different Φ positions were performed to ensure adequate data overlap. Data processing and global cell refinement were performed by Saint-Joseph (Bruker AXS (2012)). Semiempirical absorption correction was performed using SADABS version 2016 / 2 Using (Krause L (2015)), symmetric reflections measured at different angle settings The extinction coefficient was refined to 0.00048(11). The following lists the data, data collection parameters, and convergence results.

[0149] Structure analysis and refinement The structure was solved by the dual space recycling method followed by DF synthesis, and the SHE Sheldrick's SHELXTL program suite with LXL-2013 / 4 GM (2001)) was used to refine the full matrix least squares method for F2. .

[0150] References: Allen FH, Kennard O, Watson D et al (1987) Tables of Bond Lengths determined by XR ay and Neutron Diffraction.Part 1, Bond L engths in Organic Compounds.J.Chem.Soc.P erkin Trans II;S1-S19. Bruker AXS(2005)SMART V5.632.Bruker AXS Inc., Madison, WI, USA. Bruker AXS(2012)SAINT V7.36A.Bruker AXS Inc., Madison, WI, USA. Krause L, Herbst-Irmer R, Sheldrick GM et al(2015) Comparison of silver and molybde num microfocus X-ray sources for single- crystal structure determination.J.Appl.C ryst.;48:3-10. Spek AL(2003)Single-crystal structure va lidation with the program PLATON.J.Appl. Cryst.;36:7-13. Sheldrick GM(2001)SHELXTL V6.12.Bruker A XS Inc. Madison, WI, USA.

[0151] LCMS method 1: Instrumentation: Waters Acquity UPLC, photodiode array detector; Acquity UPLC BEH C 18 , 1.7 μm, 21 × 30 mm; 2 min Run time, 2% solvent B, 0–0.1 min, 2→98% solvent B:solvent A, 0.1–1.8 min min, 98% solvent B, 0.2 min. Solvents: solvent A = 0.1% formic acid in water (v / v), solvent B = 0.1% formic acid in acetonitrile (v / v); injection volume 2–5 μL; UV detection array 2 10-400, mass detection 120-1250 (electrospray ionization); at 50°C Column; flow rate 1.0 mL / min.

[0152] LCMS method 2: Instrumentation: Waters Acquity UPLC, photodiode array detector; Acquity UPLC BEH C 18 , 1.7 μm, 21 × 50 mm; 2 min Run time, 2% solvent B, 0–0.1 min, 2→98% solvent B:solvent A, 0.1–1.8 min min, 98% solvent B, 0.2 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water; Solvent B = 5 mM ammonium hydroxide in acetonitrile; injection volume 2–5 μL; UV detection Array 210-400, mass detection 120-1250 (electrospray ionization); 5 Column at 0°C; flow rate 1.0 mL / min.

[0153] LCMS method 3: Instrumentation: Waters Acquity UPLC, photodiode array detector; Acquity UPLC BEH C 18 , 1.7μm, 21×30mm; 5.2min Operation time, 2 → 98% solvent B: solvent A, 0 to 5.15 min, 98% solvent B, 5.15 ~5.20 min. Solvents: Solvent A = 0.1% formic acid in water (v / v), Solvent B = acetonitrile 0.1% formic acid in water (v / v); injection volume 2–5 μL; UV detection array 210–400, mass Detection 120-1600; column at 50°C, flow rate 1.0 mL / min.

[0154] LCMS method 4: Instrumentation: Waters Acquity UPLC, photodiode array detector; Acquity UPLC BEH C 18, 1.7μm, 21×30mm; 5.2min Operation time, 2 → 98% solvent B: solvent A, 0 to 5.15 min, 98% solvent B, 5.15 ~5.20 min. Solvents: Solvent A = 5 mM ammonium hydroxide in water, Solvent B = acetonite 5 mM ammonium hydroxide in 100 µL; injection volume 2–5 µL; UV detection array 210–40 0, mass detection 120-1600; column at 50 °C, flow rate 1.0 mL / min.

[0155] LCMS method 5: Instrument: Agilent 1200LC / G1956A, Diode Array Detector; Column: Chromolith Flash C 18 , 1.6 microns, 2 x 25 mm; 1.5 min Run time: 5 → 95% solvent B:solvent A, 0 → 1.2 min, then 95% solvent B, 1 .21 → 1.5 min. Solvents: Solvent A = 0.0375% TFA in water (v / v), Solvent B = A 0.01875% TFA in acetonitrile (v / v); injection volume 2–5 μL; UV detection 22 0 and 254 nM, mass detection 100-1000 (electrospray ionization); 50 °C Column at 100°C; flow rate 1.5 mL / min.

[0156] LCMS method 6: Equipment: SHIMADZU LCMS-2020, photodiode array detector; column :Kinetex EVO C 18 , 5uM, 1×30mm; 1.55min operation time, 5 → 95% solvent B: Solvent A, 0 → 1.20 min, then 95% solvent B, 1.21 min to 1.55 min. Solvents: Solvent A = 0.025% NH4OH in water (v / v), Solvent B = acetonitrile Nitrile. Injection volume 2-5 μL; UV detection 220 and 254 nM, mass detection 100-100 0 (electrospray ionization); column at 40° C.; flow rate 1.5 mL / min.

[0157] LCMS method 7: Instrument: API2000, Column: Mercury MS Synergi, 2μm, 20 × 4.0 mm, C12; Gradient: A- 0.1% formic acid in water / B- acetonitrile: time / % B:0.0 / 30, 0.5 / 30, 1.5 / 95, 2.0 / 95, 2.5 / 30, 3.0 / 30, flow rate 2.0 mL / min; UV detection array 190-400, mass detection 100-100 0 (electrospray ionization); column temperature 30°C.

[0158] LCMS method 8: Instrument: API3000, Column: Synergi, 2.5μm, MAX-RP, 20×4 .0mm, 100A Mercury; Gradient: 0.1% formic acid in water, B: acetonitrile :Time%B0 / 10, 0.5 / 20, 1.5 / 95, 2.0 / 95, 2.5 / 10, 3 / 10, flow rate 2.0 mL / min; UV detection array 190-400 (total wavelength chromatogram), Mass detection 100-1000 (electrospray ionization); column temperature 30 °C.

[0159] LCMS method 9: Instrument: API3000, Column: Synergi, 2.5μm, 50×4.6mm, MA X-RP100A; 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 1.2 mL / min; UV detection array 190-400 (total wavelength chroma mass detection 100-1000 (electrospray ionization); column temperature 3 0°C.

[0160] LCMS method 10: Shimadzu, Column: Mercury MS Synergi, 2.5 μm, 20 × 4.0 mm, C12; Gradient: A- 0.1% formic acid in water / B- acetonitrile: time / % B:0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5, Flow rate 2.0 mL / min; UV detection array 200-400, mass detection 100-1000 (elements chromatospray ionization); column temperature 40°C.

[0161] LCMS method 11: Shimadzu, Column: Kinetex, 5 μm, EVO C18 100A, (1 00×2.1 mm); Gradient: A-0.1% formic acid in water / B-acetonitrile: time / %B :0 / 5, 1 / 30, 3 / 95, 4 / 95, 4.1 / 5, 6 / 5, flow rate 1.4mL / min; UV detection array 200-400, mass detection 100-1000 (electrospray ion precipitation); column temperature 40°C.

[0162] LCMS method 12: Shimadzu, Column: Synergi, 2.5 μm, MAX-RP100A, (2 0×4.0 mm) Mercury; gradient: A- 0.1% formic acid in water / B- acetonitrile :Time / %B:0.1 / 5, 0.5 / 5, 1.0 / 95,1.5 / 95, 2.0 / 5, 3 .0 / 5, flow rate 2.0mL / min; UV detection array 200-400, mass detection 100-10 00 (electrospray ionization); column temperature 40°C.

[0163] LCMS method 13: Acquity, Column: UPLC BEH C18, 1.7 μm, 2.1 × 50 mm; Gradient: A- 0.1% formic acid in water / B- acetonitrile: 2.2 min run time, 2 → 98% Solvent B: Solvent A, 0 to 1.76 min, then 95% Solvent B, 1.76 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℃

[0164] Preparative HPLC method for purification: Method 1: HPLC column: XBRIDGE-C18 (19.0 x 150 mm, 5 microns ), Mobile phase-A: 0.1% TFA in HO, B: CHCN, Gradient (time / %B): 0 / 20, 2 / 20, 8 / 50) Flow rate: [19mL / min].

[0165] Method 2: HPLC column: ZORBAXECLIPSE XDB C18 (21.2 x 1 50 mm, 5 microns), mobile phase-A: 0.1% TFA in H2O, B: CH3CN, gradient Distribution (time / %B): 0 / 10, 2 / 20, 10 / 40 and flow rate: [20mL / min].

[0166] Method 3: HPLC [Column: XBRIDGE C18 (21.2 x 150 mm, 5 microns Mobile phase-A: 10mM NH4HCO3 in water, B: CH3CN, gradient (time / % B): 0 / 10, 2 / 20, 8 / 50 and flow rate: [18mL / min].

[0167] Method 4: HPLC column: Gemini NX C18 (21.2 × 150.00 mm, 5 microns); Mobile phase - (A): 0.1% TFA in water (B): Acetonitrile / methanol flow rate: 15mL / min; (time / %B, 0 / 20, 2 / 20, 8 / 20)

[0168] Method 5: HPLC column: KINETEX EVO, 5μ, C18 (21.2×150m m), Mobile phase: water (A) CH3CN (B), Gradient (time / %B): 0 / 20, 2 / 30, 7 / 70 and flow rate: [18mL / min].

[0169] Method 6: HPLC column: KINETEX C18, (21.2 x 150 mm), mobile phase A: Water, B: CH3CN:MeOH, Gradient (time / %B): 0 / 20, 2 / 30, 7 / 70, flow rate: 18mL / min].

[0170] Method 7: HPLC column: KINETEX (21.2 x 150 mm, 5 microns), transfer Phase: A = 0.05% TFA in water, B = CH3CN, Gradient (time / %B): 0 / 20, 2 / 30, 10 / 60, flow rate: 20mL / min].

[0171] Chiral preparative HPLC method for separation of isomers: Method 1: Column: CHIRALPAK IC (10 x 250 mm, 5 microns), Mobile phase : Hexane (A) IPA:MeOH, 1:1 (B); Flow rate: 8 mL / min; Isocratic: 96: 04(A:B).

[0172] Method 2: Column: REGIS WELKO (250 x 10 mm, 5 microns), Mobile phase: Hexane (A):EtOH, 1:1 (B); flow rate: 9 mL / min; isocratic: 85:15 (A :B).

[0173] Method 3: Column: CHIRALPAC IG (250 x 10 mm, 5 microns), mobile phase :IPA(A):MeOH, 1:1(B); Flow rate: 6mL / min; Isometric: 98:2(A: B).

[0174] Method 4: Column: LUX CELLULOSE-4 (10 x 250 mm, 5 microns), Mobile phase: Hexane (A) EtOH:IPA 1:1 (B); Flow rate: 8 mL / min; Isocratic: 9 0:10(A:B).

[0175] Method 5: Column: LUX CELLULOSE-4 (10 x 250 mm, 5 microns), Mobile phase: Hexane (A) EtOH: 1:1 (B); Flow rate: 8 mL / min; Isocratic: 90:1 0(A:B).

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

[0177] Method 7: Column: LUX CELLULOSE-4 (21.2 x 250 mm, 5 microns ), mobile phase: hexane (A); EtOH:MeOH 1:1 (B); flow rate: 19 mL / min; Isometric composition: 80:20 (A:B).

[0178] Method 8: Column: REGIS (10 x 250 mm, 5 microns), Mobile phase: CO2 (A) MeOH:EtOH1:1(B);FLOW:13mL / min, isocratic:80:20(A: B).

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

[0180] Chiral analytical HPLC method for the analysis of separated isomers: Method 1: Column: Lux, Cellulos-4 (250 x 4.6 mm, 5 microns; Mobile phase: A = n-hexane, B = 0.1% TFA in ethanol; 1 mL / min; Isocratic: 7 0:30(A:B)

[0181] Method 2: Column: LUX CELLULOSE-4 (4.6 × 250 mm, 5 microns; Mobile phase: Hexane (A) EtOH: 1:1 (B); Flow rate: 1 mL / min; Isometric: 50:5 0(A:B).

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

[0183] Intermediate A: Formation of ethyl 4-acetoxy-3-oxobutanoate [ka] Ethyl 4-chloro-3-oxobutanoate (200 g, 1215.1 mmol) in vinegar To the acid (1500 mL) solution 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 h). The EtOAc phases were combined and washed with saturated NaHCO3 The solution (2 L) was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. , followed by silica flash chromatography (ethyl acetate in petroleum ether, 0 → 15%) The title compound was obtained as a light brown liquid ethyl 4-acetoxy-3-oxoacetate by purification of the crude product by Obtained as xobutanoate (152 g). 1 H NMR(400MHz,CDCl3)δ 4.78(s,2H),4.20(q, J=14.1,7.2Hz,2H),3.49(s,2H),2.16(s,3H),1 .28(t,J=7.2Hz,3H).

[0184] Intermediate B: Formation of methyl (Z)-3-amino-4-fluorobut-2-enoate Method 1: [ka] Dissolve methyl acetate (36.5 g, 492.71 mmol) in tetrahydrofuran (200 mL The solution was cooled to -78°C under a nitrogen atmosphere and the lithium diisopropylamine in THF was added. (246.44 mL, 2.0 M, 492.71 mmol) was slowly added over a period of 20 min. The resulting mixture was stirred at -78°C for 1 hour, followed by The tetrahydrofuran solution of 2-fluoroacetonitrile (19.4 g, 328.9 mmol) was A solution of orchid (150 mL) was added dropwise. The reaction mixture was stirred at -78°C for an additional hour. Then, saturated ammonium chloride solution (200 mL) was added and the product was dissolved in ethyl acetate (5 The EtOAc was washed with saturated brine solution (500 mL) and extracted into Na2S The solvent was removed under reduced pressure and purified by silica flash chromatography (Stone Purification of the crude product with ethyl acetate in petroleum ether (0→10%) afforded the title compound. Methyl (Z)-3-amino-4-fluorobut-2-enoate, a white crystalline solid (16g).

[0185] Method 2: [ka] Step 1: Methyl acetate (83.78 g, 1131.0 mmol) in tetrahydrofuran A solution of lithium fluoride (800 mL) was cooled to -78°C under nitrogen and then added to the lithium fluoride (100 mL) in THF. Mudiisopropylamide (565.5 mL, 2.0 M, 1131.0 mmol) was added to the reactants. The resulting mixture was incubated at -78°C for 1 h. Stir, then add ethyl 2-fluoroacetate (100 g, 942.5 mmol) to the The mixture was added dropwise to a solution of tetrahydrofuran (200 mL) and the reaction mixture was cooled to -78°C. The mixture was stirred for another hour. Saturated ammonium chloride solution (200 mL) was added to the reaction mixture, and the resulting mixture was cooled to room temperature. The product was extracted into ethyl acetate (5 L). The EtOAc was diluted with saturated brine solution (500 mL ) and dried over Na2SO4. The solvent was removed under reduced pressure and the mixture was purified by flash quenching. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0→10%) Thus, yellow crystals of methyl 4-fluoro-3-oxobutanoate (60 g) were obtained. 1 H NMR(400MHz,CDCl3)δ 4.97(s,1H),4.85(s, 1H),3.76(d,J=2.3Hz,3H),3.62(d,J=3.7Hz,2H ).

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

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

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

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

[0190] Example 1: Methyl (R)-4-(2-((R or S)-2,2-difluorocyclopropyl (3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7 -Tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] 2-Bromo-3-fluorobenzaldehyde (60 g, 295.56 mmol) and Dissolve ethylene glycol (65.4 mL, 1182.2 mmol) in toluene (600 mL). Add p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol) to the solution. The resulting solution was heated at 120° C. for 24 hours using a Dean-Stark apparatus. The reaction mixture was poured into water (2 L) and extracted into ethyl acetate (3 L). The Ac was washed with saturated NaHCO3 solution (1 L), brine and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate, 0→10%) afforded the title compound, 2-(2-bromophenyl (3-fluorophenyl)-1,3-dioxolane (60 g) was obtained as a colorless liquid. . 1H NMR(400MHz,CDCl3)δ 7.42-7.37(m,1H),7. 34-7.29(m,1H),7.16-7.10(m,1H),6.10(s,1H) ,4.19-4.09(m,4H).

[0191] Step 2: 2-(3-fluoro-2-vinylphenyl)-1,3-dioxolane [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1) , 15 g, 60.72 mmol) and potassium vinyltrifluoroborate (16.26 g, 121.45 mmol) in isopropyl alcohol (200 mL) Aminopropylamine (25.5 mL, 182.16 mmol) and [1,1'-bis(diphenylphosphine) Sphino)ferrocene]dichloropalladium(II)·DCM (4.95 g, 6.07 m The resulting solution was degassed with argon gas for 10 minutes and heated to 80°C. The mixture was stirred for 16 hours. The reaction mixture was filtered and washed with ethyl acetate (100 mL). The mixture was added to water (1 L) and the product was extracted into ethyl acetate (2 L). The solvent was removed under reduced pressure and the resulting solution was washed with water and dried over Na2SO4. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0→10%) The title compound, 2-(3-fluoro-2-vinylphenyl)-1,3-dihydro- Xolane (7.5 g) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.45-7.41(m,1H),7. 27-7.20(m,1H),7.10-7.03(m,1H),6.82(dd,J= 17.7,11.7Hz,1H),5.82-5.78(m,1H),5.66-5.6 0(m,1H),5.95(s,1H),4.18-4.02(m,4H).

[0192] Step 3: 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl )-1,3-Dioxolane [ka] 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) (2.5 g, 16.73 mmol) was added. The resulting solution was heated at 65° C. for 24 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 reduced. This affords the title compound, 2-(2-(2,2-difluorocyclohexanediamine). (propyl)-3-fluorophenyl)-1,3-dioxolane (8 g) was obtained as a colorless liquid. I got it. 1 H NMR(400MHz,CDCl3)δ 7.42(d,J=7.5Hz,1H) ,7.34-7.28(m,1H),7.16-7.03(m,1H),6.06(s, 1H),4.20-4.01(m,4H),2.77-2.66(m,1H),2.02 -1.72(m,2H).

[0193] Step 4: 2-(2,2-difluorocyclopropyl)-3-fluorobenzaldehyde D [ka] 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3 -Dioxolane (from step 3, 8 g, 32.76 mmol) in diethyl ether (8 To the resulting solution (10 mL) was added 6N HCl (10 mL). The mixture was stirred for 2 hours. This was then diluted with water (50 mL), saturated NaHCO3 solution (100 mL), and The solvent was removed under reduced pressure and the resulting solution was washed with water and dried over Na2SO4. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0→5%) Therefore, the title compound, 2-(2,2-difluorocyclopropyl)-3-fluorophenyl The resulting mixture was treated to give 3.8 g of benzoquinone aldehyde as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 10.28(s,1H),7.70(d ,J=6.9Hz,1H),7.50-7.43(m,1H),7.36-7.26(m ,1H),2.92-2.81(m,1H),2.16-2.06(m,1H),1.6 7-1.53(m,1H).

[0194] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-diphenyl)-2-acetoxymethyl)-4-(2-methylphenyl)-2-(acetoxymethyl)-4-(2-methylphenyl)-2-acetoxymethyl)-2-(2,2-diphenyl Fluorocyclopropyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4 -Dihydropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (from the aldehyde (1 0.0g, 4.996mmol), Intermediate A (945mg, 4.996mmol) and Intermediate Compound B (665 mg, 4.996 mmol) was used to synthesize 3-ethyl 5-methyl 2 -(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-fluoro (fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxyl The crude product was subjected to further purification and analysis. It was used as a step in itself, rather than as a stepping stone to the next step.

[0195] Step 6: Methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl) (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[ 3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 5, 1.4 The crude product was purified by silica flash chromatography. The mixture was purified by elution (ethyl acetate in petroleum ether, 0 to 50%), The title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluoro (2-(fluorophenyl)-5-oxo-1,4,5,7-tetrahydrofuran 125 mg of 3,4-b-pyridine-3-carboxylate was added as an off-white solid. Chiral SFC: Column: Lux-cellulose-2, 21×250 mm, 5um; Flow rate: 80g per minute; Co-solvent: 20% 1:1 MeOH:IPA; Detection: 34 4 nm; BPR set point: 125 bar was used to chiralize the sample into two products. The mixture was separated.

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

[0197] Example 1 20 mg of the title compound (61%) as the second eluting stereoisomer as a white solid SFC Rt=2.49; Mobile phase: 5~55% (1:1) MeOH IPA w / CO2 10 mM NH4OH in, 5 mL / min; Column: Lux Cellulose-2, 4 .6×100mm, 5μm LCMS Rt=2.12 min;MS m / z, 398.3[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz, 1H),7.31(td,J=8.0,5.6Hz,1H),7.20-6.83(m, 2H),5.78-5.41(m,2H),5.22(s,1H),5.03-4.73 (m,2H),3.51(s,3H),2.86(td,J=12.4,8.5Hz,1 H),2.64-2.53(m,1H),2.18(dt,J=12.2,5.5Hz, 1H).

[0198] Example 1b 15 mg of first eluting stereoisomer (46%) as a white solid SFC Rt=2.42; Mobile phase: 5~55% (1:1) MeOH IPA w / CO2 10 mM NH4OH in, 5 mL / min; Column: Lux Cellulose-2, 4 .6×100mm, 5μm LCMS Rt=2.15 min;MS m / z, 398.2[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.08(d,J=3.2Hz, 1H),7.33(td,J=8.1,5.8Hz,1H),7.25-6.92(m, 2H),5.94-5.54(m,2H),5.27(s,1H),4.79(d,J= 1.4Hz,2H),3.44(s,3H),3.15-3.04(m,1H),2.3 5-2.19(m,1H),1.88(dtd,J=14.0,8.2,3.2Hz,1 H).

[0199] Example 1c 24 mg of the third eluting stereoisomer (73%) as a white solid SFC Rt=2.73 min; Mobile phase: 5~55% (1:1) MeOH IPA w / CO 10 mM NH4OH in 2, 5 mL / min; Column: Lux Cellulose-2, 4.6×100mm, 5μm LCMS Rt=2.16 min;MS m / z, 398.3[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz, 1H),7.31(td,J=8.0,5.6Hz,1H),7.18-6.87(m, 2H),5.61(dd,J=47.8,4.0Hz,2H),5.22(s,1H), 4.98-4.78(m,2H),3.51(s,3H),2.86(td,J=12. 5,8.5Hz,1H),2.64-2.55(m,1H),2.18(tt,J=12 .8,6.8Hz,1H).

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

[0201] Example 2: Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-( Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine Din-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3-fluorobenzaldehyde [ka] 2-Bromo-3-fluorobenzaldehyde (15 g, 73.88 mmol) and cyclohexyl A solution of propylboronic acid (7.61 g, 88.66 mmol) in toluene (160 mL) Into the mixture, 2N K2CO3 (25.5 mL, 182.16 mmol) and [1,1'-bis( Diphenylphosphino)ferrocene]dichloropalladium(II)·DCM(6.03g , 7.38 mmol) was added. The resulting solution was degassed with argon gas for 10 minutes. The mixture was 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) and The tOAc phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. By silica flash chromatography (ethyl acetate in petroleum ether, 0→1%) Purification of the crude product afforded the title compound, 2-(3-fluoro-2-vinylphenyl) -1,3-dioxolane (11.2 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.70(s,1H),7.63(d d,J=1.2,7.8Hz,1H),7.35-7.15(m,2H),2.14-2 .02(m,1H),1.19-1.09(m,2H),0.85-0.75(m,2H ).

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

[0203] Step 3: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoro (trimethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine 3-Carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 2, 7.0 The crude product was purified by silica flash chromatography. The product was purified by chromatography (ethyl acetate in petroleum ether, 0 to 50%), which The title compound, methyl 4-(2-cyclopropyl-3-fluorophenyl)-2- (Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pi Lysine-3-carboxylate (1.15 g) was obtained as an off-white solid.

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

[0205] Example 2 50 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt = 6.129 min [Chiral analysis method 1] LCMS Rt=1.538 min;MS m / z, 360.0[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.15-7.05(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). Exchangeable NH is in the spectrum Not observed.

[0206] Example 3: Methyl (R)-4-(2-((R or S)-2,2-difluorocyclopropyl (fluoromethyl)-5-oxo-1,4, 5,7-Tetrahydrofuro[3,4-b]pyridine-3-carboxylate and Example 4: Methyl (R)-4-(2-((R or S)-2,2-difluorocyclopropane (propyl)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1, 4,5,7-Tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane [ka] The title compound was prepared using 10 g of 2-bromo-3,5-difluorobenzaldehyde. Synthesized following a procedure similar to step 1 of example 1, 11.5 g of the desired product 2-(2-Bromo-3,5-difluorophenyl)-1,3-dioxolane was obtained. 1H NMR(300MHz,CDCl3)δ 7.20-7.15(m,1H),6. 49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H) .

[0207] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane [ka] The title compound is 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxo The 2-(3,5-difluorophenyl)propane was synthesized using the same procedure as in step 2 of Example 1 using The resulting product was fluoro-2-vinylphenyl-1,3-dioxolane (3.45 g). 1 H NMR(300MHz,CDCl3)δ 7.20-7.16(m,1H),6. 94-6.83(m,1H),6.82(dd,J=17.7,11.7Hz,1H), 5.60(dd,J=1.2,11.7Hz,1H),5.66-5.60(m,1H) ,5.95(s,1H),4.18-4.02(m,4H).

[0208] Step 3: 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorocyclopropyl) (phenyl)-1,3-dioxolane [ka] 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (Step From 2, 2.4 g, 11.31 mmol) and trifluoromethyltrimethylsilane (1 A solution of sodium iodide (6.1 g, 113.1 mmol) in tetrahydrofuran (15 mL) was The resulting solution was heated to 65° C. The reaction mixture was cooled to room temperature and stirred for 24 hours. (16.1 g, 113.1 mmol) and sodium iodide (850 mg, 5.65 mm ol) was added and the resulting solution was stirred at 65° C. for 24 hours. The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, which gave the title compound, 2-(2-(2,2-dichlorophenyl)-2-(4-(2,2-diphenyl)-2-(2,4-diphenyl)-2-(1,2-diphenyl)-2-(2,2-diphenyl)-2-(1,2-diphenyl)-2-(2,4 ... Fluorocyclopropyl)-3,5-difluorophenyl)-1,3-dioxolane (1 0.5g) was obtained as a brown liquid. 1 H NMR(400MHz,CDCl3)δ 7.26-7.14(m,1H),6. 90-6.77(m,1H),6.04(s,1H),4.17-4.03(m,4H) ,2.77-2.66(m,1H),1.98-1.70(m,2H).

[0209] Step 4: 2-(2,2-difluorocyclopropyl)-3,5-difluorobenzaldehyde Rudehyde [ka] 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)- 1,3-Dioxolane (from step 3, 1.5 g, 5.72 mmol) in diethyl ether To the tert-butyl ether (15 mL) solution was added 6N HCl (3 mL). The mixture was stirred at room temperature for 3 hours. This was then diluted with water (50 mL), saturated NaHCO3 solution (100 mL), The solvent was removed under reduced pressure and the silica was washed with 100 mL of ethyl acetate and brine and dried over Na2SO4. Purification of the crude product by flash chromatography (ethyl acetate in hexane, 0→5%) Purification afforded the title compound, 2-(2,2-difluorocyclopropyl)-3,5- Difluorobenzaldehyde (1.25 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.22(s,1H),7.50-7 .39(m,1H),7.20-7.05(m,1H),2.80-2.60(m,1H ),2.18-1.89(m,1H),1.65-1.53(m,1H).

[0210] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-diphenyl)-2-acetoxymethyl)-4-(2-methylphenyl)-2-(acetoxymethyl)-4-(2-methylphenyl)-2-acetoxymethyl)-2-(2,2-diphenyl Fluorocyclopropyl)-3,5-difluorophenyl)-6-(fluoromethyl)- 1,4-Dihydropyridine-3,5-dicarboxylate [ka] The title compound was prepared using general step 1 of Method I (from the aldehyde (1 0.0g, 4.58mmol), Intermediate A (862mg, 4.58mmol) and Intermediate B (608 mg, 4.58 mmol)) and 3-ethyl 5-methyl 2-(a 4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)- (fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxyl The carboxylate (2.5 g, crude) was obtained. LCMS Rt=1.683 min;MS m / z, 504[M+H]+;[Method 7]

[0211] Step 6: Methyl 4-(2-(2,2-difluorocyclopropyl)-3,5-difluoro (fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Furo[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 5, 2.5 The crude product was purified by silica flash chromatography. The product was purified by ethyl acetate in petroleum ether (0 to 50%). , the title compound, methyl 4-(2-(2,2-difluorocyclopropyl)-3,5- Difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrafluoroethylene Hydrofuro[3,4-b]pyridine-3-carboxylate (120 mg) was added to the off-white The racemic mixture was purified by chiral SFC (mobile phase: 20% IPA / CO2, 80 g / min; Column: Whelk-O1SS, 21 x 250 mm; Instrument: Thar80_SN 4740) to separate its enantiomers.

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

[0213] Example 4 20.6 mg of the second eluting stereoisomer (67.8%) as a white solid. SFC Rt=2.43 min ((SS) Whelk-O1, 4.6×100mm, 5μm, 5 → 55% IPA in CO2). LCMS Rt=2.21 min;MS m / z, 416.4[M+H]+;[Method 4] 1 H NMR (400MHz, methanol-d4) δ 6.93 -6.72 (m, 2H) ,5.74(d,J=3.6Hz,1H),5.62(d,J=4.1Hz,1H),5 .42(s,1H),5.00-4.90(m,2H),3.60(s,3H),2.9 7-2.80(m,1H),2.68-2.49(m,1H),2.02(tdd,J= 11.9, 7.8, 5.9Hz, 1H).

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

[0215] Example 3b 21.6 mg of the third eluting stereoisomer (74.1%) as a white solid. SFC Rt=2.68 min ((SS)Whelk-O1, 4.6×100mm, 5μm, 5 → 55% IPA in CO2). LCMS Rt=2.22 min;MS m / z, 416.6[M+H]+;[Method 4] 1 H NMR (400MHz, 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=11.8,7.6,5.9Hz,1H),1.90-1.7 7(m,1H).

[0216] Example 4b 20.6 mg of the fourth eluting stereoisomer (70.7%) as a white solid. SFC Rt=2.79min ((SS)Whelk-O1, 4.6×100mm, 5μm, 5 → 55% IPA in CO2). LCMS Rt=2.21 min;MS m / z, 416.3[M+H]+;[Method 4] 1 H NMR (400MHz, 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=1.6Hz,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, 5.9Hz, 1H).

[0217] Example 5: Methyl (R)-4-(3,5-difluoro-2-((R or S)-1-fluoro (2-(fluoromethyl)-5-oxo-1,4,5,7-tetra(phenyl)-2-(fluoroethyl)phenyl Hydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzal Dehyde [ka] 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (Example 4 (prepared from step 2, 5 g, 23.58 mmol) and ruthenium chloride·XH2 O (490 mg, 2.35 mmol) in dichloromethane (50 mL) and water (10 mL) To the solution was added diacetoxyiodobenzene (11.4 g, 35.37 mmol). The resulting solution was stirred at 30° C. for 2 hours. The reaction mixture was filtered and diluted with ethyl acetate ( The filtrate was added to water (200 mL) and the product was extracted with ethyl acetate (500 mL). The EtOAc phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate, 0→10%) afforded the title compound, 2-(1,3- Dioxolan-2-yl)-4,6-difluorobenzaldehyde (3g) is a colorless liquid Obtained as. 1 H NMR(300MHz,CDCl3)δ 10.41(s,1H),7.35(d ,J=9.6Hz,1H),6.95-6.85(m,1H),6.53(s,1H), 4.08(s,4H).

[0218] Step 2: 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl Nyl)ethane-1-ol [ka] 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde(s From step 1, dissolve 1.0 g (4.67 mmol) in dry tetrahydrofuran (10 mL). Methylmagnesium bromide (2.33 mL, 3 M in ether, 4.67 mM) was added to the solution at 0°C. The resulting solution was stirred at room temperature for 1 hour. The mixture was quenched with 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. The title compound, 1-(2-(1,3-dioxolan-2-yl)-4,6 (difluorophenyl)ethan-1-ol (950 mg) was obtained as a colorless liquid. The compound was carried forward to the next step without further purification. 1 H NMR(300MHz,CDCl3)δ 7.17(dd,J=2.4,6.3H z,1H),6.89-6.72(m,1H),6.17(s,1H),5.31(dd ,J=6.9,13.5Hz,1H),4.15-4.02(m,4H),2.64-2 .59(m.1H), 1.58(d,J=9.0Hz,3H).

[0219] Step 3: 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1, 3-Dioxolane [ka] 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethanoate 1-Hydroxy-1-ol (from step 2, 950 mg, 4.13 mmol) in dichloromethane ( 10 mL) solution at -78 °C, diethylaminosulfur trifluoride (1.0 g, 6.13 mm ol) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was saturated Quench with ammonium chloride (10 mL) at 0° C. and dilute with ethyl acetate (100 mL). The organic phase was separated, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The title compound, 2-(3,5-difluoro-2-(1-fluoroethyl)fluoren-2-yl)phenylacetamide, was obtained by removing the The crude compound was purified by HPLC to give 1,3-dioxolane (600 mg) as a thick yellow liquid. The material was carried forward to the next step without further purification. 1 H NMR(300MHz,CDCl3)δ 7.20(dd,J=2.4,6.3H z,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=6.6,2 2.8Hz,3H).

[0220] Step 4: 3,5-Difluoro-2-(1-fluoroethyl)benzaldehyde [ka] 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-diox Solan (from step 3, 600 mg, 2.58 mmol) in diethyl ether (10 mL) L) solution was added with 4N HCl (2 mL) at room temperature. The resulting solution was cooled to room temperature. The mixture was stirred at rt for 3 h. This was then diluted with water (50 mL), saturated NaHCO3 solution (100 mL), The mixture was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure, which gave The title compound, 3,5-difluoro-2-(1-fluoroethyl)benzaldehyde ( 200 mg) as a colorless liquid. (Note: The aldehyde obtained is naturally volatile. ) 1 H NMR(300MHz,CDCl3)δ 10.44(d,J=3.0Hz,1H ),7.20(d,J=9.3Hz,1H),7.10-6.98(m,1H),6.4 3-6.19(m,1H),1.78(dd,J=7.2,23.1Hz,3H).

[0221] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro b-2-(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydro Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 4, ( 200 mg, 1.06 mmol) and synthesized 3-ethyl 5-methyl 2-(acetamide) (3,5-difluoro-2-(1-fluoroethyl)phenyl)- Diastereomeric 6-methyl-1,4-dihydropyridine-3,5-dicarboxylate The crude product was carried onto the next step without purification. LCMS Rt=2.272 min;MS m / z, 472.3[MH]-;[Method 7]

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

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

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

[0225] Example 5 21 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=4.418 min; [Chiral analysis method 2] LCMS Rt=1.514 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR:(400MHz,CD3OD)δ 6.87-6.74(m,2H),6 .46-6.18(m,1H),5.75(t,J=1.0Hz,1H),5.63(d d,J=1.6,0.7Hz,1H),5.20-5.12(m,1H),4.91-4 .81(m,2H),3.53(s,3H),1.83(ddd,J=22.7,6.6 ,1.4Hz,3H).

[0226] Example 5b 22 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=4.792 min; [Chiral analysis method 2] LCMS Rt=1.513 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR:(400MHz,CD3OD)δ 6.87-6.74(m,2H),6 .46-6.18(m,1H),5.75(t,J=1.0Hz,1H),5.63(d d,J=1.6,0.7Hz,1H),5.20-5.12(m,1H),4.91-4 .81(m,2H),3.53(s,3H),1.83(ddd,J=22.7,6.6 ,1.4Hz,3H).

[0227] Example 5c 18 mg of the third eluting enantiomer obtained as a white solid. Chiral HPLC Rt=6.777 min; [Chiral analysis method 2] LCMS Rt=1.476 min;MS m / z, 384.1[MH]-;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 6.77-6.63(m,2H),6 .48(dd,J=44.3,6.6Hz,1H),5.85-5.77(m,1H), 5.70(d,J=4.5Hz,1H),5.10(s,1H),4.83-4.77( m,2H),3.56(s,3H),1.79(ddd,J=22.5,6.7,1.1 Hz,3H).

[0228] Example 5d 16 mg of the fourth eluting enantiomer was obtained as a white solid using chiral HPLC method 7. Mah. Chiral HPLC Rt=7.475 min; [Chiral analysis method 2] LCMS Rt=2.00 min;MS m / z, 384.2[MH]-;[Method 9] 1 H NMR(400MHz,CDCl3)δ 6.77-6.63(m,2H),6. 48(dd,J=44.3,6.6Hz,1H),5.85-5.77(m,1H),5 .70(d,J=4.5Hz,1H),5.10(s,1H),4.83-4.77(m ,2H),3.56(s,3H),1.79(ddd,J=22.5,6.7,1.1H z,3H).

[0229] Example 6: Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3-fluoro (fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Furo[3,4-b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl) -2-fluoroethane-1-one [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1) A solution of 26 g (105.23 mmol) of Example 1 in THF (250 mL) was The mixture was cooled to -78°C under air. Then, n-butyllithium (44 0.19 mL, 2.5 M, 110.49 mmol) was added and the reaction was incubated at -78 °C for 30 min. Then, ethyl 2-fluoroacetate (22.33 g, 210.47 mmol) was added. l) was added to the reaction and the resulting mixture was stirred at -78°C for an additional 60 min. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and ethyl acetate (2 The combined organic phase was extracted with water (250 mL), brine (250 mL). ) and dried over Na2SO4. The solvent was removed under reduced pressure and the mixture was purified by flash quenching. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0→10%) Therefore, the title compound, 1-(2-(1,3-dioxolan-2-yl)-6-fluoro (16.2 g)-2-fluoroethan-1-one was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.45(m,1H),7.37(d, J=7.8,1H),7.13(dd,J=9.3,8.2Hz,1H),6.02(s ,1H),5.23(d,J=1.4Hz,1H),5.11(d,J=1.3Hz,1 H), 4.08-3.87(m,4H).

[0230] Step 2: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl) -2-Fluoroethan-1-ol [ka] Stirred 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)- 2-Fluoroethan-1-one (from step 1, 19.6 g, 85.89 mmol) Sodium borohydride (3.9 g, 103.07 m The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2×250 mL). The combined organic phase was washed with water (250 mL) followed by brine (250 mL). The solvent was removed under reduced pressure and the residue was purified by silica flash chromatography. Purification of the crude product by filtration (ethyl acetate in petroleum ether, 0 → 30%) gave the following: The title compound, 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl )-2-Fluoroethan-1-ol (18 g) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.44(dd,J=7.9,1.2H z,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),4.9 8-4.51(m,2H),4.22-3.97(m,4H),3.04(m,1H).

[0231] Step 3: 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1, 3-Dioxolane [ka] 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)-2-fluoro Oroethane-1-ol (from step 2, 18 g, 78.18 mmol) The solution was cooled to -78°C in 150 mL of ethanol and then diluted with diethylaminosulfur trifluoride (D AST) (15.49 mL, 117.28 mmol) was added to the resulting reaction mixture. The mixture was stirred at -78°C for 1 hour. The reaction mixture was slowly brought to 0°C and stirred for an additional hour. Water (150 mL) was added and the product was extracted with dichloromethane (2 x 200 mL). The combined organic phases were combined and washed with saturated sodium bicarbonate solution (2 x 200 mL), water (2 The mixture was washed with water (00 mL), brine (200 mL) and dried over Na2SO4. The solvent was reduced. The eluate was removed under reduced pressure and purified by flash chromatography on silica (ethyl acetate in petroleum ether, 0 Purification of the crude product by HPLC using 10% hexanes gave the title compound, 2-(2-(1,2-diphenylphosphine)-2-propanediol. (fluoroethyl)-3-fluorophenyl)-1,3-dioxolane (12.4g) was obtained as a liquid. 1 H NMR(400MHz,CDCl3)δ 7.45(d,J=7.8Hz,1H) ,7.42-7.35(m,1H),7.12(dd,J=10.6,8.2Hz,1H ),6.21(m,1H),6.04(s,1H),5.22-4.85(m,1H), 4.75-4.42(m,1H),4.20-3.97(m,4H).

[0232] Step 4: 2-(1,2-difluoroethyl)-3-fluorobenzaldehyde [ka] 2-(2-(1,2-difluoroethyl)-3-fluorophenyl)-1,3-diox Solan (from step 3, 12.4 g, 53.40 mmol) in diethyl ether (15 To the solution of 100 mL of 2N HCl (100 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was extracted with diethyl ether (200 mL). It was extracted, washed with water (2 x 100 mL), brine (100 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica (petroleum ether ethyl acetate, 0→10%), which gave the title compound 2- (1,2-difluoroethyl)-3-fluorobenzaldehyde (10g) is a colorless liquid Obtained as. 1 H NMR(400MHz,CDCl3)δ 10.30(s,1H),7.88-7 .70(m,1H),7.56(m,1H),7.44-7.30(m,1H),6.7 0-6.36(m,1H),4.95-4.70(m,2H)

[0233] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-diphenyl Fluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydr Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using general step 1 of general procedure I (from the aldehyde from step 4) 9 g, 47.83 mmol) was used to synthesize the title compound. 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl) (3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine 3,5-Dicarboxylate as a mixture of diastereomers (25.0 g, crude) Obtained as an off-white solid.

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

[0235] Step 6: Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] Pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (mixture of intermediates from step 5) , 25 g, 52.8 mmol) to synthesize 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 The diastereomeric mixture was obtained as follows: It was separated into its two isomers using silica flash chromatography (0→80%). Separation afforded 1.51 g of the first diastereomer as a white solid and 820 mg of the second diastereomer. The diastereomers were obtained as white solids.

[0236] Previously separated diastereomers from peak 1: 200 mg and diastereomers from peak 2: Reomers: 200 mg were separated into their enantiomers using preparative chiral HPLC [Method 7]. This was further separated into four isomers.

[0237] Example 6 56 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=7.623 min; [Chiral analysis method 2] LCMS Rt=1.445 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.41-7.35(m,1H),7. 17(dt,J=7.9,1.3Hz,1H),6.98(dd,J=11.4,8.1 Hz,1H),6.66-6.33(m,1H),5.75(d,J=3.7Hz,1H ),5.68-5.56(m,1H),5.18(s,1H),5.15-4.91(m ,2H),4.85(s,2H),3.52(s,3H).

[0238] Example 6, Methyl 2-methyl-5-oxo-4-phenyl-1,4,5,7-tetrahydrofuran The configuration of dolofuro[3,4-b]pyridine-3-carboxylate was determined by single crystal X-ray crystallography. This confirmed that the active enantiomer was the R-enantiomer. We confirmed this (Figure 7).

[0239] Example 6b 54 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=8.757 min; [Chiral analysis method 2] LCMS Rt=1.443 min;MS m / z, 386.3[M+H]+;[Method 7] 1 H NMR:(400MHz,CD3OD)δ 7.41-7.35(m,1H),7 .17(dt,J=7.9,1.3,1.3Hz,1H),7.10-6.88(m,1 H),6.67-6.26(m,1H),5.82-5.70(m,1H),5.69- 5.57(m,1H),5.18(s,1H),5.15-4.91(m,2H),4. 85(d,J=0.7Hz,2H),3.52(s,3H).

[0240] Example 6c 67 mg of the third eluting enantiomer obtained as a white solid. Chiral HPLC = Rt = 10.574 min; [Chiral analysis method 2] LCMS Rt=1.379 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.41-7.35(m,1H),7. 13(dt,J=7.9,1.3,1.3Hz,1H),6.97(dd,J=11.3 ,8.2Hz,1H),6.60(ddd,J=47.2,18.0,8.4Hz,1H ),5.75(s,1H),5.63(s,1H),5.14(s,1H),5.12- 4.92(m,1H),4.84(s,2H),4.70(ddd,J=44.6,32 .7,10.8Hz,1H),3.53(s,3H).

[0241] Example 6d 69 mg of the fourth eluting enantiomer was obtained as a white solid. Chiral HPLC Rt = 13.93 min [Chiral analysis method 2] LCMS Rt=1.379 min;MS m / z, 384.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.41-7.35(m,1H),7. 13(dt,J=7.8,1.3Hz,1H),6.97(dd,J=11.3,8.2 Hz,1H),6.60(ddd,J=47.1,17.9,8.3Hz,1H),5. 75(s,1H),5.63(s,1H),5.17-5.11(m,1H),5.11 -4.92(m,1H),4.84(s,2H),4.70(ddd,J=45.1,3 3.0,11.1Hz,1H),3.53(s,3H).

[0242] Example 7: Methyl (R)-4-(2-((R or S)-1,2-difluoroethyl)-3 -fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrafluorophenyl Hydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 3-Ethoxycyclopent-2-en-1-one [ka] Cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene with stirring In a 70 mL solution of pTSA (193 mg, 1.019 mmol) and EtOH ( 2.61 ml, 387.35 mmol) was added at room temperature. The mixture thus obtained was The mixture was stirred at 120° C. for 10 hours using a Dean-Stark apparatus. The solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography (petroleum ether ethyl acetate, 0→50%) to give the title compound, 3-ethoxycyclopentene. Ter-2-en-1-one (4.3 g) was obtained as a brown solid. 1 H NMR(400MHz,CDCl3)δ 5.26(s,1H),4.02(q, J=6.6Hz,2H),2.60-2.55(m,2H),2.44-2.40(m, 2H), 1.39(t,J=7.2Hz,3H).

[0243] Step 2: 3-Aminocyclopent-2-en-1-one [ka] Stirred 3-ethoxycyclopent-2-en-1-one (from step 1, 4.3 g A solution of 1,340.08 mmol) in ethanol (50 mL) was added to an ammonium hydroxide solution (2 The resulting mixture was heated to 85° C. The mixture was stirred at rt for 16 h. Removal of the solvent under reduced pressure gave the title compound, 3-aminosilyl. Clopent-2-en-1-one (3.2 g) was obtained as a brown solid. LCMS Rt=0.114 min;MS m / z, 98.2[M+H]+;[Method 1]

[0244] Step 3: Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl) -2-(Fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclo Penta[b]pyridine-3-carboxylate [ka] To a solution of aldehyde (from Example 6, Step 4, 3.0 g, 15.944 mmol) , methyl (Z)-3-amino-4-fluorobuta-2- Enoate (Intermediate B, 2.54 g, 19.133 mmol) and cyclopentane-1, 3-dione (1.56 g, 15.944 mmol) was added. The reaction mixture was heated at 80° C. for 4 h. The mixture was stirred for 8 hours. The solvent was removed under reduced pressure to give the crude compound. The crude product was purified by silica gel column chromatography. Purified by rush chromatography (ethyl acetate in petroleum ether, 0→70%) The title compound, methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl (phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Cyclopenta[b]pyridine-3-carboxylate (500 mg, crude) It was obtained as a white solid and a mixture of diastereomers. It was separated into its two isomers using silica flash chromatography (0→80%). Separation afforded 12 mg of the first diastereomer as a white solid and 15 mg of the second diastereomer as a white solid. The second diastereomer of g was obtained.

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

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

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

[0248] Example 7c 4 mg of the third eluting enantiomer obtained as a white solid. Chiral HPLC Rt=12.453 min; [Chiral analysis method 4] LCMS Rt=1.327 min;MS m / z, 384.2[M+H]+;[Method 2] 1 H NMR (400MHz, methanol-d4) δ 7.32 (tdd, J=8.1, 5.6,1.5Hz,1H),7.08(dt,J=7.8,1.3Hz,1H),6. 93(dd,J=11.5,8.1Hz,1H),6.60-6.38(m,1H),5 .81-5.69(m,1H),5.69-5.54(m,1H),5.13-5.07 (m,2H),5.07-4.93(m,1H),3.53(s,3H),2.75-2 .67(m,2H),2.45-2.22(m,2H).

[0249] Example 7d 4 mg of the fourth eluting enantiomer obtained as a white solid. Chiral HPLC Rt=13.173 min; [Chiral analysis method 4] LCMS Rt=1.33 min;MS m / z, 384.2[M+H]+;[Method 2] 1 H NMR (400MHz, methanol-d4) δ 7.40-7.25 (m, 1H) ,7.14-7.05(m,1H),6.93(dd,J=11.4,8.2Hz,1H ),6.60-6.38(m,1H),5.80-5.66(m,1H),5.66-5 .53(m,1H),5.13-5.07(m,2H),5.07-4.94(m,1H ),3.53(s,3H),2.71(t,J=4.8Hz,2H),2.44-2.2 1(m,2H).

[0250] Example 8: Methyl (R)-4-(3-fluoro-2-((R or S)-1-fluoroethyl) (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Furo[3,4-b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl) Ethan-1-ol [ka] 2-(2-Bromo-3-fluorophenyl)-1,3-dioxolane (Step 1, A solution of 30 g (121.42 mmol) of Example 1 in THF (300 mL) was The mixture was cooled to -78°C under air. Then, n-butyllithium (58 0.3 mL, 2.5 M, 147.71 mmol) was added over 10 min, and the resulting The mixture was stirred at -78°C for 1 h. Acetaldehyde (6.42 g, 145.71 m mol) was added and the resulting mixture was stirred at -78°C for 1 hour. Quench with saturated ammonium chloride solution (50 mL) and ethyl acetate (2 x 100 mL). The combined organic phase was washed with water (50 mL), brine (50 mL) and extracted with Na2 The solvent was removed under reduced pressure and purified by flash chromatography on silica ( Purification of the crude product with ethyl acetate in petroleum ether, 0→10%) afforded the title compound 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane 1-1-ol (15 g) was obtained as a colorless liquid. 1H NMR(400MHz,CDCl3)δ 7.38(d,J=8.0Hz,1H) ,7.30-7.18(m,1H),7.10-7.01(m,1H),6.15(s, 1H),5.30-5.25(m,1H),4.15-3.95(m,4H),2.75 -2.69(m.1H),1.58(dd,J=6.6,22.8Hz,3H).

[0251] Step 2: 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-di Oxolane [ka] 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane-1 -ol (from step 1, 15 g, 70.68 mmol) in dichloromethane (150 L) solution at -78 °C, The resulting solution was stirred at room temperature for 1 hour. The mixture was quenched with ammonium chloride (20 mL) at 0° C. and diluted with ethyl acetate (100 mL). The organic phase was separated, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure. and silica flash chromatography (ethyl acetate in petroleum ether, 0 → Purification of the crude product by HPLC with 10% hexane gave the title compound, 2-(3-fluoro-2-( 1-Fluoroethyl)phenyl)-1,3-dioxolane (8.5 g) was obtained as a colorless liquid. I got it. 1 H NMR(300MHz,CDCl3)δ 7.38(d,J=7.5Hz,1H) ,7.30-7.18(m,1H),7.13-7.01(m,1H),6.20-5. 95(m,1H),6.10(s,1H),4.16-4.02(m,4H),1.74 (dd, J = 7.2, 23.1 Hz, 3H).

[0252] Step 3: 3-Fluoro-2-(1-fluoroethyl)benzaldehyde [ka] 2-(3-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxola Dissolve 100g (from step 2, 8.5 g, 69.38 mmol) in diethyl ether (150 mL ) solution was added 4N HCl (85 mL) at room temperature. The resulting solution was cooled to room temperature. The mixture was stirred at rt for 3 h. This was then diluted with water (100 mL), saturated NaHCO3 solution (200 mL), The solvent was removed under reduced pressure to give the title compound. 3-Difluoro-2-(1-fluoroethyl)benzaldehyde (6.5 g) (Note: the resulting aldehyde is naturally volatile). 1 H NMR(300MHz,CDCl3)δ 10.44(d,J=1.0Hz,1H ),7.74(d,J=7.7Hz,1H),7.45-7.42(m,1H),7.3 5-7.30(m,1H),6.45-6.38(m,1H),1.92-1.72(m ,3H).

[0253] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2 -(1-fluoroethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyri Zin-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 3, 1 0 g, 58.76 mmol) and 3-ethyl 5-methyl 2-(acetoxy) Methyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-(fluoro (trimethyl)-1,4-dihydropyridine-3,5-dicarboxylate diastereomeric This was obtained as a mixture of 13 g (crude). LCMS Rt=1.795 min;MS m / z, 454.2[MH]-;[Method 9]

[0254] Step 5: Methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-2- (Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pi Lysine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (mixture of intermediates from step 4) (13.0 g, 28.54 mmol) to synthesize 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-carboxy The rate (5 g, crude) was obtained as an off-white solid. by silica flash chromatography (ethyl acetate in hexane, 0 → 80%) Separate 1.04 g of the first diastereomer and 1.45 g of the second diastereomer obtained.

[0255] Diastereomers were separated using Chiral SFC: Column 2.1 x 25.0 cm, Chiralce l OX-H;CO2, co-solvent (solvent B) methanol isocratic method, 25% co-solvent, 80g Further separation was performed using 100 bar system pressure and 100 sulphate / min.

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

[0257] Example 8b 38 mg as the second eluting stereoisomer LCMS Rt=1.95 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt = 1.52 min; mobile phase: 20% MeOH in CO2 (0.1% isopropyl amine), 4mL / min; Column: Chiralcel OX-H, 4.6×100mm 1 H NMR:(400MHz,DMSO-d6)δ 10.12(d,J=3.3Hz ,1H),7.56-7.23(m,1H),7.25-6.94(m,2H),6.3 5(dd,J=45.5,6.9Hz,1H),5.66(dd,J=47.9,2.7 Hz,2H),5.03(s,1H),4.86(d,J=2.6Hz,2H),3.4 4(s,3H),1.80(dd,J=22.8,6.5Hz,3H).

[0258] Example 8c 42 mg as the third eluting stereoisomer LCMS Rt=1.88 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt = 2.08 min; mobile phase: 20% MeOH in CO2 (0.1% isopropyl amine), 4mL / min; Column: Chiralcel OX-H, 4.6×100mm 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz, 1H),7.33(td,J=8.0,5.4Hz,1H),7.23-6.92(m, 2H),6.49(dd,J=44.7,6.8Hz,1H),5.68(d,J=47 .8Hz,2H),4.97(s,1H),4.83(s,2H),3.44(s,3H) ), 1.70(dd, J=22.7, 6.6Hz, 3H).

[0259] Example 8d 40mg: as the fourth eluting stereoisomer LCMS Rt=1.88 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt = 3.01 min; mobile phase: 20% MeOH in CO2 (0.1% isopropyl amine), 4mL / min; Column: Chiralcel OX-H, 4.6×100mm 1 H NMR:(400MHz,DMSO-d6)δ 10.13(d,J=3.4Hz ,1H),7.33(td,J=8.0,5.4Hz,1H),7.20-6.93(m ,2H),6.69-6.31(m,1H),5.68(d,J=47.8Hz,2H) ,4.97(s,1H),4.83(s,2H),3.44(s,3H),1.70(d d, J = 22.8, 6.5 Hz, 3H).

[0260] Example 8, Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl) Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran The configuration of [3,4-b]pyridine-3-carboxylate was confirmed by single crystal X-ray crystallography. This confirmed that the active enantiomer was the R-enantiomer. (Figure 8).

[0261] Example 9: Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoro) (trimethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine 3-Carboxylate [ka] Step 1: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoro) Methoxy)phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5- Dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (2-(difluoromethoxy)benzoxazole). Zucaldehyde (350 mg, 2.033 mmol), intermediate A (382.3 mg, 2.0 33 mmol) and intermediate B (275.65 mg, 2.033 mmol) 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluorometh- yl) (phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxyl The carboxylate (600 mg, crude) was obtained, which was carried on to the next step without analysis. Passed.

[0262] Step 2: Methyl 4-(2-(difluoromethoxy)phenyl)-2-(fluoromethy (1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Ruboxylate [ka] The crude intermediate from step 1 (600 mg, 1.30 mmol) in methanol (20 mL) l) was added potassium hydroxide (293.44 mg, 5.22 mmol). The resulting solution was stirred at 65° C. for 30 minutes. Water was added to the reaction mixture, and a solid precipitated and was filtered. The solid was washed with diethyl ether, and the solid was collected and dried under reduced pressure. The title compound, methyl 4-(2-(difluoromethoxy)phenyl)-2- (Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pi Lysine-3-carboxylate (100 mg) was obtained.

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

[0264] Example 9 40 mg of the first eluting enantiomer as a white solid, 44% yield. Chiral HPLC Rt=6.481 min; [Chiral analysis method 1] LCMS Rt=1.473 min;MS m / z, 370[M+H]+;[Method 7] 1H NMR(400MHz,CDCl3)δ 7.30(dd,J=7.5,1.9H z,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 = 0.7 Hz, 3H). No exchangeable NH protons observed.

[0265] Example 9. Methyl (R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoro) (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine The configuration of the -3-carboxylate was determined by single crystal X-ray crystallography, , confirming that the active enantiomer was the R-enantiomer (Figure 9).

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

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

[0268] Step 2: 1,5-Difluoro-2-(trifluoromethyl)-3-vinylbenzene [ka] 1-Bromo-3,5-difluoro-2-(trifluoromethyl)benzene (Step 1 From this, 12.0 g, 45.99 mmol) and trifluoro(vinyl)-14-borane In an isopropyl alcohol (120 mL) solution, potassium salt (12.3 g, 91.98 m mol) and triethylamine (19.16 mL, 137.98 mmol) were added. The resulting solution was purged with argon for 10 min and then diluted with [1,1'-bis(difluorophenyl)phenyl]. [phenylphosphino)ferrocene]dichloropalladium(II)·DCM (3.75 g, 4 The reaction mixture was stirred at 80° C. for 6 hours. Filter through an elite pad, wash with ethyl acetate (100 mL), and precipitate over Na2SO4 The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica in petroleum ether. Purification of the crude product by FT-IR afforded the title compound, 1,5-difluoro-2-(trifluoromethyl)-2-(2-phenylpropanediol). (trifluoromethyl)-3-vinylbenzene (6.5 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.16-6.97(m,2H),6. 85-6.80(m,1H),5.67(d,J=17.2Hz,1H),5.49(d ,J=10.9Hz,1H).

[0269] Step 3: 3,5-Difluoro-2-(trifluoromethyl)benzaldehyde [ka] 1,5-Difluoro-2-(trifluoromethyl)-3-vinylbenzene (Step 2 From the above, 6.5 g, 31.23 mmol) and RuCl3·XH2O (647 mg, 3.1 23 mmol) in diacetoxyiodobenzene (20 g, 62.46 mmol) The resulting solution was added to a solution of 130 mL of dichloromethane:H2O (130 mL:30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of celite and diluted with dichloromethane. The mixture was washed with ethanol (200 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the silane was added. The crude was analyzed by Rikaflash chromatography (ethyl acetate in petroleum ether, 0→5%). Purification of the product afforded the title compound, 3,5-difluoro-2-(trifluoromethyl) (3.0 g) of benzaldehyde was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.34(m,1H),7.82-7 .52(m,1H),7.22-7.07(m,1H).

[0270] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluoro b-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydro Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (from the aldehyde (4 00 mg, 1.903 mmol) and synthesized 3-ethyl 5-methyl 2-(acetamide) (trifluoromethyl)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)- 6-(Fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (9 00 mg, crude product). LCMS Rt=1.76 min;MS m / z, 496.0[M+H]+;[Method 7]

[0271] Step 5: Methyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] Pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 4 (900 mg, 1.8 mmol) was used for the synthesis of the 2-amino-3-pyrrolidone ( The crude product was purified by ethyl acetate in petroleum ether (0→50%) to give the title compound Methyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(fluoro (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine The 3-carboxylate (90 mg) was obtained as an off-white solid. Racemic mixture was separated into its enantiomers using chiral HPLC [Method 7].

[0272] Example 10 30 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=5.502 min; [Chiral analysis method 2] LCMS Rt=1.542 min;MS m / z, 406[MH]-;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 7.30(d,J=7.2Hz,1H ),6.87(d,J=9.5Hz,1H),6.85 6.75(m,1H),5.7 9(t,J=1.2,1.2Hz,1H),5.67(t,J=1.1Hz,1H),5 .62(s,1H),4.80(d,J=1.2Hz,2H),3.54(s,3H).

[0273] Example 10b 30 mg of the second eluting enantiomer was obtained as a white solid. Chiral HPLC Rt=6.935 min; [Chiral analysis method 1] LCMS Rt=1.542 min;MS m / z, 406[MH]-;[Method 7] 1 H NMR:(400MHz,CDCl3)δ 7.30(d,J=7.2Hz,1H ),6.87(d,J=9.5Hz,1H),6.85 6.75(m,1H),5.7 9(t,J=1.2,1.2Hz,1H),5.67(t,J=1.1Hz,1H),5 .62(s,1H),4.80(d,J=1.2Hz,2H),3.54(s,3H).

[0274] Example 11: Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluoroacetate (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[ 3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1) A solution of 7 g (28.45 mmol) of Example 1 in THF (70 mL) was added under a nitrogen atmosphere. The mixture was cooled to -78°C. Then, n-butyllithium (13.66 mL, 2.5 M, 58.5 mmol) was added over 10 min, and the resulting mixture was The mixture was stirred at -78°C for 45 min. DMF (2.5 g, 34.15 mmol) was added as a result. The resulting mixture was added and stirred at -78°C for 1.15 hours. The reaction mixture was diluted with saturated ammonium chloride. The mixture was quenched with sodium chloride solution (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phase was washed with water (50 mL), followed by brine (50 mL) and diluted with NaSO. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica (petroleum Purification of the crude product with ethyl acetate in ether (0→50%) afforded the title compound. 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5g) Obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.52(s,1H),7.67-7 .53(m,2H),7.22-7.12(m,1H),6.50(s,1H),4.2 7-3.99(m,4H).

[0275] Step 2: 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1, 3-Dioxolane [ka] Acetonitrile (65 mL), triphenylphosphine (28.1 g, 107.1 mm ol), potassium iodide (11.85 g, 71.4 mmol) and 2-(1,3-dioxo solan-2-yl)-6-fluorobenzaldehyde (from step 1, 7 g, 35.7 A solution of 1,2,3,4-tetramethylphenylacetamide (1 mmol) was heated to 70° C. under a nitrogen atmosphere and stirred for 30 min. -Difluoro-2-(fluorosulfonyl)acetate (12 g, 62.4 mmol) It was added slowly over a period of 10 minutes (the mascara turned yellow during the addition). The resulting mixture was stirred at 70° C. for an additional 3 hours, then cooled to room temperature and diluted with diethyl ether. Dilute with ether. Filter the precipitated solid and wash with diethyl ether (100 mL). The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate, 0→5%) afforded the title compound, 2-(2-(2 ,2-difluorovinyl)-3-fluorophenyl)-1,3-dioxolane (6.9g ) was obtained as a pale yellow liquid. 1 H NMR:(300MHz,CDCl3)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).

[0276] Step 3: 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1, 3-Dioxolane [ka] 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-diox A solution of solan (from step 2, 3 g, 13.04 mmol) in ethyl acetate (60 mL) The reaction mixture thus obtained was then heated on a Parr shaker. The reaction mixture was kept at room temperature for 48 hours under a hydrogen atmosphere at 60 psi in a flask. Filtered over an elite pad and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure. and silica flash chromatography (ethyl acetate in petroleum ether, 0 → 30%) Purification of the crude product by HPLC afforded the title compound, 2-(2-(2,2-difluoroethyl) (3g)-3-fluorophenyl-1,3-dioxolane was obtained as a colorless liquid. . 1 H NMR(300MHz,CDCl3)δ 7.42-7.35(m,1H),7. 34-7.27(m,1H),7.15-7.08(m,1H),6.31-5.78( m,2H),4.19-4.02(m,4H),3.38(m,2H).

[0277] Step 4: 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde [ka] 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-diox Solan (from step 3, 3 g, 12.93 mmol) in diethyl ether (40 mL) To the solution 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. The solvent was removed under reduced pressure and the residue was purified by silica flash chromatography. Purification of the crude product by elution (ethyl acetate in petroleum ether, 0 → 5%) gave the following: The title compound, 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1 0.9 g) was obtained as a colourless liquid. 1 H NMR(400MHz,CDCl3)δ 10.14(d,J=1.6Hz,1H ),7.70-7.63(m,1H),7.52(td,J=8.0,7.9,5.2H z,1H),7.35-7.30(m 1H),6.03(m,1H),3.83-3. 58(m,2H).

[0278] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-diphenyl)-2-acetoxymethyl)-4-(2-methylphenyl)-2-(acetoxymethyl)-4-(2-methylphenyl)-2-acetoxymethyl)-2-(2,2-diphenyl Fluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydr Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 4, 4 The title compound 3-ethyl 5-methyl 2- (Acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl (fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate The compound (1 g, crude) was obtained. LCMS Rt=1.764 min;MS m / z, 473.4[M+H]+;[Method 7]

[0279] Step 6: Methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] Pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate 1g from step 5, The crude product was purified by silica flash chromatography. The title compound, methyl 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoro Methyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3 The racemic mixture was reacted with 1,2-dihydro-1,2,3-tetrahydrofuran to give the -carboxylate (85 mg) as an off-white solid. The enantiomers were separated using chiral preparative HPLC [Method 6].

[0280] Example 11 30 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=6.325 min; [Chiral analysis method 2] LCMS Rt=1.508 min;MS m / z, 386.0[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.34-7.27(m,1H),7. 21(m,1H),7.01-6.89(m,2H),6.55-6.17(m,1H) ,5.81(dd,J=1.7,0.8Hz,1H),5.69(t,J=1.1Hz, 1H),5.08(s,1H),4.78(d,J=0.9Hz,2H),3.94-3 .73(m,1H),3.60-3.55(m,1H),3.54(s,3H).

[0281] Example 11b 30 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=8.402 min; [Chiral analysis method 2] LCMS Rt=1.508 min;MS m / z, 386.4[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.34-7.27(m,1H),7. 21(td,J=8.0,8.0,5.6Hz,1H),7.01-6.89(m,2H ),6.55-6.17(m,1H),5.81(dd,J=1.7,0.8Hz,1H ),5.69(t,J=1.1,1.1Hz,1H),5.08(s,1H),4.78 (d,J=0.9Hz,2H),3.94-3.73(m,1H),3.60-3.55 (m,1H), 3.54(s,3H).

[0282] Example 12: Methyl (R)-4-(2-(2,2-difluoroethyl)-3,5-difluoro (fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Furo[3,4-b]pyridine-3-carboxylate [ka] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane [ka] 2-(2-Bromo-3,5-difluorophenyl)-1,3-dioxolane (Step 1 to Example 3, 5 g, 18.94 mmol) and potassium vinyltrifluoroborate (5.8 g, 37.89 mmol), triethylamine (7.91 mL, 56.82 m A solution of 100 mol of isopropyl alcohol (50 mL) was heated for 10 min using argon gas. Degass and dissolve [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( II)·DCM (1.55 g, 1.89 mmol) was added. The resulting solution was The mixture was degassed again with argon gas for 10 minutes and stirred at 80° C. for 5 hours. The reaction mixture was filtered. The filtrate was dissolved in water (1 L) and washed with ethyl acetate (2 L). The EtOAc was washed with brine and dried over Na2SO4. Removed under reduced pressure and purified by flash chromatography on silica (ethyl acetate in petroleum ether, Purification of the crude product by 0→10%) afforded the title compound, 2-(3,5-difluorophenyl (2-vinylphenyl)-1,3-dioxolane (3.45 g) was obtained as a colorless liquid. Note: Compound is naturally volatile, hexane present in compound. 1 H NMR(300MHz,CDCl3)δ 7.20-7.16(m,1H),6. 94-6.83(m,1H),6.82(dd,J=17.7,11.7Hz,1H), 5.60(dd,J=1.2,11.7Hz,1H),5.66-5.60(m,1H) ,5.95(s,1H),4.18-4.02(m,4H).

[0283] Step 3: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzal Dehyde [ka] 2-(3,5-Difluoro-2-vinylphenyl)-1,3-dioxolane (Step 2, 5 g, 23.58 mmol) and ruthenium chloride·XHO (490 mg, 2. To a solution of 35 mmol) of dichloromethane (50 mL) and water (10 mL), (iodo)benzene (11.4 g, 35.37 mmol) was added. The solution was stirred for 2 h at 30° C. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The filtrate was dissolved in water (200 mL) and the product was extracted into ethyl acetate (500 mL). The organics were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. and silica flash chromatography (ethyl acetate in petroleum ether, 0 → 10%) The title compound, 2-(1,3-dioxolane-2-yl) was obtained by purification of the crude product by (3 g)-4,6-difluorobenzaldehyde was obtained as a colorless liquid. The substance is natural and volatile, and hexane is present in the compound. 1 H NMR(300MHz,CDCl3)δ 10.41(s,1H),7.35(d ,J=9.6Hz,1H),6.95-6.85(m,1H),6.53(s,1H), 4.08(s,4H).

[0284] Step 4: 2-(2-(2,2-difluorovinyl)-3,5-difluorophenyl) -1,3-Dioxolane [ka] Triphenylphosphine (1.8 mL) was added to acetonitrile (4.5 mL) under a nitrogen atmosphere. 3g, 7.0mmol), potassium iodide (775mg, 4.66mmol) and 2-1 ,3-dioxolan-2-yl)-6-fluorobenzaldehyde (step 3 to 5 00 mg, 2.33 mmol) was added. The reaction was stirred at 70° C. for 30 min. Then , 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (7 83 mg, 4.07 mmol) was added slowly over a period of 10 min (without masking between additions). The color turned yellow), and the resulting mixture was stirred at 70° C. for an additional 3 h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether, and the precipitated solid was filtered. The solvent was removed under reduced pressure and the residue was washed with silica flash. Purification of the crude product by column chromatography (ethyl acetate in petroleum ether, 0→5%) The title compound, 2-(2-(2,2-difluorovinyl)-3,5-difluoro (400 mg) dioxolane was obtained as a pale yellow liquid. 1 H NMR(300MHz,CDCl3)δ 7.19-7.12(m,1H),6. 89-6.80(m,1H),5.85(d,J=0.9Hz,1H),5.31(dt ,J=26.1,1.5Hz,1H),4.16-3.98(m,4H).

[0285] Step 5: 2-(2-(2,2-difluoroethyl)-3,5-difluorophenyl) -1,3-Dioxolane [ka] 2-(2-(2,2-difluorovinyl)-3,5-difluorophenyl)-1,3- Dioxolane (from step 4, 400 mg, 1.61 mmol) in ethyl acetate (10 L) solution was added with 10% Pd-C (180 mg). The resulting reaction mixture was , kept under hydrogen atmosphere at room temperature at 60 psi pressure in a Parr shaker for 48 hours. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure and purified by silica flash chromatography (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate, 0→30%) afforded the title compound, 2-(2-(2 ,2-difluoroethyl)-3,5-difluorophenyl)-1,3-dioxolane(4 00 mg) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.22-7.12(m,1H),6. 81-6.75(m,1H),6.26-5.75(m,2H),4.20-3.99( m,4H),3.36-3.33(m,2H).

[0286] Step 6: 2-(2,2-difluoroethyl)-3,5-difluorobenzaldehyde [ka] 2-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-1,3- Dioxolane (from step 5, 400 mg, 1.6 mmol) in diethyl ether (1 To the resulting solution (0 mL) was added 5N HCl (1 mL). The resulting solution was stirred at room temperature for 1 hour. The mixture was stirred for 3 h. It was then diluted with water (50 mL), saturated NaHCO3 solution (100 mL), and The solvent was removed under reduced pressure and the silica was washed with water and dried over Na2SO4. Purification of the crude product by column chromatography (ethyl acetate in petroleum ether, 0→5%) The title compound, 2-(2,2-difluoroethyl)-3,5-difluorobenzyl The aldehyde (250 mg) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.11(d,J=1.3Hz,1H ),7.51-7.34(m,1H),7.20-7.07(m,1H),6.31-5 .73(m,1H),3.79-3.56(m,2H).

[0287] Step 7: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-diphenyl)-2-acetoxymethyl)- Fluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4- Dihydropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (from the aldehyde (2 The title compound 3-ethyl 5-methyl 2-methyl-2-propanediol was synthesized using 50 mg, 1.21 mmol) -(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3,5-difluoro (3,4-Dihydropyridine-3,5-dicarboxyl)-6-(fluoromethyl)-1,4-dihydropyridine The xylate (800 mg, crude) was obtained. LCMS Rt=1.77 min;MS m / z, 491.0[M+]+;[Method 7]

[0288] Step 8: Methyl 4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3 ,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 7, 800 The crude product was purified by silica flash chromatography. The mixture was purified by filtration (ethyl acetate in petroleum ether, 0→50%) to give the title compound. Methyl 4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2 -(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] Pyridine-3-carboxylate (44 mg) was obtained as an off-white solid. The mixture was separated into its enantiomers using chiral preparative HPLC [Method 6]. .

[0289] Example 12 11 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=5.674 min; [Chiral analysis method 2] LCMS Rt=1.561 min;MS m / z, 403.9[M+]+;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.87-6.76(m,2H),6. 64-6.26(m,1H),5.76(s,1H),5.64(s,1H),5.13 (d,J=1.4Hz,1H),4.87-4.83(m,2H),3.50-3.36 (m,1H), 3.70(s,2H), 3.53(s,3H).

[0290] Example 12b 10 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=7.215 min; [Chiral analysis method 2] LCMS Rt=1.557 min;MS m / z, 403.9[M+]+;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.87-6.76(m,2H),6. 64-6.26(m,1H),5.76(s,1H),5.64(s,1H),5.13 (d,J=1.4Hz,1H),4.87-4.83(m,2H),3.50-3.36 (m,1H), 3.70(s,2H), 3.53(s,3H).

[0291] Example 13: Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] Pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3,5-difluorobenzaldehyde [ka] 2-Bromo-3,5-difluorobenzaldehyde (10 g, 45.20 mmol) and and cyclopropylboronic acid (4.67 g, 54.2 mmol) in toluene (100 mL) The solution was added with 2N K2CO3 (102 mL, 204 mmol) and [1,1'-bis(difluorophenyl) [phenylphosphino)ferrocene]dichloropalladium(II)·DCM (3.17 g, 3 The resulting solution was degassed with argon gas for 10 minutes, The mixture was stirred for 4 hours at 100° C. 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 OAc phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the silane was added. Crude by Rikaflash chromatography (ethyl acetate in petroleum ether, 0→1%) Purification of the product afforded the title compound, 2-cyclopropyl-3,5-difluorobenzene. Zucaldehyde (8 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.71(d,J=3Hz,1H), 7.40-730(m,1H),7.05-6.90(m,1H),2.05-1.95 (m,1H),1.19-1.09(m,2H),0.85-0.75(m,2H).

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

[0293] Step 3: Methyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-( Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine Din-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 2, 4.6 The crude product was purified by silica flash chromatography. The compound was purified by chromatography (ethyl acetate in petroleum ether, 0 to 50%), 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) was obtained as an off-white solid. Ta.

[0294] The racemic mixture can be resolved into its enantiomers using chiral preparative HPLC [Method 9]. Let go.

[0295] Example 13 135 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=5.33 min; [Chiral analysis method 2] LCMS Rt=1.591 min;MS m / z, 380.2[M+H]+;[Method 7] 1 H NMR(300MHz,CD3OD)δ 6.78-6.70(m,1H),6. 66(m,1H),5.75(s,1H),5.61(d,J=14.1Hz,2H), 4.84(q,J=1.7,1.7,0.9Hz,2H),3.53(s,3H),2. 08(m,1H),1.18(m,1H),1.07-0.87(m,2H),0.75 (m,1H).

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

[0297] Example 14 17 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=8.588 min; [Chiral analysis method 3] LCMS Rt=1.548 min;MS m / z, 378.0[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.21(d,J=7.2Hz,1H) ,6.65-6.48(m,2H),5.78(d,J=0.9Hz,1H),5.65 (d,J=0.8Hz,1H),5.60-5.52(m,1H),3.56(s,3H ),2.75-2.56(m,2H),2.52-2.32(m,2H),2.20-2 .13(m,1H),1.34-1.13(m,1H),1.05-0.98(m,2H ), 0.83-0.69(m,1H).

[0298] Example 14b 17 mg of the second eluting enantiomer obtained as a white solid. Chiral HPLC Rt=11.651 min; [Chiral analysis method 3] LCMS Rt=1.548 min;MS m / z, 378.0[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.21(d,J=7.2Hz,1H) ,6.65-6.48(m,2H),5.78(d,J=0.9Hz,1H),5.65 (d,J=0.8Hz,1H),5.60-5.52(m,1H),3.56(s,3H ),2.75-2.56(m,2H),2.52-2.32(m,2H),2.20-2 .13(m,1H),1.34-1.13(m,1H),1.05-0.98(m,2H ), 0.83-0.69(m,1H).

[0299] Example 15: Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b] Pyridine-3-carboxylate [ka] Step 1: 2-(difluoromethyl)-1-fluoro-3-vinylbenzene [ka] 1-Bromo-2-(difluoromethyl)-3-fluorobenzene (2.0 g, 8.88 9 mmol) in isopropyl alcohol (20 mL) Fluoroborate (2.38 g, 17.78 mmol) and triethylamine (3.7 mL The resulting solution was purified by argon for 10 min. Purged and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II)·DCM (725 mg, 0.889 mmol) was added. The reaction mixture was heated to 80 °C. The reaction mixture was filtered through a pad of celite and diluted with ethyl acetate (10 The mixture was washed with 100 mL of ethyl acetate and dried over Na2SO4. The solvent was removed under reduced pressure and petroleum ether was added. Purification of the crude product by flash chromatography on silica in 2-(difluoromethyl)-1-fluoro-3-vinylbenzene (1.2 g) was obtained as a liquid. 1 H NMR(400MHz,CDCl3)δ 7.48-7.40(m,1H),7. 30-7.15(m,1H),7.04(t,J=53.4Hz,1H),7.04-6 .90(m,2H),5.44(d,J=11.2Hz,1H),5.70(d,J=1 1.2Hz,1H).

[0300] Step 2: 2-(Difluoromethyl)-3-fluorobenzaldehyde [ka] 2-(Difluoromethyl)-1-fluoro-3-vinylbenzene (from step 1, 1 0.2 g, 6.970 mmol) in dichloromethane:HO (20 mL:6 mL) RuCl3·XH2O (145 mg, 0.697 mmol) and diacetoxyiodine Benzene (6.73 g, 20.91 mmol) was added. The resulting solution was heated at room temperature. The reaction mixture was filtered through a pad of celite and diluted with dichloromethane. (200 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and silica The crude product was purified by flash chromatography (ethyl acetate in petroleum ether, 0→5%). The title compound, 2-(difluoromethyl)-3-fluorobenzaldehyde, was obtained by purifying the product. The aldehyde (500 mg) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 10.42(t,J=2.0Hz,1H ),8.44(d,J=8.0Hz,1H),7.70-7.59(m,1H),7.4 5-7.35(m,1H),7.30(t,J=53.2Hz,1H).

[0301] Step 3: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoro (3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyri Zin-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 2, 5 00 mg, 2.871 mmol) and 3-ethyl 5-methyl 2-(acetamide) 2-(difluoromethyl)-3-fluorophenyl)-6-(fluorophenyl)-4-(2-(difluoromethyl)-3-fluorophenyl) (1.5 g, crude)-1,4-dihydropyridine-3,5-dicarboxylate ( Product) was obtained. LCMS Rt=1.716 min;MS m / z, 460.1[M+H]+;[Method 7]

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

[0303] Example 15 90 mg of the first eluting enantiomer obtained as a white solid. Chiral HPLC Rt=10.05 min; [Chiral analysis method 2] LCMS Rt=1.947 min;MS m / z, 372.2[M+H]+;[Method 9] 1 H NMR(400MHz,CDCl3)δ 7.44-7.28(m,2H),7. 09-6.96(m,2H),5.80(d,J=0.8Hz,1H),5.68(d, J=0.9Hz,1H),5.20(s,1H),4.80(d,J=1.1Hz,2H ), 3.54 (s, 3H). No exchangeable NH protons were observed in the spectrum.

[0304] Example 15b 90 mg of the second eluting enantiomer was obtained as a white solid. Chiral HPLC Rt=12.05 min; [Chiral analysis method 2] LCMS Rt=2.09 min;MS m / z, 372.2[M+H]+;[Method 9] 1 H NMR(400MHz,CDCl3)δ 7.43-7.33(m,2H),7. 10-6.93(m,2H),5.80(d,J=0.8Hz,1H),5.68(d, J=0.9Hz,1H),5.20(s,1H),4.80(d,J=0.9Hz,2H ),3.54(s,3H).

[0305] Example 16: Methyl (R)-4-(2-((R or S)-1,2-difluoroethyl)- 3,5-Difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7 -Tetrahydrofuro[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane [ka] The title compound was prepared using 15 g of 2-bromo-3,5-difluorobenzaldehyde. 15 g of the desired product 2-(2- Bromo-3,5-difluorophenyl)-1,3-dioxolane was obtained. 1 H NMR(300MHz,CDCl3)δ 7.23-7.18(m,1H),6. 95-6.90(m,1H),6.08(t,J=1.1Hz,1H),4.24-3. 99(m,4H).

[0306] Step 2: (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluoro (O-phenyl)trimethylsilane [ka] 2-(2-Bromo-3,5-difluorophenyl)-1,3-dioxolane (Step From 1, 15.0 g, 56.59 mmol) in freshly distilled THF (150 mL) To the reaction mixture, lithium diisopropylamide (31.1 mL, 2. 0M, 62.25mmol) was added at -78°C and stirred for 30 minutes. Add aryl (7.37 g, 67.91 mmol) to the reaction mixture and stir at -78°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (250 mL) and the product was converted to ethyl acetate. The combined EtOAc phase was extracted into brine solution (250 ml). The mixture was washed with 1 L of water and dried over Na2SO4. The solvent was removed under reduced pressure and petroleum ether (1 Purification of the crude product by flash chromatography on silica in 100% aqueous solution gave the title compound. The compound (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl Thus, phenyltrimethylsilane (9.0 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.08(dd,J=8.9,1.6H z,1H),6.07(d,J=1.3Hz,1H),4.33-3.89(m,4H) ,0.37(t,J=1.6Hz,9H).

[0307] Step 3: 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3 -(Trimethylsilyl)phenyl)-2-fluoroethane-1-one [ka] (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluorophenyl Freshly distilled 1.0g (5.0g, 14.961mmol) trimethylsilane (from step 2) The distilled THF (50 mL) solution was treated with n-butyllithium (6.0 mL, A 2.5M solution in hexane (14.961 mmol) was slowly added at -78°C. Ethyl 2,2-difluoroacetate (3.1 g, 29.9 mmol) was added to the reaction mixture. The reaction mixture was stirred at -78°C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (250 mL). The mixture was quenched and extracted into ethyl acetate (2×200 mL). The combined EtOAc phases were The mixture was washed with ethyl acetate solution (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. Silica flash chromatography (ethyl acetate in petroleum ether, 0 → 10%) The title compound, 1-(6-(1,3-dioxolane-2-yl)-2-propanediol, was obtained by purifying the crude product. (yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroethene The compound was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.04(dt,J=8.9,0.8H z,1H),6.02(s,1H),5.22(d,J=1.6Hz,1H),5.07 (d,J=1.6Hz,1H),4.03-3.79(m,4H),0.37(s,9H ).

[0308] Step 4: 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3 -(Trimethylsilyl)phenyl)-2-fluoroethane-1-ol [ka] 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl) (ethylsilyl)phenyl)-2-fluoroethan-1-one (from step 3, 2.5 g, A solution of 7.854 mmol of sodium borohydride (59 4.2 mg, 15.70 mmol) was added in portions at 0° C. The temperature was slowly increased to room temperature. The reaction mixture was heated to 50° C. for 1 hour and stirred at room temperature for an additional 2 hours. The mixture was quenched with ethyl acetate (50 mL) and extracted into ethyl acetate (200 mL). The OAc was washed with brine solution (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure. and silica flash chromatography (ethyl acetate in petroleum ether, 0 → Purification of the crude product by 30% yielded the title compound, 1-(6-(1,3-dioxo-1,4-diphenyl-2,4-dioxanediol). Solan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2- Fluoroethan-1-ol (2.5 g) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.12(dd,J=9.4,1.2H z,1H),6.15(s,1H),5.42-5.35(m,1H),4.93-4. 47(m,2H),4.19-3.88(m,4H),2.96(dd,J=6.1,2 .8Hz,1H),0.36(s,9H).

[0309] Step 5: (3-(1,2-difluoroethyl)-4-(1,3-dioxolane-2- (yl)-2,6-difluorophenyl)trimethylsilane [ka] 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethylsilyl) (ethylsilyl)phenyl)-2-fluoroethan-1-ol (from step 4, 2.0 g A solution of 1,2-diethylaminosulfur trifluoride (6.24 mmol) in dichloromethane (20 mL) was DAST (1.24 mL, 9.36 mmol) was added at 0° C. The reaction was allowed to warm to room temperature. The reaction mixture was warmed and stirred for 1 hour. Water (50 mL) was added to the reaction mixture, and the product was dissolved in dichloromethane ( The DCM phases were combined and extracted with saturated NaHCO3 solution (50 mL). The solvent was removed under reduced pressure and the silica fraction was washed with ethyl acetate, brine and dried over Na2SO4. Purification of the crude product by cross-linking (ethyl acetate in petroleum ether, 0→2%) Purification afforded the title compound (3-(1,2-difluoroethyl)-4-(1,3-dioxoethyl)- (solan-2-yl)-2,6-difluorophenyl)trimethylsilane (1.1 g) Obtained as a colored liquid. 1 H NMR(400MHz,CDCl3)δ 7.23-7.04(m,1H),6. 24-6.05(m,1H),6.04(s,1H),5.15-4.89(m,1H) ,4.70-4.39(m,1H),4.14-3.99(m,4H),0.36(s, 9H).

[0310] Step 6: 2-(1,2-difluoroethyl)-3,5-difluoro-4-(trimethyl (silyl)benzaldehyde [ka] (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2 ,6-difluorophenyl)trimethylsilane (from step 5, 1.1 g, 3.41 m To a solution of 10 mL of 6N HCl (11 mL) was added 10 mL of diethyl ether. The resulting solution was stirred at room temperature for 3 h. It was diluted with water (50 mL), saturated NaH It was washed with CO3 solution (100 mL) and brine, and dried over Na2SO4. The title compound, 2-(1,2-difluoroethyl)-3,5-difluorophenyl Fluoro-4-(trimethylsilyl)benzaldehyde (900 mg) as a colorless liquid The product was used for the next step without further purification and analysis.

[0311] Step 7: 2-(1,2-difluoroethyl)-3,5-difluorobenzaldehyde [ka] (2-(1,2-difluoroethyl)-3,5-difluoro-4-(trimethylsilyl ) Benzaldehyde (from step 6, 900 mg, 3.23 mmol) in THF (20 To the solution of 1.0 mL of TBAF (8.0 mL, 1.0 M in THF, 8.08 mmol) was added. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (50 This was diluted with water (50 mL), saturated NaHCO3 solution (100 mL), and The solvent was removed under reduced pressure and the silica was washed with water and dried over Na2SO4. Purification of the crude product by column chromatography (ethyl acetate in petroleum ether, 5 → 10%) The title compound, 2-(1,2-difluoroethyl)-3,5-difluoro Benzaldehyde (400 mg) was obtained as a colorless liquid. 1 H NMR(600MHz,CDCl3)δ 10.41-10.14(m,1H), 7.54(d,J=8.3Hz,1H),7.15-7.06(m,1H),6.34- 6.30(m,1H),4.95-4.67(m,2H).

[0312] Step 8: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-diphenyl Fluoroethyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4- Dihydropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 7, 4 90 mg, 2.377 mmol) and 3-ethyl 5-methyl 2-(acetamide) 2-(1,2-difluoroethyl)-3,5-difluorophenyl )-6-(Fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.0 g, crude). Without further purification or analysis, the product was carried on to the next step. Used for the purpose.

[0313] Step 9: Methyl 4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3 ,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 8, 1.0 g, 2.03 mmol) was used for the synthesis. The crude product was extracted with ethyl acetate in petroleum ether (0→50%) to give the title compound, 4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-2-( Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine The zinzine-3-carboxylate (1.0 g, crude) was obtained as an off-white solid. The diastereomeric mixture was purified by silica flash chromatography (0→80%). The two isomers were separated by hexanes, and 70 mg of the first diastereomer was obtained as a white solid. The first isolated peak was 200 mg of the second diastereomer as a white solid. Diastereomer from peak 1: 70 mg and diastereomer from peak 2: 50 mg , which were further separated into their enantiomers using preparative chiral SFC [Method 8], Two isomers were obtained.

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

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

[0316] Example 16c 15mg of the third enantiomer eluting as a white solid Chiral HPLC Rt=14.54 min; [Chiral analysis method 3] LCMS Rt=1.472 min;MS m / z, 402.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.92-6.80(m,2H),6. 70-6.48(m,1H),5.76(s,1H),5.64(s,1H),5.48 (s,1H),5.16(s,1H),5.15-4.51(m,4H),3.55(s ,3H).

[0317] Example 16d 15 mg of the fourth enantiomer eluted as a white solid Chiral HPLC Rt=18.97 min; [Chiral analysis method 3] LCMS Rt=1.466 min;MS m / z, 402.2[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 6.92-6.80(m,2H),6. 70-6.48(m,1H),5.76(s,1H),5.64(s,1H),5.48 (s,1H),5.16(s,1H),5.15-4.51(m,4H),3.55(s ,3H).

[0318] Example 17: Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl )-2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4 -b]pyridine-3-carboxylate [ka] Step 1: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3-fluoro-2 -(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydropyri Zin-3,5-dicarboxylate [ka] The title compound was prepared using general procedure I (commercially available 3-fluoro-2-(trifluoromethyl) (1.4 g, 7.28 mmol) benzaldehyde to synthesize 3-ethyl 5- -Methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(trifluoromethyl) Phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxyl The sylate (2 g, crude) was obtained. Without further purification or analysis, the product was Used for tepp.

[0319] Step 2: Methyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)-2- (Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pi Lysine-3-carboxylate [ka] The title compound was synthesized using step 2 of general procedure I (from step 2, 2g, 4.18 mmol). Silica flash chromatography (ethyl acetate in petroleum ether) Purification of the crude product by ethanol (0→70%) afforded the title compound, methyl 4-(3-fluorophenyl Fluoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo -1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate ( The racemic mixture was purified by preparative chiral HPLC to give 240 mg of 1,2-dichlorophenyl ether (1H, 2H, 3H, 4H, 5H, 6H, 7H, 8H, 9H, 10H, 11H, 12H, 13H, 14H, 15H, 16H, 17H, 18H, 19H, 20H, 21H It was separated into its enantiomers using [Method 5].

[0320] Example 17 80 mg of the first eluting enantiomer as a white solid, 33% yield. Chiral HPLC Rt=7.549 min; [Chiral analysis method 1] LCMS Rt=1.485 min;MS m / z, 390.1[M+H]+;[Method 7] 1 H NMR(600MHz,CD3OD)δ 7.62-7.46(m,1H),7. 35-7.30(m,1H),7.20-7.02(m,1H),5.75-5.69( m,1H),5.68-5.60(m,1H),5.58-5.50(m,1H),4. 84(d,J=5.1Hz,2H),3.47(s,3H).

[0321] Example 18: Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl) Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3 ,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane [ka] The title compound was prepared using 15 g of 2-bromo-3,5-difluorobenzaldehyde. 15.4 g of 2-(2-bromo-3 ,5-difluorophenyl)-1,3-dioxolane was obtained. 1 H NMR(300MHz,CDCl3)δ 7.20-7.15(m,1H),6. 49-6.87(m,1H),6.08(s,1H),4.17-4.04(m,4H) .

[0322] Step 2: 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane [ka] The title compound is 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxo The 2-(3,5-difluorophenyl)propane was synthesized using the same procedure as in step 2 of Example 1 using The resulting product was fluoro-2-vinylphenyl-1,3-dioxolane (3.0 g). 1 H NMR(300MHz,CDCl3)δ 7.20-7.16(m,1H),6. 94-6.83(m,1H),6.82(dd,J=17.7,11.7Hz,1H), 5.60(dd,J=1.2,11.7Hz,1H),5.66-5.60(m,1H) ,5.95(s,1H),4.18-4.02(m,4H).

[0323] Step 3: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzal Dehyde [ka] The title compound was synthesized according to the same procedure as in Step 1 of Example 5, to give 22-(1,3- Dioxolan-2-yl)-4,6-difluorobenzaldehyde (1.0 g) was obtained. 1 H NMR(300MHz,CDCl3)δ 10.41(s,1H),7.35(d ,J=9.6Hz,1H),6.95-6.85(m,1H),6.53(s,1H), 4.08(s,4H).

[0324] Step 4: 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3 -Dioxolane [ka] The title compound was synthesized according to a procedure similar to that of Step 3 of Example 5 to give 2-(2-(diphenylphosphine) (fluoromethyl)-3,5-difluorophenyl)-1,3-dioxolane (570mg) obtained. 1 H NMR(300MHz,CDCl3)δ 7.29-7.25(m,1H),7. 06(t,J=1.1Hz,1H),6.95-6.84(m,1H),6.13(t, J=1.2Hz,1H),4.30-3.86(m,4H).

[0325] Step 5: 2-(Difluoromethyl)-3,5-difluorobenzaldehyde [ka] 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxo Dissolve the run (from step 4, 570 mg, 2.41 mmol) in diethyl ether (10 mL To the resulting solution was added 6N HCl (10 mL) at 0° C. The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted into diethyl ether (50 mL) and The organic phase was washed with water (30 mL). 0 mL) and dried over Na2SO4. The solvent was removed under reduced pressure to give crude compound 2- (Difluoromethyl)-3,5-difluorobenzaldehyde (360 mg) is a colorless liquid Brought as a body. 1 H NMR(300MHz,CDCl3)δ 10.42(s,1H),7.74-7 .54(m,1H),7.25(dd,J=46.8,10.4Hz,1H),7.15 -7.10(m,1H).

[0326] Step 6: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoro) Methyl)-3,5-difluorophenyl)-6-(fluoromethyl)-1,4-dihydro Pyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 5, 3 60 mg, 1.87 mmol) and 3-ethyl 5-methyl 2-(acetoxy) dimethyl)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-6-( Fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (720m g, crude product). LCMS Rt=1.698 min;MS m / z, 476.1[MH]-;[Method 7]

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

[0328] Example 18 30 mg of the first eluting enantiomer obtained as a white solid, 25% yield. Chiral HPLC Rt=17.629 min; [Chiral analysis method 1] LCMS Rt=1.454 min;MS m / z, 388.2[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.40-7.38(m,1H),6. 93(dd,J=10.3,7.6Hz,2H),5.77(d,J=0.8Hz,1H ),5.65(d,J=0.7Hz,1H),5.27(d,J=1.6Hz,1H), 4.89-4.86(m,2H),3.51(s,3H).

[0329] Example 18b 36 mg of the second eluting enantiomer obtained as a white solid, 30% yield. Chiral HPLC Rt=19.634 min; [Chiral analysis method 1] LCMS Rt=1.454 min;MS m / z, 388.0[MH]-;[Method 7] 1 H NMR(400MHz,CD3OD)δ 7.40-7.38(m,1H),6. 93(dd,J=10.3,7.6Hz,2H),5.77(d,J=0.8Hz,1H ),5.65(d,J=0.7Hz,1H),5.27(d,J=1.6Hz,1H), 4.89-4.86(m,2H),3.51(s,3H).

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

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

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

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

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

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

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

[0337] Step 2: Methyl 4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoro (trimethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine 3-Carboxylate [ka] The title compound was ethyl 4-chloro-3-oxobutanoate (346 mg, 2.10 m mol), 2-cyclopropyl-5-fluorobenzaldehyde prepared in step 1 Hydride (345 mg, 2.10 mmol), and methyl (Z)-3-amino-4-fluoro But-2-enoate (Intermediate B, 280 mg, 2.10 mmol) to General Procedure II It was prepared by the following: racemic methyl 4-(2-cyclopropyl-5-fluorophenyl)- 2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b ] Pyridine-3-carboxylate was purified by chiral SFC (mobile phase: 0.2% NH4OH / C 25% Methanol with O2, 80g / min; Column: (SS) Whelk-O1, 4.6 × 100 mm) was used to separate the enantiomers.

[0338] Example 21 21.4 mg of the first eluting enantiomer (5.6%) as a white solid. Chiral SFC Rt = 2.41 min (mobile phase: 5-55% MeOH w / 10 mM NH4 OH / CO2, 5mL / min, 120 bar; Column: (SS) Whelk-O1, 4.6 ×100mm, 5μm). LCMS Rt=0.95 min; MS m / z, 362.5[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.08(s,1H), 7.08-6.95(m,1H),6.93 -6.82(m,2H),5.78-5. 58(m,2H),5.37(s,1H),4.90-4.77(m,2H),3.45 (s,3H),1.00-0.80(m,3H),0.54-0.46(m,1H). The benzyl CH on chloropropyl is hidden under the DMSO peak.

[0339] Example 21b 10.3 mg of the second eluting enantiomer (2.7%) as a white solid. Chiral SFC Rt = 2.69 min (mobile phase: 5-55% MeOH w / 10 mM NH4 OH / CO2, 5mL / min, 120 bar; Column: (SS) Whelk-O1, 4.6 ×100mm, 5μm). LCMS Rt=0.95 min; MS m / z, 362.5[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.08(s,1H), 7.08-6.95(m,1H),6.93-6.82(m,2H),5.78-5.5 8(m,2H),5.37(s,1H),4.90-4.77(m,2H),3.45( s,3H),1.00-0.80(m,3H),0.54-0.46(m,1H).

[0340] Example 22: Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl) (1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Ruboxylate [ka] Step 1: 2-Cyclopropylbenzaldehyde [ka] Degassed 2-bromobenzaldehyde (1g, 5.40mmol), cyclopropanediol dppf·CH2Cl2 A solution of the product (0.441 g, 0.540 mmol) in dioxane (15 mL) and M K2CO3 aqueous solution (5.40 mL, 10.81 mmol) was stirred and heated to 80 °C. Upon completion, the reaction mixture was cooled to room temperature and then partitioned between water and ethyl acetate. The organic phase was washed with water and brine, then dried over MgSO4 and concentrated. Purified by silica flash chromatography [0-20% ethyl acetate in heptane]. This gave 420 mg of the title compound (53% yield). The crude product was not further purified. I accepted it without any hesitation.

[0341] Step 2: Methyl 4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5 -Oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxy rate [ka] The title compound was prepared by diluting ethyl 4-chloro-3-oxobutanoate (0.204 mL, 1.5 00mmol), 2-cyclopropylbenzaldehyde (219mg, 1.5mmol) (Prepared in Step 1) and methyl (Z)-3-amino-4-fluorobut-2-ene Prepared from acetone (Intermediate B, 200 mg, 1.50 mmol) by general procedure II. Racemic methyl-4-(2-cyclopropylphenyl)-2-(fluoromethyl)- 5-Oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate Silyl carboxylates were purified by chiral SFC (mobile phase: 10 mM NH4OH / CO2 5-55% methanol, 3 mL / min; Column: (SS)WHO; 1 4.6×100 The enantiomers were separated using a 250 sq. mm chromatography.

[0342] Example 22 7.9 mg of the first eluting enantiomer (3.0%) as a white solid. Chiral SFC Rt=2.77 min LCMS Rt=0.93 min; MS m / z, 344.5[M+H]+; [Method 4]. 1 H NMR (400MHz, methanol-d4) δ ppm 6.91-7.23 (m ,4H),5.73(d,J=1.96Hz,1H),5.61(d,J=2.93Hz ,1H),5.48(s,1H), 4.82(s,2H),3.50(s,3H),2 .53-2.65(m,1H),0.86-0.99(m,3H),0.58(d,J= 5.87Hz,1H).

[0343] Example 22b 7.5 mg of the second eluting enantiomer (2.9%) as a white solid. Chiral SFC Rt=3.19 min LCMS Rt=0.93 min; MS m / z, 344.5[M+H]+; [Method 4]. 1H NMR (400MHz, methanol-d4) δ ppm 6.91-7.23 (m ,4H),5.73(d,J=1.96Hz,1H),5.61(d,J=2.93Hz ,1H),5.48(s,1H), 4.82(s,2H),3.50(s,3H),2 .53-2.65(m,1H),0.86-0.99(m,3H),0.58(d,J= 5.87Hz,1H).

[0344] Example 23: Methyl (R)-4-(5-fluoro-2-(trifluoromethyl)phenyl )-2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4 -b]pyridine-3-carboxylate [ka] The title compound was prepared by diluting ethyl 4-chloro-3-oxobutanoate (0.318 mL, 2.3 42 mmol), commercially available 5-fluoro-2-(trifluoromethyl)benzaldehyde ( 450 mg, 2.342 mmol) and methyl (Z)-3-amino-4-fluorobuta- From the 2-enoate (Intermediate B, 312 mg, 2.342 mmol) via general procedure II Racemic methyl 4-(5-fluoro-2-(trifluoromethyl)phenyl )-2-(Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4 -b]pyridine-3-carboxylate was analyzed by chiral SFC (mobile phase: 0.2% ammonium hydroxide). 15% methanol with ammonium / CO2, 80 g / min; column: 2.0 x 25.0 cm , ChromegaChiral CC4) was used to separate it into its enantiomers. .

[0345] Example 23 12.2 mg of the first eluting enantiomer (2.7%) as a white solid. Chiral SFC Rt = 1.29 min (column: 4.6 x 100 mm, Chiralcel OZ-H; isocratic 15% methanol with 0.1% isopropylamine; 125 bar LCMS Rt=0.92 min; MS m / z, 390.0[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.16(br s,1 H),7.70(dd,J=8.80,5.38Hz,1H),7.20-7.30(m ,2H),5.72(s,1H),5.60(s,1H),5.20(s,1H),4. 74-4.91(m,2H),3.38(s,3H).

[0346] Example 23b 14.0 mg of the second eluting enantiomer (3.0%) as a white solid. Chiral SFC Rt = 1.74 min (column: 4.6 x 100 mm, Chiralcel OZ-H; isocratic 15% methanol with 0.1% isopropylamine; 125 bar ) LCMS Rt=0.92 min; MS m / z, 390.0[M+H]+; [Method 4]. 1 H NMR(400MHz,DMSO-d6)δ ppm 10.16(br s,1 H),7.70(dd,J=8.80,5.38Hz,1H),7.20-7.30(m ,2H),5.72(s,1H),5.60(s,1H),5.20(s,1H),4. 74-4.91(m,2H),3.38(s,3H).

[0347] Example 24: Methyl (R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl)- (fluoromethyl)phenyl-1,4,5,7-tetrahydrofuro[3,4-b]pyridine -3-carboxylate [ka] The title compound was prepared by distillation of ethyl 4-chloro-3-oxobutanoate (0.286 mL, 2.1 0 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) according to general procedure II. 2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl) -1,4,5,7-Tetrahydrofuro[3,4-b]pyridine-3-carboxylate , Chiral SFC (Mobile phase: 20% methanol with 0.2% ammonium hydroxide, 80 g / min; Column: 2.0 x 25.0 cm, ChromegaChiral CC4) and separated into its enantiomers.

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

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

[0350] Example 25: Methyl (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl) (phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro -1H-Cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] 2-Bromo-3-fluorobenzaldehyde (60 g, 295.56 mmol) and Dissolve ethylene glycol (65.4 mL, 1182.2 mmol) in toluene (600 mL). Add p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol) to the solution. The resulting solution was heated at 120° C. for 24 hours using a Dean-Stark apparatus. The solvent was added to water (2 L) and extracted into EtOAc (3 L). Washed with saturated NaHCO3 solution (1 L), brine and dried over Na2SO4. Removed under reduced pressure and purified by silica flash chromatography (ethyl acetate in petroleum ether) Purification of the crude product by 0→10%) afforded the title compound, 2-(2-bromo-3 -fluorophenyl)-1,3-dioxolane (60 g) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.42- 7.37(m,1H),7 .34- 7.29(m,1H),7.16- 7.10(m,1H),6.10(s, 1H), 4.19-4.09(m,4H).

[0351] Step 2: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from step 1) A solution of 7 g of 28.45 mmol) in THF (70 mL) was heated at −78° C. under a nitrogen atmosphere. The mixture was then cooled to 30°C. Then, n-butyllithium in n-hexane (13.66 mL, 2. 5M, 58.5 mmol) was added over 10 min. The resulting mixture was heated to -78 °C. The mixture was stirred at rt for 45 min, then DMF (2.5 g, 34.15 mmol) was added and the resulting The resulting mixture was stirred at -78°C for 1.15 hours. The reaction mixture was diluted with saturated ammonium chloride The mixture was quenched with ethyl acetate (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase was washed with water (50 mL), followed by brine (50 mL), and then diluted with Na2SO4 The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica (petroleum ethyl acetate). Purification of the crude product with ethyl acetate in ether (0→50%) gave the title compound. 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5g) Obtained as a colored liquid. 1 H NMR (300MHz, chloroform-d) δ 10.52(s,1H), 7.6 7-7.53(m,2H),7.22-7.12(m,1H),6.50(s,1H), 4.27-3.99(m,4H).

[0352] Step 3: 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1, 3-Dioxolane [ka] A solution of triphenylphosphine (2 8.1g, 107.1mmol), potassium iodide (11.85g, 71.4mmol) and 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (step The reaction was stirred at 70° C. for 30 min, then Then, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (12 g, 6 2.4 mmol) was added slowly over a period of 10 minutes (the mascara turned yellow during the addition). The resulting mixture was stirred at 70° C. for an additional 3 h and then cooled to room temperature. Cool, dilute with diethyl ether, and remove the precipitated solid by filtration and diethyl ether. The resulting solvent was removed under reduced pressure and the silica gel was washed with ether (100 mL). Rush chromatography (ethyl acetate in petroleum ether, 0→5%) of the crude product The title compound, 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-2-phenylpropanediol, was obtained by purification of (Orophenyl)-1,3-dioxolane (6.9 g) was obtained as a pale yellow liquid. 1 H NMR (300MHz, chloroform-d) δ 7.39 (dd, J = 7.8, 1 .4Hz,1H),7.31(m,1H),7.11(m,1H),5.87(s,1H ), 5.39(m,1H), 4.21-3.95(m,4H).

[0353] Step 4: 2-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl) -1,3-Dioxolane [ka] 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-diox Solan (from step 3, 2.7 g, 11.73 mmol) and tetrabutylammonium fluoride A solution of monium in THF (13.7 g, 1 M, 13.7 mmol) was heated to 70°C in a closed system. The reaction was cooled and diluted with diethyl ether and this was washed with water (50 mL), Washed with saturated NaHCO3 solution (100 mL) and brine, and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica (petroleum ether Purification of the crude product with ethyl acetate, 0→10%) afforded the title compound 2-(3- Fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane (1.2 g) was obtained as a colorless liquid. 1 H NMR (300MHz, chloroform-d) δ 7.49-7.42 (m, 1H) ,7.35(m,1H),7.17-7.05(m,1H),6.03(s,1H),4 .25-3.90(m,4H),3.75(m,2H).

[0354] Step 5: 3-Fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde [ka] 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 To the solution was added 6N HCl (5 mL). The resulting solution was stirred at room temperature for 3 h. This was washed with water (50 mL), saturated NaHCO3 solution (100 mL), and brine. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0→5%) gave The title compound, 3-fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde The crude product was used for the next step without further purification. It was used as a stepping stone.

[0355] Step 6: 3-Ethoxycyclopent-2-en-1-one [ka] Cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene with stirring In a 70 mL solution of pTSA (193 mg, 1.019 mmol) and EtOH ( 2.61 ml, 387.35 mmol) was added at room temperature. The mixture thus obtained was The mixture was stirred at 120° C. for 10 hours using a Dean-Stark apparatus. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica (ethyl acetate in petroleum ether, 0→50%) to obtain the title compound, 3-ethoxycyclopent-2-ene- The 1-one (4.3 g) was obtained as a brown solid. 1 H NMR(400MHz,CDCl3)δ 5.26(s,1H),4.02(q, J=6.6Hz,2H),2.60-2.55(m,2H),2.44-2.40(m, 2H), 1.39(t,J=7.2Hz,3H).

[0356] Step 7: 3-Aminocyclopent-2-en-1-one [ka] Stirred 3-ethoxycyclopent-2-en-1-one (from step 6, 4.3 g A solution of 1,340.08 mmol) in ethanol (50 mL) was added to an ammonium hydroxide solution (2 The resulting mixture was heated to 85° C. The mixture was stirred at rt for 16 h. Removal of the solvent under reduced pressure gave the title compound, 3-aminosilyl. Clopent-2-en-1-one (3.2 g) was obtained as a brown solid. LCMS Rt=0.114 min;MS m / z, 98.2[M+H]+;[Method 7]

[0357] Step 8: Methyl 4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl Nyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H- Cyclopenta[b]pyridine-3-carboxylate [ka] Aldehyde (from step 5, 200 mg, 0.9708 mmol), methyl 4-fluoro Oro-3-oxobutanoate (Method 2, Step 1 of Intermediate B, 130 mg, 0.97 0.08 mmol) in EtOH (2 mL) 1H 2 O (from step 7, 94 mg, 0.9708 mmol) was added. The reaction mixture was stirred for 80 The mixture was stirred at 5° C. for 18 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel. The title compound was purified by HPLC (ethyl acetate in petroleum ether, 0→70%). The racemic mixture was purified by chiral preparative HPLC [Method 6]. was used to separate its enantiomers.

[0358] Example 25 The second eluting enantiomer (25 mg) was obtained as a white solid. Chiral HPLC Rt=7.610 min; [Chiral analysis method 4] LCMS Rt=1.533 min;MS m / z, 401.75[M+]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.31-7.25(m,1H),7. 04(d,J=8Hz,1H),6.97-6.90(m,1H),5.76(d,J= 3.2Hz,1H),5.64(d,J=2.8Hz,2H),5.08(s,1H), 4.79-4.60(m,2H),3.70-3.55(m,2H),3.44(s,3 H), 2.66-2.61(m,2H).

[0359] Example 25b First eluting enantiomer (24 mg) as a white solid. Chiral HPLC Rt 7.103 min; [Chiral analysis method 4] LCMS Rt=1.533 min;MS m / z, 401.75[M+]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.31-7.25(m,1H),7. 04(d,J=8Hz,1H),6.97-6.90(m,1H),5.76(d,J= 3.2Hz,1H),5.64(d,J=2.8Hz,2H),5.08(s,1H), 4.79-4.60(m,2H),3.70-3.55(m,2H),3.44(s,3 H), 2.66-2.61(m,2H).

[0360] Example 26: Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluoroacetate (phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1, 3-Dioxolane [ka] 2-(2-(2,2-difluorovinyl)-3-fluorophenyl)-1,3-diox Solan (from Example 25, Step 3, 3 g, 13.04 mmol) in ethyl acetate (60 To the resulting solution was added 10% Pd-C (1 g). The reaction was kept in a shaker under hydrogen atmosphere at room temperature at 60 psi for 48 hours. The mixture was filtered through a pad of celite and washed with ethyl acetate (30 mL). Concentrated under reduced pressure and purified by silica flash chromatography (ethyl acetate in petroleum ether) Purification of the crude product by HPLC with 0→30% yielded the title compound, 2-(2-(2,2- Difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (3g) Obtained as a liquid. 1 H NMR(300MHz,CDCl3)δ 7.42-7.35(m,1H),7. 34-7.27(m,1H),7.15-7.08(m,1H),6.31-5.78( m,2H),4.19-4.02(m,4H),3.38(m,2H).

[0361] Step 2: 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde [ka] 2-(2-(2,2-difluoroethyl)-3-fluorophenyl)-1,3-diox Solan (from step 1, 3 g, 12.93 mmol) in diethyl ether (40 mL) To the solution 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. The solvent was removed under reduced pressure and the residue was purified by silica flash chromatography. Purification of the crude product by cyclohexane (ethyl acetate in petroleum ether, 0→5%) , the title compound 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1.9 g) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 10.14(d,J=1.6Hz,1H ),7.70-7.63(m,1H),7.52(td,J=8.0,7.9,5.2H z,1H),7.35-7.30(m 1H),6.03(m,1H),3.83-3. 58(m,2H).

[0362] Step 3: Methyl (R)-4-(2-(2,2-difluoroethyl)-3-fluoroacetate (phenyl)-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-carboxamide Boxylate [ka] Aldehyde (from step 2, 200 mg, 1.063 mmol), methyl 4-fluoro rho-3-oxobutanoate (method 2, step 1 of intermediate B, 142 mg, 1.063 A solution of 1 mmol of 3-aminocyclopent-2-en-1-one in EtOH (2 mL) was (Example 25, Step 7, 103 mg, 1.063 mmol) was added. The reaction mixture was The mixture was stirred at 80° C. for 18 hours. The solvent was removed under reduced pressure to give the crude compound. by Kaflash chromatography (ethyl acetate in petroleum ether, 0 → 70%) Purification gave the title compound as an off-white solid (100 mg). and separated into its enantiomers using chiral preparative HPLC [Method 6].

[0363] Example 26 The first eluting enantiomer (25 mg) was obtained as a white solid. Chiral HPLC Rt 7.341 min; [Chiral analysis method 4] LCMS Rt=1.505 min;MS m / z, 384.2[M+1]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.25-7.17(m,1H),7. 01(d,J=8Hz,1H),6.92-6.85(m,1H),6.80-6.40 (m,1H),5.76(d,J=3.2Hz,1H),5.64(d,J=2.8Hz ,1H),5.08(s,1H),4.79-4.60(m,2H),3.70-3.5 5(m,2H),3.60-3.40(m,1H),3.52(s,3H),2.75- 2.65(m,2H).

[0364] Example 26b The second eluting enantiomer (26 mg) was obtained as a white solid. Chiral HPLC Rt 9.044 min; [Chiral analysis method 4] LCMS Rt=1.505 min;MS m / z, 384.2[M+1]+;[Method 12] 1 H NMR(400MHz,CD3OD)δ 7.25-7.17(m,1H),7. 01(d,J=8Hz,1H),6.92-6.85(m,1H),6.80-6.40 (m,1H),5.76(d,J=3.2Hz,1H),5.64(d,J=2.8Hz ,1H),5.08(s,1H),4.79-4.60(m,2H),3.70-3.5 5(m,2H),3.60-3.40(m,1H),3.52(s,3H),2.75- 2.65(m,2H).

[0365] Example 27: Methyl (R)-4-(3-fluoro-2-((R or S)-1-fluoroethane (phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydrofuran 1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl) Ethan-1-ol [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (Example 25, A solution of 30 g (121.42 mmol) of 1H2O (from step 1) in THF (300 mL) was placed in a nitrogen atmosphere. n-BuLi (58.3 mL, 2.5 M, 147.71 mmol) was added dropwise over 10 minutes. The resulting mixture was The mixture was stirred at 78° C. for 1 hour, and then acetaldehyde (6.42 g, 145.71 mmol) was added. l) was added and the reaction was stirred at -78°C for 1 hour. The reaction mixture was diluted with saturated ammonium chloride The mixture was quenched with ethyl acetate (50 mL) and extracted with ethyl acetate (2×100 mL). The aqueous phase was washed with water (50 mL), brine (50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the product was purified by flash chromatography on silica (petroleum ether Purification of the crude product with ethyl acetate, 0→10%) afforded the title compound 1-(2 -(1,3-dioxolan-2-yl)-6-fluorophenyl)ethan-1-ol ( 15 g) was obtained as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.38(d,J=8.0Hz,1H) ,7.30-7.18(m,1H),7.10-7.01(m,1H),6.15(s, 1H),5.30-5.25(m,1H),4.15-3.95(m,4H),2.75 -2.69(m.1H),1.58(dd,J=6.6,22.8Hz,3H).

[0366] Step 2: 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-di Oxolane [ka] 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane-1 -ol (from step 1, 15 g, 70.68 mmol) in dichloromethane (150 L) solution at -78 °C, mol) was added. The resulting solution was allowed to warm to RT and stirred for 1 h. The reaction mixture The 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. Removed under reduced pressure and purified by flash chromatography on silica (ethyl acetate in petroleum ether, Purification of the crude product by 0→10%) afforded the title compound, 2-(3-fluoro-2-(2-(4-methyl-1,2-dihydro-2-phenylindole)). -(1-fluoroethyl)phenyl)-1,3-dioxolane (8.5 g) Obtained as. 1H NMR(300MHz,CDCl3)δ 7.38(d,J=7.5Hz,1H) ,7.30-7.18(m,1H),7.13-7.01(m,1H),6.20-5. 95(m,1H),6.10(s,1H),4.16-4.02(m,4H),1.74 (dd, J = 7.2, 23.1 Hz, 3H).

[0367] Step 3: 3-Fluoro-2-(1-fluoroethyl)benzaldehyde [ka] 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (from step 2, 8.5 g, 69.38 mmol) in diethyl ether (150 mL) To the solution was added 4N HCl (85 mL) at room temperature. The resulting solution was allowed to cool to room temperature. The mixture was stirred for 3 hours. This was then diluted with water (100 mL), saturated NaHCO3 solution (200 mL), and The mixture was washed with water 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) was added to the colorless (Note: the resulting aldehyde is naturally volatile).

[0368] Step 4: Methyl 4-(3-fluoro-2-((R or S)-1-fluoroethyl)fluor (phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Cyclopenta[b]pyridine-3-carboxylate [ka] Aldehyde (from step 3, 1 g, 5.876 mmol), methyl 4-fluoro-3 -Oxobutanoate (Method 2, Step 1 of Intermediate B, 780 mg, 5.876 mmol) l) in EtOH (10 mL), 3-aminocyclopent-2-en-1-one ( Example 25, Step 7, 570 mg, 5.876 mmol) was added to the reaction mixture. The mixture was stirred at 5° C. for 18 hours. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel. The title compound was purified by chromatography (ethyl acetate in petroleum ether, 0→70%) to give the Methyl 4-(3-fluoro-2-(1-fluoroethyl)fluoride as an off-white solid (phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Diastereomeric mixture of cyclopenta[b]pyridine-3-carboxylate (22 0 mg).

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

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

[0371] Example 27 The second eluting enantiomer (55 mg) was obtained as a white solid. Chiral HPLC Rt=5.729 min; [Chiral analysis method 2] LCMS Rt=2.25 min;MS m / z, 364.1[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6. 96-6.75(m,2H),6.52-6.30(m,1H),5.79(s,1H) ,5.67(s,1H),5.05(s,1H),3.59(s,3H),2.80-2 .60(m,2H),2.50-2.35(m,2H),2.01(dd,J=6.4, 23.2Hz,3H).

[0372] Example 27b The first eluting enantiomer (55 mg) was obtained as a white solid. Chiral HPLC Rt=5.678 min; [Chiral analysis method 2] LCMS Rt=2.25 min;MS m / z, 364.1[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6. 96-6.75(m,2H),6.52-6.30(m,1H),5.79(s,1H) ,5.67(s,1H),5.05(s,1H),3.59(s,3H),2.80-2 .60(m,2H),2.50-2.35(m,2H),2.01(dd,J=6.4, 23.2Hz,3H).

[0373] The second peak from the diastereomeric separation was purified using chiral preparative purification [Method 10]. The enantiomers were separated into peaks 3 and 4.

[0374] Example 27c Third enantiomer eluting as a white solid (10 mg). Chiral HPLC Rt=8.702 min; [Chiral analysis method 2] LCMS Rt=2.22 min;MS m / z, 364.1[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6. 96-6.75(m,2H),6.80-6.60(m,1H),5.79(s,1H) ,5.69(s,1H),5.03(s,1H),3.54(s,3H),2.75-2 .58(m,2H),2.50-2.45(m,2H),1.83(dd,J=6.4, 22.4Hz,3H).

[0375] Example 27d Fourth enantiomer eluted as a white solid (10 mg). Chiral HPLC Rt=9.851 min; [Chiral analysis method 2] LCMS Rt=2.22 min;MS m / z, 364.1[MH]-;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.25-7.15(m,2H),6. 96-6.75(m,2H),6.80-6.60(m,1H),5.79(s,1H) ,5.69(s,1H),5.03(s,1H),3.54(s,3H),2.75-2 .58(m,2H),2.50-2.45(m,2H),1.83(dd,J=6.4, 22.4Hz,3H).

[0376] Example 28: Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2- (Fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta [b] Pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3-fluorobenzaldehyde [ka] 2-Bromo-3-fluorobenzaldehyde (15 g, 73.88 mmol) and cyclohexyl A solution of propylboronic acid (7.61 g, 88.66 mmol) in toluene (160 mL) Into the mixture, 2N K2CO3 (25.5 mL, 182.16 mmol) and [1,1'-bis( Diphenylphosphino)ferrocene]dichloropalladium(II)·DCM(6.03g , 7.38 mmol) was added. The resulting solution was degassed with argon gas for 10 minutes. The mixture was 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 Na2SO4. The solvent was removed under reduced pressure. , by silica flash chromatography (ethyl acetate in petroleum ether, 0→1%) The title compound, 2-cyclopropyl-3-fluorobenzoyl ester, was obtained by purification of the crude product. The aldehyde (11.2 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.70(s,1H),7.63(d d,J=1.2,7.8Hz,1H),7.35-7.15(m,2H),2.14-2 .02(m,1H),1.19-1.09(m,2H),0.85-0.75(m,2H ).

[0377] Step 2: Methyl 4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoro (trimethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pi Lysine-3-carboxylate [ka] Aldehyde (from step 1, 900 mg, 5.481 mmol), methyl (Z)-3 -Amino-4-fluorobut-2-enoate (Intermediate B, 537.76 mg, 5.48 A solution of 1 mmol) of cyclopentane-1,3-dione (875 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 flash chromatography on silica (petroleum Purification with ethyl acetate in ether (0→70%) afforded the title compound, methyl-4- (2-Cyclopropyl-3-fluorophenyl)-2-(fluoromethyl)-5-oxo -4,5,6,7-Tetrahydro-1H-cyclopenta[b]pyridine-3-carboxy The racemic mixture was purified by chiral fractionation to give the ethyl acetate (130 mg) as an off-white solid. The enantiomers were separated using HPLC [Method 11].

[0378] Example 28 The first eluting enantiomer (46 mg) was obtained as a white solid. Chiral HPLC Rt=10.37 min; [Chiral analysis method 3] LCMS Rt=1.47 min;MS m / z, 360.2[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.10-7.01(m,1H),6. 95-6.90(m,1H),6.78-6.71(m,1H),5.68(d,J=0 .9Hz,1H),5.58-5.52(m,2H),3.53(s,3H),2.70 -2.65(m,2H),2.45-2.12(m,4H),1.34-1.25(m, 1H),1.05-0.89(m,2H),0.80-0.69(m,1H).

[0379] Example 28b The second eluting enantiomer (48 mg) was obtained as a white solid. Chiral HPLC Rt=15.216 min; [Chiral analysis method 3] LCMS Rt=1.47 min;MS m / z, 360.2[M+H]+;[Method 7] 1 H NMR(400MHz,CDCl3)δ 7.10-7.01(m,1H),6. 95-6.90(m,1H),6.78-6.71(m,1H),5.68(d,J=0 .9Hz,1H),5.58-5.52(m,2H),3.53(s,3H),2.70 -2.65(m,2H),2.45-2.12(m,4H),1.34-1.25(m, 1H),1.05-0.89(m,2H),0.80-0.69(m,1H).

[0380] Example 29: Methyl (R)-4-(3,5-difluoro-2-((S or R)-1-fluoro) (O-ethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydrofuran Hydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzal Dehyde [ka] 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane (Example 3 (5 g, 23.58 mmol) and RuCl⋅XHO (490 mg, 2.35 mmol) in dichloromethane (50 mL) and water (10 mL) Acetoxyiodobenzene (11.4 g, 35.37 mmol) was added. The resulting solution was stirred at 30° C. for 2 hours. The reaction mixture was filtered and diluted with ethyl acetate (200 mL). The filtrate was dissolved in water (200 mL) and extracted into ethyl acetate (500 mL). The solvent was removed under reduced pressure and the residue was purified by silica flash chromatography. Purification of the crude product by elution with ethyl acetate in petroleum ether (0→10%) gave The title compound, 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzo The aldehyde (3 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.41(s,1H),7.35(d ,J=9.6Hz,1H),6.95-6.85(m,1H),6.53(s,1H), 4.08(s,4H).

[0381] Step 2: 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl Nyl)ethane-1-ol [ka] 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde(s From step 1, dissolve 1.0 g (4.67 mmol) in dry tetrahydrofuran (10 mL). Methylmagnesium bromide (2.33 mL, 3 M in ether, 4.67 mM) was added to the solution at 0°C. The resulting solution was stirred at room temperature for 1 hour. The mixture was quenched with 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. The compound 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl The crude compound was purified further to give 1,3-diethyl-1-ethanediol (950 mg) as a colorless liquid. The test was carried forward to the next step without any modification. 1H NMR(300MHz,CDCl3)δ 7.17(dd,J=2.4,6.3H z,1H),6.89-6.72(m,1H),6.17(s,1H),5.31(dd ,J=6.9,13.5Hz,1H),4.15-4.02(m,4H),2.64-2 .59(m.1H), 1.58(d,J=9.0Hz,3H).

[0382] Step 3: 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1, 3-Dioxolane [ka] 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl)ethanoate 1-Hydroxy-1-ol (from step 2, 950 mg, 4.13 mmol) in dichloromethane ( 10 mL) solution at -78 °C, diethylaminosulfur trifluoride (1.0 g, 6.13 mm ol) was added. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was saturated Quench with ammonium chloride (100 mL) at 0° C. and dilute 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. The compound 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3 -dioxolane (600 mg) was obtained as a thick yellow liquid. The crude compound was not further purified. We moved on to the next step without any problems. 1 H NMR(300MHz,CDCl3)δ 7.20(dd,J=2.4,6.3H z,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=6.6,2 2.8Hz,3H).

[0383] Step 4: 3,5-Difluoro-2-(1-fluoroethyl)benzaldehyde [ka] 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3-diox Solan (from step 3, 600 mg, 2.58 mmol) in diethyl ether (10 mL) L) solution was added with 4N HCl (2 mL) at room temperature. The resulting solution was cooled to room temperature. The mixture was stirred at rt for 3 h. This was then diluted with water (50 mL) and saturated NaHCO3 solution (100 mL). The mixture was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure to give the title compounds 3,5 -Difluoro-2-(1-fluoroethyl)benzaldehyde (200 mg) was dissolved in a colorless liquid (Note: the aldehyde obtained is naturally occurring and volatile.) 1 H NMR(300MHz,CDCl3)δ 10.44(d,J=3.0Hz,1H ),7.20(d,J=9.3Hz,1H),7.10-6.98(m,1H),6.4 3-6.19(m,1H),1.78(dd,J=7.2,23.1Hz,3H).

[0384] Step 5: 3-Ethoxycyclopent-2-en-1-one [ka] Cyclopentane-1,3-dione (5.0 g, 50.96 mmol) in toluene with stirring In a 70 mL solution of pTSA (193 mg, 1.019 mmol) and EtOH ( 2.61 ml, 387.35 mmol) was added at room temperature. The mixture thus obtained was The mixture was stirred at 120° C. for 10 hours using a Dean-Stark apparatus. The solvent was removed under reduced pressure. The crude product was purified by silica flash chromatography (petroleum ether ethyl acetate, 0→50%) to give the title compound, 3-ethoxycyclopentene. Ter-2-en-1-one (4.3 g) was obtained as a brown solid. 1 H NMR(400MHz,CDCl3)δ 5.26(s,1H),4.02(q, J=6.6Hz,2H),2.60-2.55(m,2H),2.44-2.40(m, 2H), 1.39(t,J=7.2Hz,3H).

[0385] Step 6: 3-Aminocyclopent-2-en-1-one [ka] Stirred 3-ethoxycyclopent-2-en-1-one (from step 5, 4.3 g A solution of 1,340.08 mmol) in ethanol (50 mL) was added to an ammonium hydroxide solution (2 The resulting mixture was heated to 85° C. The mixture was stirred at rt for 16 h. Removal of the solvent under reduced pressure gave the title compound, 3-aminosilyl. Clopent-2-en-1-one (3.2 g) was obtained as a brown solid. LCMS RT=0.114 min;MS m / z, 98.2[M+H]+;[Method 7]

[0386] Step 7: Methyl 4-(3,5-difluoro-2-(1-fluoroethyl)phenyl) -2-(Fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclo Penta[b]pyridine-3-carboxylate [ka] Aldehyde (from step 4, 700 mg, 3.7204 mmol), methyl 4-fluoro Oro-3-oxobutanoate (Step 1 of Intermediate B; Method 2, 598.73 mg, 4 .4645 mmol) and 3-aminocyclopent-2-en-1-one (Step 6, 361.32 mg, 3.7204 mmol) in t-butanol (15 mL). The mixture was stirred at 80° C. for 48 h. The solvent was removed under reduced pressure to give the crude compound. The material was purified by flash chromatography on silica (ethyl acetate in petroleum ether, 0→50%). The title compound, methyl 4-(3,5-difluoro-2-(1-fluoro- (2-(fluoromethyl)-5-oxo-4,5,6,7-tetrafluoroethyl)phenyl Hydro-1H-cyclopenta[b]pyridine-3-carboxylate (580 mg) as a white solid, and as the first of the diastereomers and an off-white solid. Obtained as a mixture of diastereomers (320 mg, peak 1). Mixture (580 mg) was further purified by preparative HPLC purification (Method 8) to give the second dimer as an off-white solid. The asastereomer (80 mg, peak 2) was obtained.

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

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

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

[0390] Example 29c 24.2 mg of the third elution was obtained as a white solid using chiral HPLC [Method 11] Enantiomers. Chiral HPLC: RT: 14.455 min; [Chiral analysis method 3] LCMS RT=1.504 min;MS m / z, 382.0[MH]-;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),7.14 -6.96(m,1H),6.75(d,J=9.8Hz,1H),6.63(dq,J =44.2,6.8Hz,1H),5.71(s,1H),5.59(s,1H),4. 88(s,1H),3.47(s,3H),2.62(q,J=4.5Hz,2H),2 .25(t,J=4.9Hz,2H),1.68(dd,J=22.8,6.5Hz,3 H).

[0391] Example 29d 32.4 mg of the fourth elution was obtained as a white solid using chiral HPLC [Method 11] Enantiomers. Chiral HPLC: RT: 18.561 min [Chiral analysis method 3] LCMS RT=1.514 min;MS m / z, 382.0[MH]-;[Method 10] 1 H NMR(400MHz,DMSO-d6)δ 10.13(s,1H),7.05 -7.00(m,1H),6.75(d,J=9.7Hz,1H),6.62(dt,J =44.2,6.6Hz,1H),5.71(s,1H),5.59(s,1H),4. 88(s,1H),3.47(s,3H),2.62(q,J=4.6Hz,2H),2 .25(t,J=4.9Hz,2H),1.68(dd,J=22.8,6.4Hz,3 H).

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

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

[0394] Example 30 First eluting enantiomer, 30mg as a pale yellow solid. Chiral HPLC Rt = 5.952 min (column: LUX CELLULOSE-4 (15 0×4.6mm×5μ); Mobile phase: A=n-hexane, B: ethanol:methanol (5 0:50);Flow rate: 1.0mL / min). LCMS Rt=1.53 min;MS m / z, 332.0[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),7.13 -7.10(m,4H),5.71(s,1H),5.59(s,1H),4.98(s ,1H),4.82(s,2H),3.44(s,3H),2.98-2.92(m,2 H), 1.25(t,J=7.8Hz,3H).

[0395] Example 30b Second eluting enantiomer, 29mg as a pale yellow solid. Chiral HPLC Rt = 7.581 min (column: LUX CELLULOSE-4 (15 0×4.6mm×5μ); Mobile phase: A=n-hexane, B: ethanol:methanol (5 0:50);Flow rate: 1.0ml / min). LCMS Rt=1.528 min;MS m / z, 332.0[M+H]+;[Method 7] 1 H NMR(400MHz,DMSO-d6)δ 10.03(s,1H),7.13 -7.10(m,4H),5.71(s,1H),5.59(s,1H),4.98(s ,1H),4.82(s,2H),3.44(s,3H),2.98-2.92(m,2 H), 1.25(t,J=7.8Hz,3H).

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

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

[0398] Step 2: 3-Ethyl 5-methyl 4-(3-fluoro-2-(1-fluoroethyl)fluor (phenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxyl Silate [ka] Stirred 5-ethyl 3-methyl 2-(dimethoxymethyl)-4-(3-fluoro-2- (1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5- 1,4-dioxodicarboxylate (from step 1, 1.7 g, 3.86 mmol) The solution of 10.0 mL of dimethylformamide was cooled to 0° C. A 6N aqueous solution of hydrochloric acid (15.0 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water to obtain the product. Extraction into ethyl acetate. Wash the combined organic layers with a saturated solution of sodium bicarbonate. It was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure. Purification was performed by flash chromatography (12→15% ethyl acetate in hexanes). , diastereomer 1 of the title compound (400 mg, 26%) and diastereomer 2 (3 00mg, 20%) as a yellow sticky liquid.

[0399] Diastereomer 1 LCMS Rt=1.606 min;MS m / z, 392.0[MH]-;[Method 10] 1 H NMR(300MHz,DMSO-d6)δ 10.13(s,1H),9.05 (s,1H),7.33(dd,J=13.8,7.2Hz,1H),7.10-7.0 2(m,2H),6.45-6.23(m,1H),5.19(s,1H),4.06- 3.98(m,2H),3.63(s,3H),2.35(s,3H),1.76(dd ,J=22.8,6.6Hz,3H),1.13(t,J=6.9Hz,3H)

[0400] Diastereomer 2 LCMS Rt=1.461 min;MS m / z, 392.0[MH]-;[Method 14] 1 H NMR(300MHz,DMSO-d6)δ 10.12(s,1H),9.07 (s,1H),7.33(dd,J=13.8,7.2Hz,1H),7.10-7.0 3(m,2H),6.44-6.22(m,1H),5.18(s,1H),4.13- 3.87(m,2H),3.67(s,3H),2.35(s,3H),1.74(dd ,J=22.8,6.6Hz,3H),1.11(t,J=6.9Hz,3H).

[0401] Step 3: 5-ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2 -(1-fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5 -Dicarboxylate [ka] Stirred 3-ethyl 5-methyl 4-(3-fluoro-2-(1-fluoroethyl)phenyl Nyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxy Diastereoisomer 1 from step 2 (0.40 g, 1.01 mmol) The chloromethane (5.0 mL) solution was cooled to -78°C. 0.16mL, 1.22mmol) was added in portions at -78°C, and the reaction mixture was allowed to stand at room temperature. The reaction mixture was quenched with ice-cold water and the product was dissolved in dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate solution and extracted with anhydrous sodium sulfate. The mixture was dried over silica gel, filtered, and the solvent 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-dica carboxylate (0.3g). LCMS Rt=1.632 min;MS m / z, 414.0[MH]-;[Method 10] 1 H NMR(300MHz,DMSO-d6)δ 9.38(s,1H),7.58- 7.23(m,2H),7.09-7.01(m,2H),6.43-6.22(m,1 H),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),1.1 3(t,J=6.9Hz,3H)

[0402] Step 4: 3-Ethyl 5-methyl 2-(bromomethyl)-6-(difluoromethyl)- 4-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,4-dihydropyridine 3,5-Dicarboxylate [ka] 5-Ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoro) (fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarbox xylate (from step 3, 0.3 g, 0.722 mmol) in dichloromethane (5. The solution was cooled to -78°C. Pyridinium tribromide (0.254 g, 0.794 mL) was added to mol) was added at -78°C and stirred at the same temperature for 1 hour. The reaction mixture was then cooled to room temperature. The reaction mixture was stirred at rt for 30 min. The reaction mixture was diluted with ice-cold water and the product was extracted into dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude compound was purified by silica flash chromatography (10→12% acetic acid in hexane). The title compound was obtained as a yellow viscous liquid. Methyl 2-(bromomethyl)-6-(difluoromethyl)-4-(3-fluoro-2-( 1-Fluoroethyl)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.2g, 56%) LCMS Rt=1.653 min;MS m / z, 491.95[MH]-;[Method 10 ] 1 H NMR(300MHz,DMSO-d6)δ 9.38(s,1H),7.58- 7.23(m,2H),7.09-7.01(m,2H),6.43-6.22(m,1 H),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),1.1 3(t,J=6.9Hz,3H)

[0403] Step 5: Methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoro) (triethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] Pyridine-3-carboxylate [ka] 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 In a solution of 5.0 mL of ethanol, potassium hydroxide (0.005 g, 0.101 mmol) was added at room temperature. The reaction mixture was heated to 60° C. and stirred for 8 hours. Tetra-n-butylamine was added at 100° C. ammonium iodide (0.007 g, 0.020 mmol) was added at room temperature, and the reaction mixture was The reaction mixture was heated to 65° C. for 12 hours. The reaction mixture was diluted with water and the product was extracted into dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (column: ZORBAX XDB( 250mm x 21.2mm), 5.0μ; Mobile phase: A=water, B=ACN; flow rate: 18ml / min) to give the title compound as a cream-colored solid. (3-fluoro-2-(1-fluoroethyl)phenyl)-5-oxomethyl so-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate (20mg, 26%). LCMS Rt=1.503 min;MS m / z, 384.05[MH]-;[Method 10 ]

[0404] The racemic sample was analyzed by chiral HPLC (column: CHIRALPAK IJ, 250 mm x 4 .3MM x 5 microns; Mobile phase: A=Hexane, B=0.1% HCOOH in MeOH: The enantiomers were separated by EtOH, 1:1, flow rate: 5 mL).

[0405] Example 31: First eluting peak on chiral HPLC, 3.4mg as a cream coloured solid. Chiral HPLC Rt = 6.393 min (column: CHIRAL PAK IJ (250× 4.6 mm x 5 μ); Mobile phase: A: n-hexane, B: ethanol; Flow rate: 1.0 mL / Minutes. LCMS Rt=1.502 min;MS m / z, 384.05[MH]-[Method 10] 1 H NMR(300MHz,DMSO-d6)δ 10.43(s,1H),7.64 -7.28(m,2H),7.10-7.02(m,2H),6.44-6.22(m, 1H),5.13(s,1H),4.88(s,2H),3.49(s,3H),1.8 0(dd,J=22.8,6.0Hz,3H)

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

[0407] Crystal morphology X-ray powder diffraction measurement (XRPD) XRPD was performed using a nickel filter monochromator and a Cu-K alpha 1,2 irradiation LYNXEY with open angle: 2.948° using (wavelength 0.15419nm) The measurements were performed on a Bruker D8Advance diffractometer equipped with a 1D mode E detector. The fractograms were taken step by step in the angular range of 2° to 40° 2θ at ambient conditions. A step size of 0.0164° (2 theta value) was applied in 0.3 seconds to the tube voltage of 40 kV. The recordings were made at a voltage of 0.01 V and a tube current of 40 mA. The scan time was 768 seconds. Typical accuracy is in the range of ±0.2° 2 theta, preferably ±0.1° 2 theta. For example, methyl(R)-4- (3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl) (1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate The diffraction peaks for crystalline form A of carboxylate are ( 10.4-0.2)° to (10.4+0.2)° 2 theta, preferably (10.4- It can occur in the range of (0.1)° to (10.4+0.1)° 2 theta.

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

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

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

[0411] Crystal form C Approximately 100 mg of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl) (phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Furo[3,4-b]pyridine-3-carboxylate and various stoichiometric amounts of citric acid ( 4:1, 3:1, 2:1 or 1:1 base:acid ratio) with tert-butyl methyl ether The resulting solid form was methyl(R)-4-(3-fluoro-2-((R )-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4, Corresponding to 5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate form C did.

[0412] Alternative synthesis: 40 mL of heptane was added to a 100 mL EasyMax reactor at 25 °C. 2 g of Form A was dissolved in 5 mL of isopropyl acetate at room temperature. Then, 20 mg The resulting mixture was stirred at 25° C. The solution of Form A in isopropyl acetate was added to the syringe pump for 30 minutes. The resulting mixture was added dropwise to the reactor over a period of 2 hours using 100% ethanol. Equilibrated at °C for 2 hours. In-process control showed a mixture of Form C and Hydrate A. The solid material was then slurried in 10 mL of isopropyl acetate / heptane (1 / 7) for 2 days. The suspension was then filtered and dried at 40°C for 18 hours. PD corresponded to Form C. Water content by KF was 0.3%.

[0413] Crystalline form hydrate A 1.97 g of Form A was weighed into a 100 mL EasyMax glass vial and diluted with 35 mL of 1 mL of water, and the suspension was incubated at 50 °C for 3 h under overhead stirring at 300 rpm. The mixture was stirred for 1 hour, then cooled to 25° C. at about 0.07° C. / min for 6 hours, and then cooled to 25° C. at about 0.07° C. / min for 6 hours. Stirring was continued for 24 hours. The solid material was isolated by filtration. XRPD of the solid form showed that it was hydrophilic. Compatible with Japanese A.

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

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

[0416] Alternative synthesis: Hydrate B was obtained by air drying of crystalline form B in methanol solvate. Hydrate B shows a mass loss of about 4.4% by TGA, which is also consistent with the monohydrate ( Hydrate B begins to dehydrate below 20% RH and reaches a calculated water content of 4.7%. With the subsequent increase in relative humidity, this reduces to about 3.5% at 25°C. It absorbs only 100% of water.

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

[0418] Biological Data Many known calcium channel activators are V 1.2 The complex mechanism of activation These molecules not only increase the peak current, but also, for example, Increases intracellular calcium concentration by shifting pressure sensitivity to more negative membrane potentials Figure 6 shows a simulated myocardial action potential from the epicardial environment. Shown is Ca at potential (mV) versus time (ms). V 1.2 Activation voltage is set to a more negative membrane potential These further mechanisms are illustrated by showing the effect of shifting the Further mechanisms of action include cardiovascular effects, such as increased blood pressure, changes in heart rate or contractility, and and / or may promote or enhance arrhythmias due to QT prolongation. Using the model, we can determine the effect of Ca on action potential duration and arrhythmia tendency. V 1.2 Effect of adjustment A hyperpolarizing shift in the activation curve of >12 mV was associated with >15% QT prolongation and It has been identified that these conditions may potentially lead to an increased risk of arrhythmias and voltage sensitivity. Minimizing the shift in QT intervals would allow the development of compounds with reduced risk of QT prolongation and cardiac arrhythmias. It can bring things.

[0419] The compounds of formula (I) have the biophysical properties that minimize the cardiovascular risks outlined above. Highly potent Ca V 1.2 Activation Substances. First, the compound of formula (I) The compounds improve their sensitivity to voltage by minimizing the hyperpolarizing shift to <9 mV. Second, the compounds of formula (I) have the effect of limiting the Ca V 1.2 It increases the peak current by at most 2.5-fold, thereby limiting channel overactivation. Third, the compounds of formula (I) may address the pathophysiology underlying the cardiac symptoms of Timothy syndrome. The mechanism is Ca V 1.2 does not delay channel inactivation. Furthermore, the compounds of formula (I) , designed to maximize brain exposure by not exhibiting significant brain spillover .

[0420] Ca V 1.2-Generation and maintenance of HEK293(AUX) cell line Monoclonal Ca V 1.2-HEK293(AUX) cell line is a human Ca V 1.2 Al It constitutively expresses the alpha 1C (α1C) subunit (CACNA1C) and 2 delta (α2△2) auxiliary subunit (CACNA2D2) and beta 2 (β2) auxiliary The cell line was generated with doxycycline-inducible expression of the CACNB2 subunit. To express this gene, the expression vector pcDNA5.0 / FRT-TO-CACNA2D2-FCS was used. -P2A-CACNB2 and pCMV6-Entry-CACNA1C were used for gene synthesis and The pcDNA5.0 / FRT-TO plasmid was established by cloning. pCMV6-entry was from Origene. FCS represents the furin cleavage site, and P2A represents the porcine teschovirus-1-derived FRT is a peptide self-cleavage sequence derived from the cleavage site of Flippase. Next, the parental line Flp-In™ 293T-Rex (Invitrogen) was cloned with pcD NA5.0 / FRT-TO-CACNA2D2-FCS-P2A-CACNB2 and Fl The ippase vector pOG44 (Invitrogen) was transfected and Fl CACNA into pre-engineered FRT sites in p-In™ 293T-Rex Targeted integration of the 2D2-FCS-P2A-CACNB2 expression cassette was established. Transfect pCMV6-Entry-CACNA1C into the intermediate cell line and generate stable CACNA1C expression was established. Clonal isolation was achieved under neomycin selection. Cell clones with voltage-dependent barium currents (see electrophysiology methods below) 2-19B) Ca V 1.2 Activators were selected for characterization.

[0421] To maintain the cell line, the cells were passaged twice a week. At each passage, growth medium (Table 6) was added. ) was completely removed, and the cells were resuspended in 10 ml of D-PBS and 5 ml of warm TrypLE ( ) Express Enzyme (Gibco), D-PBS and TrypLE Both the ELISA kit and the ELISA kit were rinsed and then immediately removed. The cells were incubated at room temperature for 3-5 minutes. Then, 10 mL of warm 37°C complete medium was added to the cells. The growing surface was flushed and the dissociated cells were collected. Cells were counted and T175cm 2 For each flask 2~3×10 6 The cells were seeded into new flasks at a target density of 100 cells.

[0422] [Table 6]

[0423] Ca V 1.2-Ca using HEK293(AUX) cell line and QPatch V 1.2 Electrophysiological characterization of activators 24 h before electrophysiology experiments, add doxycycline (1 μg / ml) to the growth medium. (Table 6) 25 μM verapamil was co-applied to reduce calcium influx induced by Cell confluency should reach 70%-80% immediately prior to the experiment.

[0424] (For example, T175cm 2 To harvest the cells (from the flask), remove the growth medium completely. The cells were then removed and rinsed with 10 mL of D-PBS. The D-PBS was aspirated and 10 mL of D-PBS was added. Etachin (Genlantis) was added and the plate was incubated in a 37°C incubator. The detached cells were placed in a 15 mL conical tube and incubated at 1000 rpm for 2 min. The supernatant was removed and the cells were resuspended in QPatch complete medium for 150 min per QPatch step. The cells were resuspended to the desired cell density of ~3 million cells (Table 7). mL of cells are used.

[0425] Cell suspensions were cultured on the Sophion QPatch platform using whole-cell voltage clamp. and Ca2+ on single-hole QPlates. V 1.2 Conduction through Barium The patch clamp solutions for extracellular and intracellular were listed in Tables 7 and 8, respectively. A dose-response assay protocol was used to measure the peak inward current ( Emax) and potency (EC 50The maximum fold change in the number of cloning cycles was determined. The first liquid phase was to stabilize the current amplitude, which was -80m. Monitored using repeated 200ms voltage pulses stepped from V to 0mV The second period consisted of a single 20 ms voltage step from -80 mV to 0 mV. Pressure pulses were used to determine baseline current amplitudes in the presence of vehicle control. The third to eighth liquid periods were used, and the voltage was changed stepwise from -80mV to 0mV. A single 20 ms voltage pulse was used to measure the 6-fold dose response to compound treatment. EC 50 is expressed by the following equation I concentration =I base +(I full -I base ) * c n / (XC 50 n +c n ) where c is the concentration and n is the Hi The I coefficient is a constant. full is the maximum achievable current, and I ba se is 0. Current-voltage relationship using the channel biophysics assay protocol (IV curve), mid-channel activation voltage (V 1 / 2 ), percentage of channel inactivation (tau) We determined the channel gating properties, including the amplitude of the V and tail current. 1 / 2 is the equation G(V)=G Vmin +(G Vmax -G Vmin ) / (1+exp(- (V-V1 / 2) / V slope )) (wherein G represents conductance, G Vmin is equal to 0, and G Vmaxis the maximum conductance, and V slope is a slope G(V) is derived from fitting the The equation for the applied depolarization potential (V) and the corresponding current amplitude (I(V)) is G(V) = I It was pre-calculated from (V) / (V-0.06), where the 0.06 in the equation is the actual value in volts. The reversal potential was experimentally determined. The protocol had four liquid periods. The first liquid period The duration was to stabilize the current amplitude, which was done in steps from -80 mV to 0 mV. The current amplitude was monitored using repeated 200 ms voltage pulses. Thus, a single exponential fit of the inactivation phase of the current trace gives the tau of inactivation. The second liquid period was used to determine a baseline value for the current in the presence of vehicle control. The third liquid period is to measure the baseline value that constitutes the voltage curve, and the third liquid period is the current voltage The purpose of the study was to measure the effect of the compound on the curve. During this time, the cells were charged with a voltage of -80 mV, with incremental values ​​ranging from -55 mV to +35 mV ( Ten 20 ms voltage pulses were applied, stepwise increasing in size from 0.01 to 0.1 V (increment size 10 mV). During the fourth liquid period, a 200 ms voltage pulse of -80 mV to 0 mV was again delivered to inactivate the The effect of the compounds on tau proliferation was measured.

[0426] [Table 7]

[0427] [Table 8]

[0428] [Table 9]

[0429] [Table 10]

[0430] Assessment of compound exposure - cFos induction (PK-PD) relationships in wild-type mice Animal Care and Ethics. All animals were kept in a controlled temperature and light cycle (22°C, 12:00 h light cycle). The mice were incubated in a 12-h light / 12-h dark cycle with unrestricted access to food and water. All animal studies were performed under the supervision of the Novartis Institutes for Biological Studies. oMedical Research, Inc. (Cambridge, MA, US) A) Animal Care and Use Committee (IACUC) approved by the University of Tokyo. The study was conducted in accordance with the facility guidelines.

[0431] Compound administration and brain tissue collection. Wild-type C57BL / 6J male mice were cultured at Jackson The Ca V 1.2 Acute single-dose effects of activators were evaluated in male 8-week-old mice (n=6 mice per compound). Each compound was evaluated in a 10% PEG 300, 10% Solutol, Compounds were dissolved in 10% Cremophore EL and 70% phosphate buffered saline. The drugs were administered intraperitoneally (ip) at concentrations ranging from 1 mg / kg to 30 mg / kg depending on the patient. One hour after compound administration, animals were euthanized by exsanguination under deep anesthesia. Drug levels Blood was collected in EDTA tubes for downstream analysis. Brains were quickly removed from the skull. The cerebral cortex and cerebellum were locally dissected. The cerebellar samples were snap frozen in liquid nitrogen and then cryopreserved. Cortical samples for cFos assessment were placed in 500 μl of R The RNA integrity of the samples was confirmed by placing them in NAlater solution (ThermoFisher). Samples were kept in RNAlater at 4°C for at least 24 hours and then processed. The supernatant was then transferred to -80°C for storage prior to injection.

[0432] Quantification of cFos mRNA induction. TissueLyse for 96-well plates Tissue homogenization was performed using the Qiagen r system. First, frozen cortical samples were thawed and removed from RNAlater, buffer RLT containing 0.5% Reagent DX, and one 5 mm TissueLyser metal bead The TissueLyser tube was placed in the TissueLyser II The homogenizer was loaded for three homogenization rounds, each at 30 Hz. The bead-battering frequency was continued for 5 min. RNeasy96Plus kit (Qiagen) Total RNA was purified from the homogenates using HPLC and the RNA concentration and A260 / A280 ratio were analyzed. was quantified by Nanodrop (ThermoFisher), and all samples were analyzed at 10 The concentration was normalized to 0 ng / μL. Superscript III First-st RNA was synthesized using the rand synthesis SuperMix kit (ThermoFisher). For each sample, 6 μL of RNA (total 600 ng) was reverse transcribed into cDNA. Mix with Oligo dT and 1 µl annealing buffer and heat to 65 °C for 5 min. Next, 10 μL of 2× First-Strand Reaction Mix and 2 μl of Enzyme Mix were added. Mixture was added to achieve a total reaction volume of 20 uL. The samples were then heated to 50° C. for 50 minutes, then cDNA synthesis was completed by heating to 85° C. for 5 min.

[0433] Quantitative PCR is performed using the Quantitect on the cDNA samples using a Multiplex RT-PCR kit (Qiagen). Each PCR well contained 2 μl of cDNA (total 60 ng), 10 μL of RT-PCR mastermix, 1 μL of cFos FAM Taqman probe (Mm004 87425_m1(FAM)#4351368), 1μL of GAPDH VIC Taq man probe (Mm99999915-g1(VIC)#4448486), 0.2μ 1 μl Multiplex RT mix and 5.8 μl RNase-free water Samples were run for 9 min on a ViiA7 real-time PCR system (ThermoFisher). 5°C for 15 min, then 45 cycles between 94°C for 45 s and 60°C for 45 s. The cFos Ct values ​​were exported and the GAPDH Ct values ​​were and expressed as relative fold changes using the delta-delta Ct relative quantification method. The cFos fold changes between compound treatment and vehicle were analyzed using one-way ANOVA, These were subsequently analyzed by Tukey post-hoc comparisons.

[0434] Quantification of compound exposure. Cerebellar tissue samples were soaked in 4 ml of 20% acetonitrile per gram of tissue. and homogenized in 80% phosphate buffered saline (5x dilution). Tissues were homogenized using either: a handheld probe system, 30°C for 4 min; s -1TissueLyser system with 5 mm steel beads at a frequency of or OMNI Bead Ruptor Elimination for 30 seconds to 1 minute depending on tissue type. e Homogenizer. Add tissue samples to a 96-well plate (12.5 uL of sample) and weigh They were then processed for quantification by analytical methods.

[0435] result

[0436] [Table 11]

[0437] [Table 12]

[0438] Comparative Example Other Ca V 1.2 activators are known, but these compounds also have cardiovascular Risk of heart failure, e.g., increased blood pressure, changes in heart rate or contractility, and / or QT prolongation Minimize arrhythmias while not being too strong and / or activating the channel and sufficient It does not have the desirable biophysical properties required to have brain exposure.

[0439] [Table 13]

[0440] [Table 14]

Claims

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

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

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

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

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

6. R ２ The compound of claim 4 , wherein is H.

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

8. R ３ each of which is substituted with 1 to 3 F; The compound of claim 4 which is a pill.

9. R ３ But CHF ２ Or CF ３ 5. The compound of claim 4,

10. R ３ is ethyl substituted by one or two F, or is unsubstituted or The compound of claim 4 which is cyclopropyl substituted with two F's.

11. A is CH ２ The compound according to any one of claims 1 to 3,

12. R ２ The compound of claim 11 , wherein is F.

13. R ３ is ethyl substituted with 1 to 3 F. The compounds listed above.

14. A compound according to formula (III) or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 4】 (In the formula: A is O or CH ２ and R １ is H or F; R ２ is H or F; R ３ OCHF, each of which is optionally substituted with 1 to 3 F. ２ , methyl, ethene cyclopropyl, or cyclopropyl; R ４ is H or F).

15. The compound of claim 14 , wherein A is O.

16. R ２ The compound of claim 15 , wherein is F.

17. R ２ The compound of claim 15 , wherein

18. R ３ However, O.C.H.F. ２ 16. The compound of claim 15,

19. R ３ each optionally substituted with 1 to 3 F; 16. The compound of claim 15 which is cyclopropyl.

20. R ３ But CHF ２ Or CF ３ 16. The compound of claim 15,

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

22. R ３ The compound of claim 15, wherein is ethyl.

23. R ４ The compound of claim 15 , wherein is F.

24. R ４ The compound of claim 15 , wherein is H.

25. A is CH ２ 15. The compound of claim 14, wherein

26. R ２ The compound of claim 23 , wherein is F.

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

28. R ４ The compound of claim 23 , wherein is F.

29. R ４ The compound of claim 23, wherein is H.

30. Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluoro (fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Furo[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluoro (trifluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrophenyl b[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-carbo Xylates; Methyl (R)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-di Fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran dolofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-2,2-difluorocyclopropyl)-3,5-di Fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran dolofuro[3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl (fluoromethyl)-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 (fluoromethyl)-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 (fluoromethyl)-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-carbo Xylates; 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-(fluoro (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine -3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoro (Oromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine -3-carboxylate; Methyl (R)-4-(2-((R)-1,2-difluoroethyl)-3,5-difluoro Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran [3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(2-((S)-1,2-difluoroethyl)-3,5-difluoro Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuran [3,4-b]pyridine-3-carboxylate; Methyl (R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoro (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridin ketone-3-carboxylate; Methyl (R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2- (Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pi Lysine-3-carboxylate; Methyl (R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-(fluoro (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridin ketone-3-carboxylate; Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethoxy) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- Carboxylate; Methyl (R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluorophenyl) ethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3- Carboxylate; Methyl (R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-phenyl xo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate to; Methyl(R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-(fluoro (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridin ketone-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-carbo or a pharma- ceutically acceptable salt or solvate thereof.

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

31. Ethyl (R)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl nyl)-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 (fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-phenyl Clopenta[b]pyridine-3-carboxylate; (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2 -(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopentene ta[b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoro (oromethyl)-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-cyclopentadiene pent[b]pyridine-3-carboxylate; Methyl(R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopentadiene pent[b]pyridine-3-carboxylate; Methyl (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluorophenyl) ethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin ketone-3-carboxylate; Methyl (S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phenyl (fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-phenyl Clopenta[b]pyridine-3-carboxylate; and Methyl (S)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phenyl (fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-phenyl clopenta[b]pyridine-3-carboxylate; or a pharma- ceutically acceptable salt thereof; Solvates 2. The compound of claim 1 selected from the group consisting of:

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

4. The compound according to claim 4.

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

34. 34. The crystalline form of claim 33, which is form A.

35. 34. The crystalline form of claim 33, which is form B.

36. 34. The crystalline form of claim 33, which is form C.

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

38. 38. The crystalline hydrated form of claim 37 which is Hydrate A.

39. 38. The crystalline hydrated form of claim 37 which is Hydrate B.

40. A compound according to any one of claims 1 to 32, and a pharma- ceutically acceptable excipient. , pharmaceutical compositions.

41. Schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-Mac Dermoid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease Methods for the treatment of Immer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome - Patents.com administering to a patient in need of such treatment an effective amount of any one of claims 1 to 32 A method comprising the administration of a compound as described herein or a pharma- ceutically acceptable salt thereof.

42. Schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-Mac Dermoid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease Methods for the treatment of Immer's disease, Brugada syndrome, short QT syndrome, or early repolarization syndrome - Patents.com administering to a patient in need of such treatment a compound according to any one of claims 1 to 32. or a pharma- ceutically acceptable salt thereof.

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