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-tetrahydrofluoro[3,4-B]pyridine-3-carboxylate as CAV1.2 activating substances

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] This 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-tetrahydro Flo[3,4-b]pyridine-3-carboxylate compounds, and pharmaceutical compositions containing them. Matters, as well as mental disorders including schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders. Harm; neurodevelopmental disorders, such as attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and Autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and and Alzheimer's disease; as well as cardiac conditions, such as Brugada syndrome, QT shortening syndrome, and Calcium signaling deficiencies and / or synaptic dysfunction in early repolarization syndrome Ca for treatment V 1.2 Regarding the use of such compounds as activators. [Background technology]

[0002] Advances in human genomics have shed light on the genetic basis of mental disorders. Genome-wide association studies (GWAS) in allergies have shown that Ca V 1.2, and neuro More than 100 diseases, including other genes involved in calcium signaling. Related gene loci have been identified. Cross-disorder GWAS analysis has shown that schizophrenia, bipolar disorder, and bipolar disorder are related. It is strongly associated with polarity disorders, major depressive disorder, ADHD, and autism spectrum disorder. te Ca V 1.2 and its channel-forming beta subunit (CACNB2) were identified. In addition to evidence from GWAS, exome sequencing in patients with schizophrenia has revealed enrichment of disruptive mutations in Ca V 1.2 and other gene members of the neuronal calcium signaling pathway, including the CACNA2D, CACNB, and CAMK2 genes. Ca 1.2 has been shown to be important for neuronal differentiation and migration, V neurite outgrowth, synaptic signaling, gene expression, and brain plasticity. Ca 1.2 has also been shown to play a role in brain emotion, learning and memory, V executive function, and reward response. Ca 1.2 is widely expressed throughout the body and plays a crucial role in multiple

[0003] organ systems, including the cardiovascular system; however, the physiological V function of Ca 1.2 in the cardiovascular system is different from its function in the brain. Ca V 1.2 is an important contributor to action potential generation in the heart, whereas it is a major driver of intracellular signaling and gene expression in V neurons, with a minimal role in action potential generation. Studies have shown that in Timothy syndrome, the Ca 1.2 mutation p.G406R results in distinct cell phenotypes between cardiomyocytes and neurons. Ca V 1.2 mutations that cause cardiovascular-specific disorders (Brugada syndrome and long QT syndrome type 8) are further evidence of the diverse functions of Ca 1.2 in the heart and brain. V [[ID=​​​​​​​​ Further investigation into their use has been limited by their effects on the cardiovascular system. In fact, many of these molecules have potential therapeutic uses in heart failure. It was initially investigated and developed for this purpose. Related Ca from psychiatric GWAS studies. V 1.2SN Most P nucleotides are located in the introns of genes, and these risk SNPs are often... This is associated with a reduction in mRNA expression that leads to an overall reduction in calcium current amplitude. This has been shown. Therefore, small molecules that can increase the overall current amplitude can be used in patients. This could be the most beneficial approach. [Overview of the project]

[0005] This disclosure provides compounds according to formula (I) or pharmaceutically acceptable salts thereof, [ka] During the ceremony: A is either O or CH2; R 1 is either H or F; R 2 is either H or F; R 3 Each of these is optionally substituted with 1 to 3 F atoms, OCHF2, methyl, and E. It is til or cyclopropyl.

[0006] In a second embodiment, the Disclosure relates to a compound according to formula (III) or a pharmaceutically acceptable compound thereof. The salt or solvate is provided. [ka] During the ceremony: A is either O or CH2; R 1 is either H or F; R 2 is either H or F; R 3 Each of these is optionally substituted with 1 to 3 F atoms, OCHF2, methyl, and E. It is cyclopropyl or tyl; R 4 It is either H or F.

[0007] In a third aspect, the disclosure includes compounds of formula (I) or pharmaceutically acceptable salts thereof. To provide a pharmaceutical composition.

[0008] In a fourth aspect, this disclosure relates to the treatment of, in particular, schizophrenia, bipolar disorder, and schizophrenia. Mental disorders, including psychotic disorders and substance use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder. Sexual disorders, Phelan-McDermid syndrome, and autism spectrum disorder; neurodegenerative disorders, For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions, For example, it is used in the treatment of Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the purpose of [doing something].

[0009] In a fifth embodiment, the disclosure relates to an effective amount of formula (I) to a patient in need of the treatment. Administration of compounds or pharmaceutically acceptable salts thereof by the facilitator, for the treatment of schizophrenia, bipolar disorder, and other conditions. Mental disorders, including depressive disorders and substance use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder. Movement disorders, Phelan-McDermid syndrome, and autism spectrum disorder; neurodegenerative disorders For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions. For example, methods for treating Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. To provide.

[0010] In a sixth aspect, the disclosure relates to schizophrenia, bipolar disorder, major depressive disorder, and substances. Mental disorders, including use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder, ferran-majority disorder. Kudarmid syndrome and autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis. , frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions, such as Brugada syndrome. In the manufacture of pharmaceuticals for the treatment of the group, QT shortening syndrome, and early repolarization syndrome, formula (I The use of compounds of ) or pharmaceutically acceptable salts thereof is provided.

[0011] In a seventh embodiment, the present disclosure relates to the treatment of a patient in need of such treatment using formula (I). Administration of a compound or pharmaceutically acceptable salt thereof for schizophrenia, bipolar disorder, major depressive disorder Mental disorders, including disorders and substance use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD). , Phelan-McDermid syndrome, and autism spectrum disorder; neurodegenerative disorders, for example , multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions, for example This provides methods for treating Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. ru.

[0012] In the eighth aspect, the Disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical composition containing the following:

[0013] In the ninth aspect, the disclosure relates to the treatment of, in particular, schizophrenia, bipolar disorder, and schizophrenia. Mental disorders, including psychotic disorders and substance use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder. Sexual disorders, Phelan-McDermid syndrome, and autism spectrum disorder; neurodegenerative disorders, For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions, For example, it is used in the treatment of Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof for the purpose of [doing something].

[0014] In a tenth embodiment, the present disclosure relates to an effective amount of formula (I) to a patient in need of the treatment. II) Administration of compounds or pharmaceutically acceptable salts thereof, including schizophrenia, bipolar disorder Mental disorders including harm, major depressive disorder, and substance use disorders; neurodevelopmental disorders, for example, attention Attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and autism spectrum disorder; neurological disorders Sexual disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; and heart For the treatment of conditions such as Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. This provides a method for doing so.

[0015] In the eleventh aspect, the disclosure relates to schizophrenia, bipolar disorder, major depressive disorder, and physical Mental disorders including quality use disorders; neurodevelopmental disorders, e.g., attention deficit hyperactivity disorder, Phelan- McDermid syndrome and autism spectrum disorder; neurodegenerative disorders, such as multiple sclerosis. Diseases, frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions, such as Brugada disease. In the manufacture of pharmaceuticals for the treatment of syndromes, QT shortening syndrome, and early repolarization syndrome, formula ( III) The use of the compound or a pharmaceutically acceptable salt thereof is provided.

[0016] In a twelfth aspect, the present disclosure relates to formula (III) to a patient in need of such treatment. Administration of compounds or pharmaceutically acceptable salts thereof, including schizophrenia, bipolar disorder, and schizophrenia. Mental disorders, including psychotic disorders and substance use disorders; neurodevelopmental disorders, such as attention deficit hyperactivity disorder. Sexual disorders, Phelan-McDermid syndrome, and autism spectrum disorder; neurodegenerative disorders, For example, multiple sclerosis, frontotemporal dementia, and Alzheimer's disease; as well as cardiac conditions, For example, methods for treating Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. provide. [Brief explanation of the drawing]

[0017] [Figure 1] A representative XRPD of morphology A of methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate of the present disclosure is shown. The x-axis represents a scattering angle of °2 theta, and the y-axis represents the intensity of the scattered X-ray beam in the count of detected photons. [Figure 2] A representative XRPD of morphology B of [methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate] of the present disclosure is shown. The x-axis represents a scattering angle of °2 theta, and the y-axis represents the intensity of the scattered X-ray beam in the count of detected photons. [Figure 3] A representative XRPD of morphology C of methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate of the present disclosure of the present invention is illustrated. The x-axis represents a scattering angle of °2 theta, and the y-axis represents the intensity of the scattered X-ray beam in the count of detected photons. [Figure 4]A representative XRPD of methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate hydrate A of the present disclosure is shown. The x-axis represents a scattering angle of °2 theta, and the y-axis represents the intensity of the scattered X-ray beam in the count of detected photons. [Figure 5] A representative XRPD of hydrate B of methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate of the present disclosure is shown. The x-axis represents a scattering angle of °2 theta, and the y-axis represents the intensity of the scattered X-ray beam in the count of detected photons. [Figure 6] This diagram illustrates simulated myocardial action potentials from the epicardial environment, demonstrating the effect of CaV1.2 activation on shifting the voltage towards a more negative membrane potential. The x-axis represents time (ms), and the y-axis represents potential. [Figure 7] To confirm that the active enantiomer is the R-enantiomer, a single X-ray crystal of methyl(R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate from Example 6 is shown as an example. [Figure 8] To confirm that the active enantiomer is the R-enantiomer, a single X-ray crystal of methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate from Example 8 is shown. [Figure 9] To confirm that the active enantiomer is the R-enantiomer, a single X-ray crystal of methyl(R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate from Example 9 is shown as an example. [Modes for carrying out the invention]

[0018] 5.1.Definition In general, the nomenclature used herein, and the organic chemistry described herein, Laboratory procedures in medicinal chemistry and pharmacology are well known and generally practiced in this field. It is used. Unless otherwise defined, all technical terms and scientific terms used herein are used. Terms generally have the same meaning as those generally understood by a person skilled in the art to which this disclosure pertains. .

[0019] In this specification, "administer," "to administer," and "to administer" are used interchangeably. This refers to the format in which the compounds described herein are presented to the subject.

[0020] As used herein, "optionally replaced" means that the base being referred to is Any one or any combination of the following elements at one or more positions This means that it can be replaced with "se".

[0021] As used herein, "halo" or "halogen" means as used herein. In that case, it may be fluorine, chlorine, bromine, or iodine.

[0022] As used herein, “subject” means the pharmaceutical composition described herein. Diseases or disorders described herein that can be treated by administration (e.g., schizophrenia) Mental disorders including bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders, For example, Attention Deficit Hyperactivity Disorder, Phelan-McDermid Syndrome, and other autism spectrum disorders Lamb's disease; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease. - Diseases; and cardiac conditions, such as Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. This refers to a living organism suffering from one or more of the syndromes. Examples include mammals. For example, humans and animals such as dogs, cows, horses, monkeys, pigs, sheep, goats, and cats. This includes mice, rabbits, rats, and genetically modified non-human animals. In this embodiment, the subject is a human, for example, a person with a disease described herein (e.g., an integrated disease). Mental disorders, including ataxia, bipolar disorder, major depressive disorder, and substance use disorders; neurodevelopmental disorders Harm, for example, attention deficit hyperactivity disorder, Phelan-McDermid syndrome, and other autism spectrum disorders. Clutch disorders; neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia, and Alzheimer's disease. Imer's disease; as well as cardiac conditions, such as Brugada syndrome, QT shortening syndrome, and early recombination syndrome. In individuals who have, are at risk of developing, or are potentially capable of developing (extreme syndrome) be.

[0023] Throughout this specification and in the following claims, if the context should be interpreted otherwise, Except for the word "include," or its variations, such as "included" or "the act of including," This means including the integer or step, or group of integers or steps, that has been described. However, it excludes any other integer or step, or any group of integers or steps. It should be understood that it does not mean anything.

[0024] If there is a discrepancy between the shown structure and the chemical name given to that structure, the shown structure Weight is given by the structure. Furthermore, the three-dimensional arrangement of the structure or a part of the structure is, for example, thick line or If not indicated by a dashed line, the structure or part of the structure is all solid of the structure or part of the structure. This is interpreted as including isomers.

[0025] 5.2. Compounds Compounds according to formula (I) or pharmaceutically acceptable salts or solvates thereof [ka] During the ceremony: A is either O or CH2; R 1 is either H or F; R 2 is either H or F; R 3 Each of these is optionally substituted with 1 to 3 F atoms, OCHF2, methyl, and E. It is til or cyclopropyl.

[0026] One embodiment involves a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof. be. [ka]

[0027] Another embodiment is a compound of formula (Ib) or a pharmaceutically acceptable salt or solvate thereof. That is the case. [ka]

[0028] In another embodiment, A is O.

[0029] In another embodiment, A is CH2.

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

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

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

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

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

[0035] In another embodiment, R 3 Each of these is replaced by 1 to 3 F's of arbitrary selection. It is ethyl, cyclopropyl, or chloropropyl.

[0036] In another embodiment, R 3 Each of these is substituted with 1 to 3 F atoms, methyl, eth It is either ru or cyclopropyl.

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

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

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

[0040] In another embodiment, R 3 This is either unsubstituted or cyclosubstituted with two Fs. It is propyl.

[0041] Compounds according to formula (III) or pharmaceutically acceptable salts or solvates thereof [ka] During the ceremony: A is either O or CH2; R 1 is either H or F; R 2 is either H or F; R 3 Each of these is optionally substituted with 1 to 3 F atoms, OCHF2, methyl, and E. It is cyclopropyl or tyl; R 4 It is either H or F.

[0042] In another embodiment, A is O.

[0043] In another embodiment, A is CH2.

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

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

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

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

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

[0049] In another embodiment, R 3 Each of these is replaced by 1 to 3 F's of arbitrary selection. It is ethyl, cyclopropyl, or chloropropyl.

[0050] In another embodiment, R 3 Each of these is substituted with 1 to 3 F atoms, methyl, eth It is either ru or cyclopropyl.

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

[0052] In another embodiment, R3 This is ethyl methyl substituted with one or two fluorine atoms.

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

[0054] In another embodiment, R 3 This is either unsubstituted or cyclosubstituted with two Fs. It is propyl.

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

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

[0057] Certain compounds, Methyl(R)-4-(2-((R)-2,2-difluorocyclopropyl)-3-fluor (Lopenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrof [3,4-b]pyridine-3-carboxylate; Methyl(R)-4-(2-((S)-2,2-difluorocyclopropyl)-3-fluor (Lopenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrof [3,4-b]pyridine-3-carboxylate; (R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl) -5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carb xylate; Methyl(R)-4-(2-((R)-2,2-difluorocyclopropyl)-3,5-di Fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetramethyl 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-tetramethyl Droflo[3,4-b]pyridine-3-carboxylate; Methyl(R)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phen (Lu)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3, 4-b] Pyridine-3-carboxylate; Methyl(R)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phen (Lu)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3, 4-b] Pyridine-3-carboxylate; Methyl(R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenyl (Lu)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3, 4-b] Pyridine-3-carboxylate; Methyl(R)-4-(2-((R)-1,2-difluoroethyl)-3-fluorophenyl (Lu)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H- Clopenta[b]pyridine-3-carboxylate; Methyl(R)-4-(2-((S)-1,2-difluoroethyl)-3-fluorophenicol (Lu)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H- Clopenta[b]pyridine-3-carboxylate; Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b Pyridine-3-carboxylate; Methyl(R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b Pyridine-3-carboxylate; Methyl(R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoromethyl) -5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carb xylate; Methyl(R)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[3,4-b] Pyridine-3-carboxylate; Methyl(R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[3,4-b] Pyridine-3-carboxylate; Methyl(R)-4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl )-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4 -b] Pyridine-3-carboxylate; Methyl(R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(full Olomethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine -3-carboxylate; Methyl(R)-4-(2-cyclopropyl-3,5-difluorophenyl)-2-(full Olomethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b] Pyridine-3-carboxylate; Methyl(R)-4-(2-(difluoromethyl)-3-fluorophenyl)-2-(Flu Olomethyl)-5-oxo-1,4,5,7-tetrahydrofl[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-tetrahydrofluoro [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-tetrahydrofluoro [3,4-b]pyridine-3-carboxylate; Methyl(R)-4-(3-fluoro-2-(trifluoromethyl)phenyl)-2-( Luoromethyl)-5-oxo-1,4,5,7-tetrahydroflox[3,4-b]pyridyl n-3-carboxylate; Methyl(R)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-2- (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]p Lysine-3-carboxylate; Methyl(R)-4-(2-(difluoromethoxy)-3-fluorophenyl)-2-( Luoromethyl)-5-oxo-1,4,5,7-tetrahydroflox[3,4-b]pyridyl n-3-carboxylate; Methyl 4-(2-(difluoromethoxy)-5-fluorophenyl)-2-(fluoromethyl (Chill)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3- Carboxylate; Methyl(R)-4-(2-cyclopropyl-5-fluorophenyl)-2-(fluoromethyl (Chill)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3- Carboxylate; Methyl(R)-4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5-O Kiso-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate to; Methyl(R)-4-(5-fluoro-2-(trifluoromethyl)phenyl)-2-( Luoromethyl)-5-oxo-1,4,5,7-tetrahydroflox[3,4-b]pyridyl n-3-carboxylate; Methyl(R)-2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl )phenyl)-1,4,5,7-tetrahydrofluoro[3,4-b]pyridine-3-carb xylate; (R)-4-(3-fluoro-2-(2,2,2-trifluoroethyl)phenyl)-2 -(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopene Ta[b]pyridine-3-carboxylate; Methyl(R)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2 -(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1Hcyclopenta [b] Pyridine-3-carboxylate; Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclop Nta[b]pyridine-3-carboxylate; Methyl(R)-4-(3-fluoro-2-((S)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclop Nta[b]pyridine-3-carboxylate; Methyl(R)-4-(2-cyclopropyl-3-fluorophenyl)-2-(fluoromethyl (Tyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridyl n-3-carboxylate; Methyl(S)-4-(3,5-difluoro-2-((S)-1-fluoroethyl)phen (Lu)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H- Clopenta[b]pyridine-3-carboxylate; and Methyl(S)-4-(3,5-difluoro-2-((R)-1-fluoroethyl)phen (Lu)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H- Clopenta[b]pyridine-3-carboxylate Includes.

[0058] Certain compounds, Methyl(R)-4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo-1 ,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate; and Methyl(R)-2-(difluoromethyl)-4-(3-fluoro-2-(1-fluoromethyl) (Tyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyri Zin-3-carboxylate It also includes.

[0059] Depending on the selection of starting materials and the procedure, the compound can be stereochemically determined by the number of chiral carbon atoms. In one form of isomer, or as a mixture thereof, for example, as a pure optical isomer, Alternatively, they exist as a mixture of stereoisomers, for example, a mixture of racemic compounds and diastereoisomers. This disclosure can be made of racemic mixtures, diastereomer mixtures and optically pure This means including all such possible stereoisomers, including the optically active ( The (R) and (S) stereoisomers can be prepared using chiral synthons or chiral reagents. Alternatively, it may be decomposed using conventional techniques. If the compound contains a double bond, the substituents are It may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, cyclo Alkyl substituents may have cis or trans configurations. All tautomers also include To receive.

[0060] As used herein, the term "salt" refers to an acid addition salt or base addition salt of the compound disclosed herein. This refers to the addition of salt. "Salt" specifically includes "pharmaceutically acceptable salt." The salts that retain the biological efficacy and properties of the compounds of this disclosure are typically biological This refers to a salt that is not undesirable in any way or otherwise. In many cases, the compounds of this disclosure The presence of an amino and / or carboxyl group or a similar group results in an acidic salt and / Alternatively, it can form a basic salt.

[0061] Pharmacologically 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, and nitric acid. It contains phosphoric acid, etc.

[0063] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, and glycosides. Malic 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, etc.

[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 the periodic table. It contains metals from groups I to XII. In certain embodiments, the salt is sodium, potassium Derived from iron, ammonium, calcium, magnesium, iron, silver, zinc, and copper; in particular Suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts. nothing.

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

[0067] In another embodiment, this disclosure relates to acetates, ascorbic acid salts, adipine salts, and asparagus Salts, benzoates, besilates, bromides / hydrobromides, bicarbonates / carbonates, sulfates Raw salt / sulfate, camphor sulfonate, caprine, chloride / hydrochloride, chlortheof Ironate, citrate, ethane disulfonate, fumarate, gluceptate, gluconate Sodium, glucuronide, glutamate, glutarate, glycolate, hippurate, Hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate Salt, malate, maleate, malonate, mandelate, mesylate, methylsulfate Mucait, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, Provided are compounds of the present disclosure in the form of oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate triphenate, trifluoroacetate or xinafoate. Compounds of the present disclosure containing a group capable of acting as a donor and / or acceptor for hydrogen bonding, i.e., compounds of formula (I), can form co-crystals with suitable co-crystallization agents. These co-crystals can be prepared from compounds of formula (I) by known co-crystallization procedures. Such procedures include grinding, heating, simultaneous sublimation, simultaneous melting, or contacting the compound of formula (I) with a co-crystallization agent under crystallization conditions in solution, and isolating the co-crystals thus formed. Suitable co-crystallization agents include those described in WO 2004 / 078163 pamphlet. Accordingly, the present disclosure further provides co-crystals comprising a compound of formula (I). Furthermore, the compounds of the present disclosure, including their salts, can also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present disclosure can inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); thus, the present disclosure is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salts) having one or more solvent molecules. Such solvent molecules are

[0068] recipients The compounds of the present disclosure, i.e., the compounds of formula (I), which contain a group capable of acting as a donor and / or acceptor for hydrogen bonding, can form co-crystals with suitable co-crystallization agents. These co-crystals can be prepared from compounds of formula (I) by known co-crystallization procedures. Such procedures include grinding, heating, simultaneous sublimation, simultaneous melting, or contacting the compound of formula (I) with a co-crystallization agent under crystallization conditions in solution, and isolating the co-crystals thus formed. Suitable co-crystallization agents include those described in WO 2004 / 078163 pamphlet. Therefore, the present disclosure further provides co-crystals comprising a compound of formula (I). Furthermore, the compounds of the present disclosure, including their salts, can also be obtained in the form of their hydrates or include other solvents used for their crystallization.

[0069] The compounds of the present disclosure can inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water); thus, the present disclosure is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salts) having one or more solvent molecules. Such solvent molecules are recipients of the disclosure and are included within the scope of the present disclosure. Those that are known to be harmless to humans and are commonly used in pharmaceutical technology, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0070] This disclosure includes unlabeled and isotopically labeled forms of the compounds of formula (I). Isotopically labeled compounds have the structures shown by the formulas indicated herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of this disclosure include, for example, isotopes of hydrogen. In addition, the incorporation of certain isotopes, particularly deuterium (i.e.,

[0071] H or D), may provide certain therapeutic benefits resulting from greater metabolic stability, such as an increase in the in vivo half-life or a reduction in the required dose of administration, or 2 an improvement in the therapeutic index or tolerability. Deuterium is understood to be considered a substituent of the compounds of this disclosure in this context. The concentration of deuterium can be defined by the isotope enrichment factor. The term "isotope enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope, as used in this specification. When it is indicated that a substituent in the compounds of this disclosure is deuterium, such compounds have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (6 7.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation). (including deuterium uptake), at least 6333.3 (95% deuterium uptake), at least 6466. 7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or At least 6633.3 (99.5% deuterium uptake) of each specified deuterium source It has an isotope enrichment factor. The term "isotope enrichment factor" is used to describe deuterium. It should be understood that this can be applied to any isotope in the same manner as [the previous method].

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

[0073] Other examples of isotopes that can be incorporated into the compounds of this disclosure include hydrogen, carbon, nitrogen, and oxygen. , phosphorus, fluorine, and chlorine isotopes, for example, respectively 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 This disclosure includes, for example, radioactive isotopes, for example, 3 H and 14 Including C Compounds incorporating one or more of the above isotopes, or compounds containing non-radioactive isotopes Position, for example, 2 H and 13 It should be understood that this includes compounds in which C is present. Eel isotope-labeled compounds are used in metabolic studies. 14 (by C), reaction kinetic studies (for example, 2 H or 3 Detection or imaging techniques (by H), for example, for drugs or substrate tissues Positron emission tomography (PET) or single-photon emission computer, including distribution assays. - Useful in tomography (SPECT) or in radioactive treatment of patients. to, 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotopically labeled compounds of the disclosure are generally known to those skilled in the art by conventional techniques, or previously Use an appropriate isotope-labeled reagent instead of the unlabeled reagent used, as provided. It can be prepared by a method similar to that described in the examples and preparations.

[0074] Any chiral atom (e.g., carbon) in the compounds of this disclosure may be racemic or enantiomerically concentrated. It can exist in a contracted configuration, for example, the (R), (S) or (R,S) configuration. In certain embodiments, each chiral atom is at least a 50% mirror image in the (R) or (S) configuration. Body excess rate, at least 60% enantiomer excess rate, at least 70% enantiomer excess rate, at least 80% enantiomer excess, at least 90% enantiomer excess, at least 95% enantiomer excess, Or having at least 99% enantiomer excess. Substitution in atoms with unsaturated double bonds. The base may, if possible, exist in cis-(Z)- or trans-(E)- form.

[0075] Thus, as used herein, the compounds of the disclosure are in one form of the possible stereoisomers , rotamers, atropisomers, tautomers or mixtures thereof, for example , substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemic compounds or mixtures thereof.

[0076] Any resulting mixture of stereoisomers can be separated, for example, by chromatography and / or by fractional crystallization, based on the physicochemical differences of the constituents, into pure or substantially pure geometric isomers or optical isomers, diastereomers, racemic compounds. It is possible.

[0077] Any resulting racemic compound of the compounds or intermediates of the disclosure can be resolved into the optical enantiomers by known methods, for example, by separation of the diastereomeric salts obtained with an optically active acid or base, and liberation of the optically active acidic or basic compound. In particular, the basic moiety can be used in this way, for example, by fractional crystallization of the salts formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or borneol-10-sulfonic acid, to resolve the compounds of the disclosure into their optical enantiomers. The racemic compounds or racemic intermediates of the disclosure can also be resolved by chiral chromatography, such as high pressure liquid chromatography (HPLC), using a chiral adsorbent. It can be decomposed into optical enantiomers by liberation of the optically active acidic or basic compound. In particular, the basic moiety is used in this way, for example, by fractional crystallization of salts formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or borneol-10-sulfonic acid, to resolve the compounds of the disclosure into their optical enantiomers. The disclosed compounds can be resolved into their optical enantiomers by fractional crystallization of salts formed with malic acid or borneol-10-sulfonic acid. The racemic compounds or racemic intermediates of the disclosure can also be resolved by chiral chromatography, such as high pressure liquid chromatography (HPLC), using a chiral adsorbent. The disclosed racemic compounds or racemic intermediates can also be resolved by chiral chromatography, such as high pressure liquid chromatography (HPLC), using a chiral adsorbent. It can be decomposed by chiral chromatography, such as high pressure liquid chromatography (HPLC), using a chiral adsorbent.

[0078] Methods of Use The compounds of the disclosure, in free form or in the form of a pharmaceutically acceptable salt, can be used, for example, in the following section As shown in the in vitro and in vivo tests provided in [the document] It possesses valuable pharmacological properties, such as Ca V 1.2 It exhibits activation properties, and therefore, therapeutic It is indicated for use as a research chemical, for example, as a tool compound.

[0079] The compounds disclosed herein may be useful in treating indications selected from the list below. Mental 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. Disease spectrum disorder; and Neurodegenerative disorders, such as multiple sclerosis, frontotemporal dementia and Alzheimer's disease, and Cardiac conditions, such as Brugada syndrome, QT shortening syndrome, and early repolarization syndrome. In terms of morphology, the indications include mental disorders, such as schizophrenia, bipolar disorder, major depressive disorder, and In another embodiment, the indications are schizophrenia or bipolar disorder. .

[0080] Thus, in a further aspect, the present disclosure relates to the compounds or pharmaceuticals of the present disclosure in the treatment of the therapeutic The use of the salt is permitted in a further embodiment. V 1.2 A disease is selected from those that can be treated by activation. In another embodiment, the disease is selected from among the indications. Selected from the list above.

[0081] Thus, in a further aspect, the present disclosure relates to the chemicals of the present disclosure for use in therapeutic purposes. Provides a phytotoxic or pharmaceutically acceptable salt thereof. In a further embodiment, the treatment is Ca V 1 A disease is selected from those that can be treated by the activation of .2. In another embodiment, the disease is an adaptation The symptoms are selected from the list above.

[0082] In another embodiment, the Disclosure may be used to provide a therapeutically effective amount of the Compound of the Disclosure or a pharmaceutically acceptable amount. Ca V 1.2 A method for treating diseases treated by activation is proposed. Provided. In further embodiments, the disease is selected from the above-mentioned list of indications.

[0083] In another embodiment, the Disclosure describes the administration of the compounds of the Disclosure or pharmaceutically acceptable salts thereof. Includes Ca V 1.2 Provides a method for treating diseases treated by activation. In this embodiment, the disease is selected from the above-mentioned list of indications.

[0084] Thus, in a further aspect, the present disclosure relates to the compounds of the present disclosure for the manufacture of pharmaceuticals or Provides the use of its pharmaceutically acceptable salt. In a further embodiment, the pharmaceutical is Ca V 1 This is for the treatment of diseases that can be treated by the activation of .2. In another embodiment, the disease is The indications are selected from the list above.

[0085] In another embodiment, the Disclosure may be used to provide a therapeutically effective amount of the Compound of the Disclosure or a pharmaceutically acceptable amount. Ca V Schizophrenia and bipolar disorder are treated by activation of 1.2. Harm, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism Spectrum disorders, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome The present invention provides a method for treating group, QT shortening syndrome, or early repolarization syndrome.

[0086] In another embodiment, the Disclosure describes the administration of the compounds of the Disclosure or pharmaceutically acceptable salts thereof. Includes, schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan- McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Al For the treatment of Zheimer's disease, Brugada syndrome, QT shortening syndrome, or early repolarization syndrome Provide a method.

[0087] Thus, in a further aspect, this disclosure relates to schizophrenia, bipolar disorder, and major depressive disorder. Harm, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder Multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, QT shortening syndrome Compounds or agents of this disclosure for treating a disease selected from the group or early repolarization syndrome Provides scientifically acceptable use of that salt.

[0088] Thus, in a further aspect, this disclosure relates to schizophrenia, bipolar disorder, and major depressive disorder. Harm, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder Multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, QT shortening syndrome The present disclosure is intended for use in the treatment of diseases selected from the group or early repolarization syndrome. Provide a compound or a pharmaceutically acceptable salt thereof.

[0089] In another embodiment, the Disclosure may be used to provide a therapeutically effective amount of the Compound of the Disclosure or a pharmaceutically acceptable amount. This salt is used in the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorders, and ADH. D, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal syndrome Type 1 dementia, Alzheimer's disease, Brugada syndrome, QT shortening syndrome, or early repolarization syndrome To provide a method for treating [the condition].

[0090] In another embodiment, the Disclosure describes the administration of the compounds of the Disclosure or pharmaceutically acceptable salts thereof. Includes, schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan- McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Al For the treatment of Zheimer's disease, Brugada syndrome, QT shortening syndrome, or early repolarization syndrome Provide a method.

[0091] Thus, in a further aspect, this disclosure relates to schizophrenia, bipolar disorder, and major depressive disorder. Harm, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder Multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, QT shortening syndrome The compounds or pharmaceuticals of this disclosure for the manufacture of a pharmacopoeia for the treatment of premature repolarization syndrome. It provides the use of that salt which is generally acceptable.

[0092] Pharmaceutical composition In another embodiment, the Disclosure relates to the compounds of the Disclosure or pharmaceutically acceptable salts thereof, and drugs. The present invention provides a pharmaceutical composition comprising a scientifically acceptable carrier. In a further embodiment, the composition comprises The carrier comprises at least two pharmaceutically acceptable carriers, for example, those described herein. The pharmaceutical composition is administered via a specific route of administration, for example, orally, parenterally (for example, by injection). It can be formulated for ingestion, percutaneous or topical administration, and rectal administration. Administration may also relate to inhalation or intranasal application. The pharmaceutical compositions of this disclosure are in solid form (these (but not limited to, capsules, tablets, pills, granules, powders or suppositories), It is prepared in liquid form (including, but not limited to, solutions, suspensions, or emulsions). The tablets can be film-coated by methods known in the art. Alternatively, it may be enterically coated. Typically, the pharmaceutical composition is a) Excipients, e.g., lactose, dextrose, sucrose, mannitol, sorbitol Toll, cellulose, and / or glycine; b) Also for tablets, lubricants, such as silica, talc powder, stearic acid, and magnesium Um or calcium salts and / or polyethylene glycol; c) If necessary, a binder, such as magnesium aluminum silicate, starch paste, etc. Latin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or foaming agents. Mixtures of properties; and e) Absorbents, colorants, flavorings, and sweeteners It is a tablet or gelatin capsule containing one or more of the active ingredients together.

[0093] The pharmaceutical compositions or combinations disclosed herein are used for approximately 50-70 kg of subjects, and approximately 1-100 0 mg of active ingredient, or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-15 Unit dose of the active ingredient: 0 mg, approximately 0.5-100 mg, or approximately 1-50 mg That is fine. The therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof is the target. Depending on the species, weight, age, and individual condition, the disorder or disease being treated, or its severity It is decided. A physician, clinician, or veterinarian of ordinary skill can prevent, treat, or prevent the progression of a disability or disease. The effective amount of each active ingredient required for inhibition can be easily determined.

[0094] The above dosage characteristics are advantageous for mammals, such as mice, rats, dogs, monkeys, or mononuclear. Using separated organs, tissues, and their preparations, in vitro and in vivo This can be demonstrated in the test. The compounds disclosed herein can be tested in vitro in solution, for example. , in aqueous solution form, and in vivo enterally, parenterally, advantageously intravenously, for example It can be applied as a suspension or in an aqueous solution. The in vitro dosage is: about 10 -3 Molar concentration ~10 -9 It can be within the range of molar concentration. In vivo therapeutic effects The effective dose varies depending on the route of administration, ranging from approximately 0.1 to 500 mg / kg, or approximately 1 to 100 mg / kg. It could be within the range of.

[0095] Crystal morphology This disclosure relates to methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro [3,4-b]Pyridine-3-carboxylate crystalline form and method for its preparation This disclosure relates to, preferably, a predetermined amount and / or an effective amount of methyl(R) )-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(full Olomethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine The crystalline form of -3-carboxylate, and at least one pharmaceutically acceptable additive. This relates to a pharmaceutical composition containing an agent. The pharmaceutical composition of this disclosure is particularly useful for schizophrenia, bipolar disorder, Major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder Clutch disorders, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, Used as a medicine for the treatment and / or prevention of QT shortening syndrome or early repolarization syndrome. It is possible.

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

[0097] Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4- [b] The crystalline form of pyridine-3-carboxylate is used to characterize the solid in pharmaceutical products. These can be characterized by analytical methods that are well known in the field of industry. Not limited to, but including XRPD, SXRD, FTIR, Raman, DSC, TGA, and G Includes MS (Gravity Measurement System). The form is determined by one or two of the above analytical methods. Alternatively, the characteristics can be determined by combining more of the same elements.

[0098] Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4- b) The crystalline form of pyridine-3-carboxylate is shown herein in Figure " It can be mentioned that such data is characterized by diagrammatic data. For example, this includes powder X-ray diffraction, FTIR, and Raman spectroscopy. Factors, for example, instrument type, Variation in response, as well as variability in sample orientation, sample concentration, and sample purity. When presented in a diagrammatic form, variations can be small in nature. For example, this can result in variations regarding the precise peak position and intensity. Those skilled in the art will understand. However, the graphical data in the figures herein may differ from or not be available. Comparison with diagrammatic data created for the solid form of knowledge, and the two sets of diagrammatic data being the same crystal Confirmation regarding the shape falls well within the scope of the knowledge of a person skilled in the art.

[0099] The term "reflection," as used herein in relation to powder X-ray diffraction, refers to X-ray diffraction. This refers to the peak in the lactogram, which represents the parallel plane of atoms in the solid material. Constructive interference from X-rays scattered by this process results in a specific diffraction angle (Bragg angle). This is caused by regular and repetitive patterns in long-range positional order. It is distributed in turns. Such solid materials are classified as crystalline materials, while Amo Rufus material lacks long-range order and exhibits only short-range order, therefore, It is defined as a solid material that produces a wide range of scattering. According to the literature, long-range order is, for example, This generally involves 100 to 1000 atoms, while short-range order involves 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 of the reflection position and the reflection in relation to powder X-ray diffraction. This means taking relative intensity into account. For example, the typical precision of a two-theta value is ±0. The range is 2°²theta, preferably within ±0.1°²theta.

[0101] Furthermore, relative reflectance is affected by the variability between devices, as well as the degree of crystallinity, preferred orientation, The variability is due to particle size, sample preparation, and other factors known to those skilled in the art, and only qualitative measurements are performed. Those skilled in the art will recognize that it should be received in this manner.

[0102] The terms “solid form” or “solid state form” are to be used interchangeably in this specification. This 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. This refers to the physical form. Amorphous compounds lack long-range order and do not exhibit definitive X-ray diffraction due to reflection. The folding pattern is not shown.

[0104] As used herein, the term "polymorph" means having the same chemical composition but with a crystalline form. This refers to a crystalline form that has a different spatial arrangement of the molecules, atoms, and / or ions that form it.

[0105] The term "cocrystal" as used herein refers to nonionic and noncovalent bonds. Two or more different molecular compounds are associated within the same crystal lattice. This refers to a crystalline material containing individual molecular compounds and / or ionic compounds, where the individual molecular compounds and / or ionic compounds are included. At least two of the ONE compounds are solid at room temperature.

[0106] The term "hydrate," as used herein, refers to a crystalline solid, where water is , either interacting within the crystal structure or being contained by the crystal structure, for example, water , is either part of the crystal structure or is trapped within the crystal (hydrated). Thus, water It can exist in stoichiometric or non-stoichiometric quantities. Hydrates can be referred to by adding a Greek numeral prefix. For example, hydrate A substance can be referred to as a hemihydrate or a monohydrate, depending on the stoichiometry of water / compounds. Water content can be measured, for example, by Karl Fischer coulometry.

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

[0108] The term "solvate," as used herein, refers to a crystalline solid, where 1 One or more organic solvents interact with each other in the crystalline structure, or are absorbed by the crystalline structure. It is contained, for example, as part of the crystalline structure or trapped within the crystal (water-containing). As a result, one or more organic solvents are present in stoichiometric or non-stoichiometric amounts. It is possible. When one or more organic solvents are present in stoichiometric amounts, the solvate They can be referred to by adding a Greek numeral prefix. For example, solvates are soluble. Depending on the stoichiometry of the medium / compound, it may be referred to as a hemisolvate or monosolvate. The solvent content is For example, it can be measured by GC, NMR, SXRD and / or TGA / MS. ru.

[0109] The term "non-hygroscopic" as used herein refers to a relative humidity range of 0–95%RH. When measured by GMS at humidity and a temperature of (25.0±0.1)℃, the weight of the compound is Based on this, it refers to compounds that exhibit a maximum water uptake of 2% by weight during the sorption cycle.

[0110] As used herein, the term "about" means a statistically significant range of a given value. Such ranges are within one digit, typically within 10% of the indicated value or range. Typically, it's within 5%, more typically within 1%, and most typically 0.1%. It may be within. Occasionally, such a range is used for measuring and / or determining a given value or range. It can be within the experimental error specific to the standard method used.

[0111] As used herein, the term “substantially free of any other solid form” This is methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl )-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4 -b] With regard to compositions comprising a specific solid form of pyridine-3-carboxylate, However, based on the weight of the composition, it should be at most 20% by weight, preferably at most 10% by weight. More preferably, a maximum of 5% by weight, even more preferably, a maximum of 2% by weight, most preferably Mashaku is 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 tetrahydroflo[3,4-b]pyridine-3-carboxylate It means to include.

[0112] As used herein, "substantially pure" means, when used in relation to form, Based on the weight of the compound, over 90% by weight, over 91% by weight, over 92% by weight, over 93% by weight, Over 94% by weight, over 95% by weight, over 96% by weight, over 97% by weight, over 98% by weight, and 99% by weight This includes % by weight, as well as methyl(R)-4-(3-fluoro- 2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo -1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate This refers to compounds with a purity of over 90% by weight, including the remaining material. This includes the form and / or reaction impurities and / or processing impurities resulting from its preparation. For example, methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phen (Lu)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3, The crystalline form of [4-b]pyridine-3-carboxylate is currently known in the art. Furthermore, it has a purity of over 90% by weight, as measured by generally accepted means. It can be considered substantially pure in that respect, where the remaining less than 10% by weight of material The material contains other forms of [compound ABC] and / or reaction impurities and / or processing impurities. include.

[0113] Crystal form A In a further embodiment, this disclosure relates to methyl(R)-4-(3-fluoro-2-((R) -1-Fluoroethyl)phenyl)-2-(Fluoromethyl)-5-oxo-1,4,5 Crystal form A of ,7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate We provide methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ The most prominent X-ray powder count for morphology A of [3,4-b]pyridine-3-carboxylate The 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)° and (22.4±0.2)°; or (6.7±0.2)°, (7.2±0.2)°, (8.5±0.2)°, (10.4±0 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 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)° Characterized by having an XRPD pattern that includes reflections at a 2-theta angle, Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b This provides form A of pyridine-3-carboxylate.

[0116] In yet another embodiment, the present disclosure provides a temperature range of 20-30°C at 0.15418n Cu-K alpha with a wavelength of m 1,2 When measured by irradiation, as shown in Figure 1 of this disclosure Characterized by having an XRPD pattern that is essentially the same as that of, Tyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[3,4-b] Regarding the crystalline form of pyridine-3-carboxylate, form A.

[0117] In another embodiment, the present disclosure is 98± when measured by DSC at a heating rate of 10K / min. Characterized by having a melting point onset temperature of 5°C, methyl(R)-4-(3-F Luoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5 -Oxo-1,4,5,7-tetrahydroflo[3,4-b]pyridine-3-carboxy Regarding the rate and the crystalline form of form A.

[0118] In another embodiment, the present disclosure shows that when measured by DSC at a heating rate of 10K / min, 104 Methyl(R)-4 is characterized by having a maximum melting point peak temperature of ±5°C. -(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)phenyl (Chill)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3- This concerns the crystalline form of carboxylate form A.

[0119] Crystal form B In a further embodiment, this disclosure relates to methyl(R)-4-(3-fluoro-2-((R) -1-Fluoroethyl)phenyl)-2-(Fluoromethyl)-5-oxo-1,4,5 Provide Form B of [[[ID=]],7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate To do. Methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl yl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3, 4-b]pyridine-3-carboxylate, the most prominent X-ray powder diffraction peaks for Form B are shown in Table 2. Shown in

[0120]

Table 2

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

[0122] In yet another embodiment, the present disclosure provides a temperature range of 20-30°C at 0.15418n Cu-K alpha with a wavelength of m 1,2 When measured by irradiation, as shown in Figure 2 of the present invention Characterized by having an XRPD pattern that is essentially the same as that of, Tyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[3,4-b] This relates to the crystalline form of pyridine-3-carboxylate form B.

[0123] In another embodiment, the present disclosure shows that when measured by DSC at a heating rate of 10K / min, 184 Characterized by having a melting point onset temperature of ±5°C, methyl(R)-4-(3- Fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)- 5-Oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboc Regarding the crystal form of silate form B.

[0124] In another embodiment, the present disclosure shows that when measured by DSC at a heating rate of 10K / min, 185 Methyl(R)-4 is characterized by having a maximum melting point peak temperature of ±5°C. -(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)phenyl (Chill)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3- This concerns the crystalline form of carboxylate form B.

[0125] Crystal form C In further embodiments, the present disclosure relates to methyl(R)-4-(3-fluoro-2-((R) -1-Fluoroethyl)phenyl)-2-(Fluoromethyl)-5-oxo-1,4,5 Provides form C of ,7-tetrahydroflo[3,4-b]pyridine-3-carboxylate Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl (Lu)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3, The most prominent X-ray powder diffraction pattern for morphology C of [4-b]pyridine-3-carboxylate The details are shown in Table 3.

[0126] [Table 3]

[0127] In one embodiment, the disclosure relates to 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, (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 0.6±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (20. 6±0.2)° and (22.7±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18. 2±0.2°, (20.6±0.2°) and (22.7±0.2°); or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (18. (2±0.2)°, (20.6±0.2)°, (22.7±0.2)° and (22.0±0 .2)°; or (10.3±0.2)°, (11.3±0.2)°, (15.5±0.2)°, (16. 6±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0. 2)° and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15. 5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0. 2)°, (22.7±0.2)° and (22.0±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.8±0.2)°, (15. 5±0.2)°, (16.6±0.2)°, (18.2±0.2)°, (20.6±0. 2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)° ; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12. 8±0.2)°, (15.5±0.2)°, (16.6±0.2)°, (18.2±0. 2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12. 8±0.2°, (15.5±0.2°), (16.6±0.2°), (17.3±0. 2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)°; or (10.3±0.2)°, (11.3±0.2)°, (12.3±0.2)°, (12. 8±0.2°, (14.0±0.2°), (15.5±0.2°), (16.6±0. 2)°, (17.3±0.2)°, (18.2±0.2)°, (20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and (23.2±0.2)°; or (7.0±0.2)°, (10.3±0.2)°, (11.3±0.2)°, (12.3 (±0.2)°, (12.8±0.2)°, (14.0±0.2)°, (15.5±0.2) )°, (16.6±0.2)°, (17.3±0.2)°, (18.2±0.2)°, ( 20.6±0.2)°, (22.7±0.2)°, (22.0±0.2)° and (23. 2±0.2)° Characterized by having an XRPD pattern that includes reflections at a 2-theta angle, Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b Provides form C of pyridine-3-carboxylate.

[0128] In yet another embodiment, the present disclosure provides a temperature range of 20-30°C at 0.15418n Cu-K alpha with a wavelength of m 1,2 When measured by irradiation, as shown in Figure 3 of the present invention Characterized by having an XRPD pattern that is essentially the same as that of, Tyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[3,4-b] This relates to the crystalline form of pyridine-3-carboxylate form C.

[0129] In another embodiment, the present disclosure shows that when measured by DSC at a heating rate of 10K / min, 178 Characterized by having a melting point onset temperature of ±5°C, methyl(R)-4-(3- Fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)- 5-Oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboc Regarding the crystal form of silate form C.

[0130] In one embodiment, the present disclosure is measured by DSC at a heating rate of 10 K / min and yields 178 ± Characterized by having a maximum melting point peak temperature of 5°C, methyl(R)-4- (3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl (Lu)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4-b]pyridine-3-ca Regarding the crystal morphology of the boxylate form C.

[0131] Hydrate A In a further embodiment, this disclosure relates to methyl(R)-4-(3-fluoro-2-((R) -1-Fluoroethyl)phenyl)-2-(Fluoromethyl)-5-oxo-1,4,5 We propose hydrate A of 7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate. Provided. Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) (Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3 The most notable X for hydrate A of the crystalline form of [4-b]pyridine-3-carboxylate The linear powder diffraction peaks are shown in Table 4.

[0132] [Table 4]

[0133] In one embodiment, the disclosure relates to 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, (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)° Characterized by having an XPRD pattern that includes reflections at a 2-theta angle, Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b We provide pyridine-3-carboxylate hydrate A.

[0134] In yet another embodiment, the present disclosure provides a temperature range of 20-30°C at 0.15418n Cu-K alpha with a wavelength of m 1,2 When measured by irradiation, as shown in Figure 4 of the present invention Characterized by having an XRPD pattern that is essentially the same as that of, Tyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[3,4-b] This relates to the crystalline form of pyridine-3-carboxylate hydrate A.

[0135] In another embodiment, the present disclosure shows that when measured by DSC at a heating rate of 10K / min, 109 Characterized by a wide range of endothermic phenomena with peak maximum values ​​at temperatures of ±10℃. The specified methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ This relates to the crystalline form of [3,4-b]pyridine-3-carboxylate hydrate A.

[0136] Hydrate B In a further embodiment, this disclosure relates to methyl(R)-4-(3-fluoro-2-((R) -1-Fluoroethyl)phenyl)-2-(Fluoromethyl)-5-oxo-1,4,5 We propose hydrate B of 7-tetrahydrofluoro[3,4-b]pyridine-3-carboxylate. Provided. Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) (Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3 Most notable X-rays for 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 disclosure relates to 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, (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 0.2)° and (19.6±0.2)°; or (5.5±0.2)°, (8.4±0.2)°, (8.7±0.2)°, (13.0±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 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 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 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 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)° Characterized by having an XRPD pattern that includes reflections at a 2-theta angle, Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b We provide pyridine-3-carboxylate hydrate B.

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

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

[0141] In another aspect, the present invention relates to a composition comprising a crystalline form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2 -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4- b]pyridine-3-carboxylate as defined in any one of the above embodiments, wherein the composition is essentially free of any other solid form of methyl (R)-4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2 -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b] pyridine-3-carboxylate. For example , Methyl(R)-4-(3-fluoro-2-((R)-1-fluoroethyl) phosphate (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ A composition containing crystalline hydrate A of [3,4-b]pyridine-3-carboxylate is a composition Based on the weight, a maximum of 20% by weight, preferably a maximum of 10% by weight, more preferably The maximum amount of methyl(R)- is 5% by weight, 4% by weight, 3% by weight, 2% by weight, or 1% by weight. 4-(3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoro Methyl)-5-oxo-1,4,5,7-tetrahydroflo[3,4-b]pyridine-3 -Includes any other solid form of carboxylate.

[0142] Ca V 1.2-HEK293(AUX) cell line In one embodiment, this disclosure relates to human Ca V 1.2 Alpha 1C (α1C) subunit ( Human CACNA1C transcription variant 14; GenBank ID: NM_001129840 (coded by), alpha-2 delta (α2△2) auxiliary subunit (human C ACNA2D2 transcription variant 3; GenBank ID: NM_001174051 (and coded as), and the beta-2 (β2) auxiliary subunit (human CACNB2 transcription) Includes variant 2 (encoded by GenBank ID: NM_201596). Regarding the cells, the α1C subunit is constitutively expressed, while the α2△2 subunit is constitutively expressed. The nit and β2 subunits are expressed in a doxycycline-inducible manner. In another embodiment... This disclosure relates to methods for screening compounds for biological activity. This relates to cells for which... In one embodiment, cells constitutively express the α1C subunit... Furthermore, the α2△2 subunit and β2 subunit are doxycycline-induced It is expressed in stable cell lines, such as HEK293. In another embodiment, stable Such cell lines can be transfected by DNA transfection, or, for example, by lentivirus or bacteriophage. It is produced by viral transduction via a provirus. In one embodiment, the cell is The α1C subunit is constitutively expressed after transient DNA transfection. Furthermore, the α2△2 subunit and β2 subunit are expressed in a doxycycline-inducible manner. It is found in cell lines such as HEK293. In another embodiment of this disclosure, the compound is Ca V 1.2 It is an activating substance. In another embodiment, this disclosure relates to a disease or disorder, for example, Schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-Magda -Mid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease Treatment, prevention, and / or treatment of Marr's disease, Brugada syndrome, QT shortening syndrome, or early repolarization syndrome. Or relating to cells for use in methods for identifying drugs for diagnostic purposes. In this manner, the drug is Ca V 1.2 It is an activating substance. [Examples]

[0143] Intermediates and Examples The following embodiments are intended to illustrate the present disclosure and are to be construed as limitations thereof. It will not be done.

[0144] All examples were isolated to their single enantiomers, and the biological data sectors are described below. The test was performed using the Sophion Qpatch assay described in the section. However, The stereoconfiguration of each enantiomer could not be determined. Example 6 Methyl(R)-4-(2 -((S)-1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl (Chill)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3- Carboxylate, and methyl(R)-4-(2-(difluoromethoxy)f of Example 9 (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ Stereochemical configuration of the active enantiomer of [3,4-b]pyridine-3-carboxylate This was analyzed using single-crystal X-ray crystallography, and the active enantiomer was found to be R-enantiomer It was determined that - Therefore, the methyl 2-(fluoromethyl)- shown below 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-tetrahydrofl[3,4-b]pyridine-3-carboxy 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.) all assume that the activated energy has an R configuration. Given for the antiomer. All other isomers isolated from synthesis have letters. Example numbers (Example 1b, 2b, 3b, etc.) were given. The R configuration is the desirable stereochemical configuration. There is strong evidence to suggest that the S-enantiomer is the active enantiomer. The possibility of obtaining it still exists.

[0146] Temperatures are given in Celsius. Unless otherwise specified, all evaporation is under reduced pressure, typically approximately The process is carried out at 15 mm Hg to 100 mm Hg (= 20 to 133 millibars). Final generation The structure of substances, intermediates, and starting materials is determined by standard analytical methods, such as trace analysis and spectroscopic analysis. The characteristic is confirmed by, for example, MS, IR, and NMR.

[0147] All starting materials, structural blocks, reagents, and acids used to synthesize the compounds of this disclosure The base, dehydrating agent, solvent, and catalyst are either commercially available or known to those skilled in the art through organic synthesis methods. It can be produced by [method]. Furthermore, the compounds of this disclosure are shown in the following examples. It can be produced by organic synthesis methods known to those skilled in the art. The abbreviations used are: The following are common in this technical field: 1 1H NMR Proton Nuclear Magnetic Resonance AUX Ca V 1.2 channel auxiliary subunit Celsius CD3OD methanol-d4 CDCl3 Chloroform-d CHO Chinese hamster ovary cells Threshold cycle in Ct 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 Medium DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) DMSO-d6 Dimethyl sulfoxide-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 HCl ethyl acetate FAM 6-Carboxyfluorescein FCS Furin Cutting Site FRT flippase recognition target site g grams h time H2O (Water) HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid HOBt 1-hydroxy-7-azabenzotriazole HPLC (High-Pressure Liquid Chromatography) HRMS high-resolution mass spectrometry Hrs time Hz Hertz IACUC Animal Experimentation Committee IPA Isopropyl Alcohol kg (kilogram) L (liters) LC-MS (Liquid Chromatography-Mass Spectrometry) M moles m multiplet m / z mass-to-charge ratio mg milligrams MHz (megahertz) min mL (milliliter) ml (milliliter) mL / min (milliliters per minute) mm (millimeters) mM millimoles mmol millimol mRNA messenger ribonucleic acid MS mass spectrometry mV (millivolts) N Normal n-BuLi n-butyllithium NMR nuclear magnetic resonance NOESY Nuclear Overhauser Effect Spectroscopy pCMV Cytomegalovirus Promoter Peptide autocleavage sequence derived from P2A porcine swine virus-1 PdCl2(dppf) dichloro[1,1'-bis(diphenylphosphin)ferroce Palladium(II) PD Pharmacodynamics PK (Pharmacokinetics) ppm parts per million PyBOP Benzotriazole-1-yloxytripyrrolidinophosphonium hexaf Luorophosfeto QT interval: the time interval between the Q wave and T wave in an electrocardiograph. rac racemi 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 High Performance Liquid Chromatography) UV ultraviolet light VIC 2'-Chloro-7'phenyl-1,4-dichloro-6-carboxy-fluorescein in v / v volume / volume percentage

[0148] Small molecule X-ray crystal structure analysis Data collection Intensity data was obtained using SMART software (Bruker AXS (2003)). and a monochromator-equipped Cu(Kα) radiation, microfocus rotating anode source, and Bruker AXS 3-axis diffractometer with Smart6000 CCD detector: 100 The data was collected at K. Sixteen ω-scans were performed at different Φ positions to ensure appropriate data overlap. Confirmed. Data processing and global cell refinement are handled by Saint(Bruker AXS). This was done in (2012). Semi-empirical absorption correction was performed using SADABS version 2016 / 2. Using Krause L (2015), the symmetric reflections measured at different angle settings were The method was applied based on intensity. The extinction coefficient was refined to 0.00048(11). List the data, data acquisition parameters, and convergence results.

[0149] Structural analysis and refinement The structure was analyzed by a dual-space recycling method and subsequent DF synthesis, and SHE SHELXTL program suite with LXL-2013 / 4 (Sheldrick The GM(2001)) was refined based on the complete 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: Equipment: Waters Acquity UPLC, photodiode array detector; color M:Acquity UPLC BEH C 18 , 1.7 μm, 21 × 30 mm; 2 minutes Operating time: 2% solvent B, 0-0.1 min; 2 → 98% solvent B:solvent A, 0.1-1.8 min. 0.2 minutes in 98% solvent B. Solvent: Solvent A = 0.1% formic acid (v / v) in water, solvent B = 0.1% formic acid (v / v) in acetonitrile. 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: Equipment: Waters Acquity UPLC, photodiode array detector; color M:Acquity UPLC BEH C 18 , 1.7 μm, 21 × 50 mm; 2 minutes Operating time: 2% solvent B, 0-0.1 min; 2 → 98% solvent B:solvent A, 0.1-1.8 min. 0.2 minutes in 98% solvent B. Solvent: 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: Equipment: Waters Acquity UPLC, photodiode array detector; color Acquity UPLC BEH C 18 , 1.7μm, 21×30mm; 5.2min Operating time, 2 → 98% solvent B: solvent A, 0-5.15 mins, 98% solvent B, 5.15 ~5.20 minutes. Solvents: Solvent A = 0.1% formic acid (v / v) in water, Solvent B = acetonitrile Contains 0.1% formic acid (v / v). Injection volume 2-5 μL; UV detection array 210-400, mass Detection was performed at 120-1600°C on a column at 50°C, with a flow rate of 1.0 mL / min.

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

[0155] LCMS method 5: Equipment: Agilent 1200LC / G1956A, diode array detector; Column: Chromolith Flash C 18 1.6 microns, 2 x 25 mm; 1.5 minutes The operation time was 5 → 95% solvent B:solvent A, 0 → 1.2 minutes, then 95% solvent B, 1 0.21 → 1.5 minutes. Solvent: Solvent A = 0.0375% TFA (v / v) in water, Solvent B = A 0.01875% TFA (v / v) in cetonitrile. Injection volume 2-5 μL; UV detection 22 0 and 254 nM, mass detection 100-1000 (electrospray ionization); 50°C Column; flow rate 1.5 mL / min.

[0156] LCMS method 6: Equipment: SHIMADZU LCMS-2020, photodiode array detector; column :Kinetex EVO C 18 5uM, 1 x 30mm; 1.55 min operating time, 5 →95% solvent B:solvent A, 0→1.20 min, then 95% solvent B, from 1.21 min 1.55 minutes. Solvent: Solvent A = 0.025% NH4OH (v / v) in water, Solvent B = acetone 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 ×4.0mm, C12; Gradient: A-0.1% formic acid in water / B-acetonitrile: hour / % 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 0.0 mm, 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 chromatograph) (Togram), mass detection 100-1000 (electrospray ionization); column temperature 3 0℃.

[0160] LCMS method 10: Shimadzu, Column: Mercury MS Synergi, 2.5 μm, 20 ×4.0mm, C12; Gradient: A-0.1% formic acid in water / B-acetonitrile: hour / % 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 (element) Ctrospray ionization; column temperature 40°C.

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

[0162] LCMS method 12: Shimadzu, Column: Synergi, 2.5 μm, MAX-RP100A, (2 (0 x 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 0.0 / 5, flow rate 2.0 mL / min; UV detection array 200-400, mass detection 100-10 00 (Electrospray ionization); Column temperature 40°C.

[0163] LCMS method 13: Acquity, Column: ULC BEH C18, 1.7 μm, 2.1 × 50 mm; Gradient: A - 0.1% formic acid in water / B - acetonitrile: 2.2 minutes of operation, 2 → 98% Solvent B: Solvent A, 0 → 1.76 min, then 95% solvent B, 1.76 min to 2.0 min Flow rate 1.0 mL / min; UV detection array 210-400 nm; Mass range 100-2050 Da;HRMS_2 minutes;Column temperature 50°C

[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 H2O, B: CH3CN, gradient (time / %B): 0 / 20, 2 / 20, 8 / 50) Flow rate: [19mL / min].

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

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

[0167] Method 4: HPLC column: Gemini NX C18 (21.2 × 150.00 mm) 5 microns); Mobile phase - (A): 0.1% TFA in water (B): Acetonitrile / methano Flow rate: 15 mL / 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: [18 mL / min].

[0169] Method 6: HPLC column: KINETEX C18 (21.2 × 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), mobile 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 isomer separation: Method 1: Column: CHIRALPAK IC (10 × 250 mm, 5 microns), mobile phase Hexane(A)IPA:MeOH, 1:1(B); Flow rate: 8 mL / min; Fixed composition: 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; Fixed composition: 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:IPA1:1(B); Flow rate: 8 mL / min; Fixed composition: 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; Fixed composition: 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; Fixed group 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 analysis HPLC method for analyzing separated isomers: Method 1: Column: Lux, Cellulos-4 (250 x 4.6 mm, 5 microns; transfer Dynamic phase: A = n-hexane, B = 0.1% TFA in ethanol; 1 mL / min; constant composition: 7 0:30 (A:B)

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

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

[0183] Intermediate A: Formation of ethyl 4-acetoxy-3-oxobutanoate [ka] Ethyl 4-chloro-3-oxobutanoate (200g, 1215.1 mmol) vinegar Potassium acetate (357 g, 3645.4 mmol) was added to the acid (1500 mL) solution. The solution obtained in this way was stirred at 90°C for 18 hours. The solvent was dissolved in water (2 L), Extraction was performed in ethyl acetate (1 L x 4 hours). Combined with the phenyl phase, saturated NaHCO3 The solution (2 L) was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. , silica flash chromatography (ethyl acetate in petroleum ether, 0 → 15%) By purification of the crude product, the title compound was obtained as a light brown liquid ethyl 4-acetoxy-3-o It was obtained as xobutanoate (152g). 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-fluorobuta-2-enoate Method 1: [ka] Methyl acetate (36.5g, 492.71 mmol) in tetrahydrofuran (200mL) The solution was cooled to -78°C under a nitrogen atmosphere, and lithium diisopropylamine in THF was collected. (246.44 mL, 2.0 M, 492.71 mmol) slowly over a period of 20 minutes. In addition to the reactants, the resulting mixture was stirred at -78°C for 1 hour, and then... Then, tetrahydrof 2-fluoroacetonitrile (19.4 g, 328.9 mmol) The rand solution (150 mL) was added dropwise. The reaction mixture was stirred at -78°C for a further 1 hour. Then, saturated ammonium chloride solution (200 mL) is added, and the product is mixed with ethyl acetate (5 Extracted in L). Washed SiO with saturated brine solution (500 mL) and Na2S The material was dried on O4. The solvent was removed under reduced pressure, and silica flash chromatography was performed (stone The title compound was obtained by purification of the crude product with ethyl acetate in oil ether (0-10%). Methyl(Z)-3-amino-4-fluorobuta-2-enoate is a white crystalline solid. (16g) was obtained.

[0185] Method 2: [ka] Step 1: Tetrahydrofuel of methyl acetate (83.78 g, 1131.0 mmol) The solution (800 mL) was cooled to -78°C under a nitrogen atmosphere, and then the lithium in THF was added. Mu diisopropylamide (565.5 mL, 2.0 M, 1131.0 mmol) was used as a reaction product. The mixture was slowly added over a period of 20 minutes. The resulting mixture was then incubated at -78°C for 1 hour. Stirring, then adding ethyl 2-fluoroacetate (100g, 942.5 mmol) Add the solution of trahydrofuran (200 mL) dropwise, and the reaction mixture is heated at -78°C. Then, stir for 1 hour. Add saturated ammonium chloride solution (200 mL) to the reaction mixture and The product was extracted in ethyl acetate (5L). τ was then extracted in saturated brine solution (500mL). Washed with ) and dried on Na2SO4. Removed the solvent under reduced pressure and dried on silica flakes. For the purification of crude product by chromatography (ethyl acetate in petroleum ether, 0 → 10%) Therefore, yellow crystals (60g) of methyl 4-fluoro-3-oxobutanoate 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 in a sealed tube ( Step 1: Add 60g of saturated ammonia solution in methanol (300mL) to room temperature. The mixture was then added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The compound in question is a white solid methyl(Z)-3-amino-4-fluorobuta-2-enoyl It was obtained as (51g). 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: Add methyl (Z) to the aldehyde (1 mmol) solution in EtOH (10 mL). -3-amino-4-fluorobuta-2-enoate (intermediate B, 1 mmol or 1.2 mL) (mol) and ethyl 4-acetoxy-3-oxobutanoate (intermediate A, 1 mmol or (1.2 mmol) was added. The resulting solution was stirred at 80°C for 16 hours. The solvent was removed under reduced pressure to obtain the title compound (crude product).

[0188] Step 2: Add potassium carbonate to the crude intermediate from Step 1 in methanol (10 mL). (5 mmol) was added. The resulting solution was stirred at room temperature for 2 hours. The solvent was reduced. Removed under pressure and added to water. The product was extracted in ethyl acetate (100 mL) and b Washed in the line and dried on Na2SO4. Removed the solvent under reduced pressure and then flushed with silica. The crude product was purified by chromatography.

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

[0190] Example 1: Methyl(R)-4-(2-((R or S)-2,2-difluorocyclopropyl (L)-3-fluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7 -Tetrahydroflo[3,4-b]pyridine-3-carboxylate [ka] Step 1: 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane [ka] 2-Bromo-3-fluorobenzaldehyde (60g, 295.56 mmol) and E Diethylene glycol (65.4 mL, 1182.2 mmol) dissolved in toluene (600 mL) Add p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol) to the solution. The solution thus obtained was then incubated at 120°C for 24 hours using a Dean-Stark apparatus. The mixture was stirred. The reaction mixture was poured into water (2 L) and extracted in ethyl acetate (3 L). EtO Ac was washed with saturated NaHCO3 solution (1 L) and brine, and dried on Na2SO4. Remove the solvent under reduced pressure, and perform silica flash chromatography (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate (0-10%) revealed the title compound 2-(2-bromide). Mo-3-fluorophenyl)-1,3-dioxolane (60g) 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) , 15g, 60.72 mmol) and potassium vinyl trifluoroborate (16.26 In a 200 mL solution of isopropyl alcohol (g, 121.45 mmol), triethyl Luamine (25.5 mL, 182.16 mmol) and [1,1'-bis(diphenylho Sphino) Ferrocene] Dichloropalladium(II)·DCM (4.95g, 6.07mg) (mol) was added. The resulting solution was degassed with argon gas for 10 minutes and then heated to 80°C. The mixture was stirred for 16 hours. The reaction mixture was filtered and washed with ethyl acetate (100 mL). Filtrate The butyl phase was added to water (1 L) and the product was extracted in ethyl acetate (2 L). Washed with water and dried on Na2SO4. Removed the solvent under reduced pressure and flushed with silica. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0 → 10%) Therefore, the title compound is 2-(3-fluoro-2-vinylphenyl)-1,3-diode Xollan (7.5g) 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) , 6.5g, 33.47 mmol) and trifluoromethyltrimethylsilane (50 mL) Add sodium iodide to a 334.7 mmol (120 mL) solution of tetrahydrofuran. (2.5g, 16.73 mmol) was added. The resulting solution was incubated at 65°C for 24 hours. The mixture was stirred for a specified time. The solvent was evaporated under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). This was washed with water (50 mL) and brine, and dried on Na2SO4. The solvent was reduced. It is removed under pressure, thereby obtaining the title compound 2-(2-(2,2-difluorocyclo Prepare a colorless liquid using propyl)-3-fluorophenyl)-1,3-dioxolane (8g). I obtained 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 Do [ka] 2-(2-(2,2-difluorocyclopropyl)-3-fluorophenyl)-1,3 - Dioxolane (from step 3, 8g, 32.76 mmol) diethyl ether (8 To the 0 mL solution, 10 mL of 6 N HCl was added. The resulting solution was then left at room temperature. It was stirred for 2 hours. This was then mixed with water (50 mL), saturated NaHCO3 solution (100 mL), and bran. Washed with water and dried on Na2SO4. Removed the solvent under reduced pressure and flushed with silica. For the purification of crude product by chromatography (ethyl acetate in petroleum ether, 0 → 5%) Therefore, the title compound is 2-(2,2-difluorocyclopropyl)-3-fluorobe 3.8 g of benzoaldehyde was obtained 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-di 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 step 4 of aldehyde (1 (0.0g, 4.996 mmol), intermediate A (945 mg, 4.996 mmol) and intermediate Synthesized using form B (665 mg, 4.996 mmol), 3-ethyl 5-methyl 2 -(acetoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3-flu Olophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dical A 1.4g crude oxylate was obtained. The crude product should be further purified and analyzed. Instead, it was used as a stepping stone to the next stage.

[0195] Step 6: Methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluoro (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ [3,4-b]pyridine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 5, 1.4 The crude product was synthesized using g, 2.884 mmol. The crude product was subjected to silica flash chromatography. Raffy (ethyl acetate in petroleum ether, 0 → 50%) is purified, and this is done. The title compound is methyl 4-(2-(2,2-difluorocyclopropyl)-3-fluorinated compound. (Lopenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrof [3,4-b]pyridine-3-carboxylate (125 mg) in an off-white solid Obtained as a whole. Chiral SFC: Column: Lux-cellulose-2, 21 × 250 mm, 5um; flow rate: 80g / min; cosolvent: 20% 1:1 MeOH:IPA; detection: 34 Using a 4nm BPR setpoint of 125 bar, the sample is converted into two types of sparkling products. It was separated.

[0196] Peaks 1 and 2, resulting from the previous separation, are chiral SFC:column:WO1 SS, 21×250mm; Flow rate: 80g / min; Co-solvent: 15% IPA; Detection: 344n The four isomers were separated using a BPR set point of 150 bar.

[0197] Example 1 20 mg of the title compound (61%) was eluted as a second stereoisomer, appearing as a white solid. SFC Rt=2.49; Mobile phase: 5~55% (1:1) MeOH IPA w / CO2 10 mM NH4OH, 5 mL / min; Column: Lux Cellulose-2, 4 0.6 × 100 mm, 5 μm LCMS Rt=2.12 min;MS m / z, 398.3[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz, 1H),7.31(td,J=8.0,5.6Hz,1H),7.20-6.83(m, 2H),5.78-5.41(m,2H),5.22(s,1H),5.03-4.73 (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 the first eluted stereoisomer (46%) was observed as a white solid. SFC Rt=2.42; Mobile phase: 5~55% (1:1) MeOH IPA w / CO2 10 mM NH4OH, 5 mL / min; Column: Lux Cellulose-2, 4 0.6 × 100 mm, 5 μm LCMS Rt=2.15 min;MS m / z, 398.2[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.08(d,J=3.2Hz, 1H),7.33(td,J=8.1,5.8Hz,1H),7.25-6.92(m, 2H),5.94-5.54(m,2H),5.27(s,1H),4.79(d,J= 1.4Hz,2H),3.44(s,3H),3.15-3.04(m,1H),2.3 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 eluted stereoisomer (73%) was obtained 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 x 100 mm, 5 μm LCMS Rt=2.16 min;MS m / z, 398.3[M+H]+;[Method 3] 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz, 1H),7.31(td,J=8.0,5.6Hz,1H),7.18-6.87(m, 2H),5.61(dd,J=47.8,4.0Hz,2H),5.22(s,1H), 4.98-4.78(m,2H),3.51(s,3H),2.86(td,J=12. 5,8.5Hz,1H),2.64-2.55(m,1H),2.18(tt,J=12 .8, 6.8Hz, 1H).

[0200] Example 1d 15 mg of the fourth eluted stereoisomer (46%) was found 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 x 100 mm, 5 μm LCMS Rt=2.11 min;MS m / z, 398.1[M+H]+;[Method 3] 1 H NMR:(400MHz,DMSO-d6)δ 10.08(d,J=3.3Hz ,1H),7.33(td,J=8.0,5.6Hz,1H),7.14-6.94(m ,2H),5.72(dd,J=47.8,4.8Hz,2H),5.27(s,1H) ,4.79(d,J=1.4Hz,2H),3.44(s,3H),3.15(d,J= 14.7Hz,1H),2.33-2.20(m,1H),1.99-1.79(m,1 H).

[0201] Example 2: Methyl(R)-4-(2-cyclopropyl-3-fluorophenyl)-2-( Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyri Zin-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3-Fluorobenzaldehyde [ka] 2-Bromo-3-fluorobenzaldehyde (15g, 73.88mmol) and cyclamate Toluene (160 mL) solution of propylboronic acid (7.61 g, 88.66 mmol) In addition, 2N K2CO3 (25.5 mL, 182.16 mmol) and [1,1'-bis( Diphenylphosphinosenoferrocene]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 solution was purified. The filtrate was added to water (500 mL), and the product was extracted in ethyl acetate (2 L). The tOAc phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. Silica flash chromatography (ethyl acetate in petroleum ether, 0 → 1%) Purification of the crude product yielded 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 (-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3 ,5-Dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 1, 4 Synthesized using 0.0g and 24.36 mmol, 3-ethyl 5-methyl 2-(acetoxide) (Cymethyl)-4-(2-cyclopropyl-3-fluorophenyl)-6-(fluoromethyl (Lu)-1,4-dihydropyridine-3,5-dicarboxylate (7.0g, crude product) I 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 (methyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine- 3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 2, 7.0 The crude product was synthesized using g, 15.57 mmol. The crude product was then subjected to silica flash chromatography. It was purified using Raffy (ethyl acetate in petroleum ether, 0 → 50%), but this The title compound is methyl 4-(2-cyclopropyl-3-fluorophenyl)-2- (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]p Lysine-3-carboxylate (1.15 g) was obtained as an off-white solid.

[0204] 150 mg of the racemic mixture was subjected to chiral preparative HPLC [Method 6] for its enantitis It separated into Omar.

[0205] Example 2 50 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 6.129 mins [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). Interchangeable NHs are in the spectrum. Not observed.

[0206] Example 3: Methyl(R)-4-(2-((R or S)-2,2-difluorocyclopropyl (Lu)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4, 5,7-Tetrahydrofl[3,4-b]pyridine-3-carboxylate And Example 4: Methyl(R)-4-(2-((R or S)-2,2-difluorocyclop Ropyr)-3,5-difluorophenyl)-2-(fluoromethyl)-5-oxo-1, 4,5,7-Tetrahydrofl[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. The desired product was synthesized by following the same procedure as in Step 1 of Example 1, yielding 11.5 g. 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 Synthesized using ran, following the same procedure as in Step 2 of Example 1, 2-(3,5-diph Luoro-2-vinylphenyl)-1,3-dioxolane (3.45 g) was obtained. 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-difluoro Enyl)-1,3-Dioxolane [ka] 2-(3,5-difluoro-2-vinylphenyl)-1,3-dioxolane(steppe) 2 to 2.4 g, 11.31 mmol) and trifluoromethyltrimethylsilane (1 In a 15 mL solution of 6.1 g (113.1 mmol) tetrahydrofuran, sodium iodide is added. Lilium (850 mg, 5.65 mmol) was added. The resulting solution was then heated to 65°C. The mixture was stirred for 24 hours. The reaction mixture was cooled to room temperature and then mixed with trifluoromethyltrimethylsilane. (16.1g, 113.1mmol) and sodium iodide (850mg, 5.65mg) Add (ol) and stir the resulting solution at 65°C for 24 hours. Then, the reaction mixture The mixture was partitioned into ethyl acetate and water, the organic phase was washed with brine, and dried on Na2SO4. The solvent was removed under reduced pressure, thereby obtaining the title compound 2-(2-(2,2-di 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-difluorobenzal Ludehyde [ka] 2-(2-(2,2-difluorocyclopropyl)-3,5-difluorophenyl)- 1,3-Dioxolane (from Step 3, 1.5g, 5.72 mmol) diethyl A To a 15 mL solution of tereol, 3 mL of 6 N HCl was added. The resulting solution The mixture was stirred at room temperature for 3 hours. This was then mixed with water (50 mL) and saturated NaHCO3 solution (100 mL). Washed with brine and dried on Na2SO4. Removed the solvent under reduced pressure and silica Crude product obtained by flash chromatography (ethyl acetate in hexane, 0 → 5%) Upon purification, 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-di Fluorocyclopropyl)-3,5-difluorophenyl)-6-(fluoromethyl)- 1,4-Dihydropyridine-3,5-Dicarboxylate [ka] The title compound was prepared using the general step 1 of Method I (from step 4, aldehyde (1 Intermediate A (0.0g, 4.58 mmol), intermediate A (862 mg, 4.58 mmol), and intermediate B (608 mg, 4.58 mmol) is used to synthesize 3-ethyl 5-methyl 2-(A Cethoxymethyl)-4-(2-(2,2-difluorocyclopropyl)-3,5-diflu Olophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dical A boxylate (2.5 g, crude product) 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-diflu Olophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Flo[3,4-b]pyridine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 5, 2.5). The product was synthesized using g, 4.97 mmol. The crude product was analyzed using silica flash chromatography. It was purified using Phi (ethyl acetate in petroleum ether, 0 → 50%), but this The title compound is methyl 4-(2-(2,2-difluorocyclopropyl)-3,5- Difluorophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetra Hydrofloflo[3,4-b]pyridine-3-carboxylate (120 mg) off-white It was obtained as a solid of a certain color. The racemic sample was chiral SFC (mobile phase: 20% IPA / CO2, 80%). g / min; Column: Whilk-O1SS, 21 x 250 mm; Equipment: Thar80_SN It was separated into its enantiomer by 4740).

[0212] Example 3 The first eluted stereoisomer was present as a white solid at a concentration of 20.9 mg (68.8%). 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 ¹H NMR (400 MHz, methanol-d4) δ 6.93-6.73 (m, 2H) ,5.90-5.77(m,1H),5.77-5.64(m,1H),5.46(s, 1H),4.83(s,2H),3.54(s,3H),3.20-3.02(m,1H ),2.09(tdd,J=11.8,7.5,5.9Hz,1H),1.95(ddt (J=16.5,7.8,3.4Hz,1H).

[0213] Example 4 20.6 mg of the second eluted stereoisomer (67.8%) was obtained 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 ¹H NMR (400 MHz, 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, 5.9 Hz, 1H).

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

[0215] Example 3b 21.6 mg of the third stereoisomer was eluted as a white solid (74.1%). 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 ¹H NMR (400 MHz, methanol-d4) δ 6.78-6.63 (m, 2H) ,5.76-5.64(m,1H),5.64-5.52(m,1H),5.33(s, 1H),4.70(s,2H),3.41(s,3H),3.07-2.91(m,1H ),1.96(tdd,J=11.8,7.6,5.9Hz,1H),1.90-1.7 7(m,1H).

[0216] Example 4b The fourth eluted stereoisomer (70.7%) was found as a white solid at a concentration of 20.6 mg. 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 ¹H NMR (400 MHz, methanol-d4) δ 6.91-6.73 (m, 2H) ,5.80-5.67(m,1H),5.67-5.55(m,1H),5.41(d, J=1.6Hz,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, 5.9 Hz, 1 H).

[0217] Example 5: Methyl(R)-4-(3,5-difluoro-2-((R or S)-1-fluor (Roethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetra Hydrofl[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, 5g, 23.58 mmol) and ruthenium chloride XH2 Dichloromethane (490 mg, 2.35 mmol) (50 mL) and water (10 mL) Diacetoxyiodobenzene (11.4 g, 35.37 mmol) was added to the solution. The resulting solution was stirred at 30°C for 2 hours. The reaction mixture was filtered and ethyl acetate ( Washed with 200 mL of water. The filtrate was added to 200 mL of water, and the product was dissolved in ethyl acetate (500 mL). The SiO2 phase was extracted in (mL). The SiO2 phase was washed with brine and dried over Na2SO4. Remove the solvent under reduced pressure, and perform silica flash chromatography (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate (0-10%) revealed the title compound 2-(1,3- Dioxolan-2-yl)-4,6-difluorobenzaldehyde (3g) in a colorless liquid It was obtained as such. 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-dioxolalan-2-yl)-4,6-difluorophen Nylethane-1-ol [ka] 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde(s Step 1: Dissolve 1.0 g (4.67 mmol) of dry tetrahydrofuran in 10 mL of water. Add methylmagnesium bromide (2.33 mL, 3 M in ether, 4.67 mL) to the solution at 0°C. The reaction mixture was then saturated. Quench with ammonium chloride (10 mL) at 0°C, then dilute with ethyl acetate (100 mL). The organic phase was separated, washed with brine, and dried over Na2SO4. The solvent was then reduced under reduced pressure. Remove below and the title compound is 1-(2-(1,3-dioxolan-2-yl)-4,6 -Difluorophenyl)ethane-1-ol (950 mg) was obtained as a colorless liquid. Crude The compound was moved on 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 0.59 (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)ethanol N-1-ol (from step 2, 950 mg, 4.13 mmol) of dichloromethane ( (10 mL) Diethylaminosulfur trifluoride (1.0 g, 6.13 mm) is dissolved in the solution at -78°C. Add ol). The resulting solution was stirred at room temperature for 1 hour. Reaction mixture saturated. Quench with ammonium chloride (10 mL) at 0°C, then dilute with ethyl acetate (100 mL). The organic phase was separated, washed with brine, and dried over Na2SO4. The solvent was then reduced under reduced pressure. It is removed by 2-(3,5-difluoro-2-(1-fluoroethyl)f Enyl-1,3-dioxolane (600 mg) was obtained as a concentrated yellow liquid. The material was moved on to the next step without further refinement. 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-dioxy Solan (from Step 3, 600 mg, 2.58 mmol) diethyl ether (10 ml) To the solution (L), 2 mL of 4N HCl was added at room temperature. The resulting solution was then prepared at room temperature. The mixture was stirred for 3 hours. This was then mixed with water (50 mL), saturated NaHCO3 solution (100 mL), and b The lines were washed and dried over Na2SO4. The solvent was removed under reduced pressure, thereby... The title compound is 3,5-difluoro-2-(1-fluoroethyl)benzaldehyde ( 200 mg was obtained as a colorless liquid. (Note: The obtained aldehyde 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-difluor Ro-2-(1-fluoroethyl)phenyl)-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, ( Synthesized using 200 mg (1.06 mmol), 3-ethyl 5-methyl 2-(acetate). Toxymethyl)-4-(3,5-difluoro-2-(1-fluoroethyl)phenyl)- 6-methyl-1,4-dihydropyridine-3,5-dicarboxylate diastereoma It was obtained as a mixture of the two components. The crude product was carried over to the next step without purification. LCMS Rt=2.272 min;MS m / z, 472.3[MH]-;[Method 7]

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

[0223] Diastereomer mixtures are subjected to combiflash chromatography (0-80%). The two isomers were separated using a method, and 100 mg of the first diastereomer was obtained as a white solid. As and 80 mg of the second diastereomer were obtained as a white solid.

[0224] Peak 1: 100 mg and Peak 2: 80 mg were separated using preparative chiral HPLC [Method 7] By further separating it into its enantiomers, four isomers were obtained.

[0225] Example 5 21 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 4.418 mins; [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 A 22 mg second eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 4.792 mins; [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 eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 6.777 mins; [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 elution enantio, obtained as a white solid using chiral HPLC method 7. Mar. Chiral HPLC Rt = 7.475 mins; [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-Fur Olophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Flo[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) In Example 1, a 26g (105.23 mmol) THF (250 mL) solution was prepared under a nitrogen atmosphere. It was cooled to -78°C under gas pressure. Then, n-butyllithium (44) in n-hexane solution. Add 0.19 mL, 2.5 M, 110.49 mmol) and react the mixture at -78°C for 30 minutes. Stirring was performed. Then, ethyl 2-fluoroacetate (22.33 g, 210.47 mmol) was added. l) was added to the reactants, and the resulting mixture was stirred at -78°C for a further 60 minutes. Quench the reaction mixture with saturated ammonium chloride solution (100 mL), then ethyl acetate (2 Extraction was performed using 250 mL of water and brine. Washed with ) and dried on Na2SO4. Removed the solvent under reduced pressure and dried on silica flakes. For the purification of crude product by chromatography (ethyl acetate in petroleum ether, 0 → 10%) Therefore, the title compound is 1-(2-(1,3-dioxolan-2-yl)-6-fluor Lophenyl)-2-fluoroethane-1-one (16.2 g) 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-dioxolanan-2-yl)-6-fluorophenyl) -2-fluoroethane-1-ol [ka] Stirred 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)- 2-Fluoroethane-1-one (from Step 1, 19.6 g, 85.89 mmol) In a methanol (100 mL) solution, add sodium borohydride (3.9 g, 103.07 ml) (mol) was added at 0°C under a nitrogen atmosphere. The resulting mixture was left at room temperature for 1 hour. Stirring was maintained. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2 × 250 mL). The combined organic phase was then washed with water (250 mL), followed by brine (250 mL). The samples were dried on Na2SO4. The solvent was removed under reduced pressure, and the samples were subjected to silica flash chromatography. By purifying the crude product with Phi (ethyl acetate in petroleum ether, 0 → 30%), the table The compound in question is 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl )-2-fluoroethane-1-ol (18g) 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-flu Dichloromethyl oleotan-1-ol (from Step 2, 18g, 78.18mmol) The tan (150 mL) solution was cooled to -78°C, and then diethylaminosulfur trifluoride (D Add AST (15.49 mL, 117.28 mmol) and the reaction mixture obtained in this manner. The mixture was stirred at -78°C for 1 hour. The reaction mixture was slowly reduced to 0°C and stirred for another 1 hour. Mixed. Add water (150 mL) and extract the product with dichloromethane (2 × 200 mL). Combined the organic phases, saturated sodium bicarbonate solution (2 x 200 mL), water (2 Washed with brine (200 mL) and dried on Na2SO4. Reduce the solvent. Remove under pressure, then silica flash chromatography (ethyl acetate in petroleum ether, 0 →Purification of the crude product with 10% yields the title compound 2-(2-(1,2-diph (Oroethyl)-3-fluorophenyl)-1,3-dioxolane (12.4g) is colorless It 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-dioxy Solan (from Step 3, 12.4g, 53.40 mmol) diethyl ether (15 To the 0 mL solution, 100 mL of 2N HCl was added at 0°C. The reaction obtained in this way The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was extracted with diethyl ether (200 mL). Wash with water (2 x 100 mL) and brine (100 mL), then dry on Na2SO4. The solvent was removed under reduced pressure, and silica flash chromatography (in petroleum ether) was performed. It was produced by ethyl acetate, 0-10%, which resulted in the title compound 2- (1,2-difluoroethyl)-3-fluorobenzaldehyde (10g) in a colorless liquid It was obtained as such. 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-di Fluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihyde Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using General Step 1 of General Procedure I (Aldehyde from Step 4) (Using 9g and 47.83 mmol) it was synthesized, and this resulted in the title compound. 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(1,2-difluoroethyl (Lu)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyridine- 3,5-Dicarboxylate as a mixture of diastereomers (25.0 g, crude product) It was obtained as an off-white solid.

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

[0235] Step 6: Methyl 4-(2-(1,2-difluoroethyl)-3-fluorophenyl) -2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4- b) Pyridine-3-carboxylate [ka] The title compound is a mixture of intermediates from step 5 using step 2 of general procedure I. The title compound, methyl 4-(2-( 1,2-difluoroethyl)-3-fluorophenyl)-2-(fluoromethyl)-5- Oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate A sample (1g, crude) was obtained as an off-white solid. The diastereomer mixture was The two isomers were separated using silica flash chromatography (0-80%). Separate the first diastereomer as a white solid (1.51 g) and the second diastereomer (820 mg). The diastereomer was obtained as a white solid.

[0236] Previously isolated diastereomers from peak 1: 200 mg and diastereomers from peak 2 Leomar: 200 mg was subjected to preparative chiral HPLC [Method 7] to enantiolysis of its components. Further separation into Mar yielded four isomers.

[0237] Example 6 56 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 7.623 mins; [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-tetraphenyl The stereochemistry of drofloe[3,4-b]pyridine-3-carboxylate was determined by single-crystal X-ray crystallography. This is determined by analysis, and thereby the active enantiomer is the R-enantiomer. This was confirmed (Figure 7).

[0239] Example 6b A 54 mg second eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 8.757 mins; [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 A 67 mg third eluted enantiomer was obtained as a white solid. Chiral HPLC = Rt = 10.574 mins; [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] Est. 6d A 69 mg fourth eluted 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, 11.1 Hz, 1 H), 3.53 (s, 3 H).

[0242] Example 7: Methyl(R)-4-(2-((R or S)-1,2-difluoroethyl)-3 -Fluorophenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetra Hydro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 3-Ethoxycyclopenta-2-en-1-one [ka] Stirred cyclopentane-1,3-dione (5.0 g, 50.96 mmol) Add pTSA (193 mg, 1.019 mmol) and EtOH (2) to a 70 mL solution. 2.61 ml (387.35 mmol) was added at room temperature. The resulting mixture was then obtained. The mixture was stirred at 120°C for 10 hours using a Dean-Stark apparatus. The solvent was removed under reduced pressure. The crude compound was obtained. The crude product was subjected to silica flash chromatography (in petroleum ether). The compound 3-ethoxycyclopene was purified by ethyl acetate (0-50%). TA-2-EN-1-ONE (4.3g) 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-aminocyclopenta-2-en-1-one [ka] Stirred 3-ethoxycyclopenta-2-en-1-one (from Step 1, 4.3g) Mix ammonium hydroxide solution (2) in ethanol (50 mL) solution (34.08 mmol). 5 mL (387.35 mmol) was added at room temperature. The resulting mixture was then heated to 85°C. The mixture was stirred for 16 hours. By removing the solvent under reduced pressure, the title compound, 3-aminosine, was obtained. Chlopenta-2-en-1-one (3.2g) 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] In the solution of aldehyde (Example 6, from step 4, 3.0 g, 15.944 mmol) , methyl(Z)-3-amino-4-fluorobuta-2- in t-butanol (25 mL) 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 minutes. The mixture was stirred for 8 hours. The solvent was removed under reduced pressure, yielding the crude compound. The crude product was then processed using silica f Purification by Rush chromatography (ethyl acetate in petroleum ether, 0-70%). Furthermore, the title compound is methyl 4-(2-(1,2-difluoroethyl)-3-fluoroethyl (enyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Cyclopenta[b]pyridine-3-carboxylate (500 mg, crude product) off-white It was obtained as a white solid and a mixture of diastereomers. The diastereomer mixture was The two isomers were separated using silica flash chromatography (0-80%). Separate the first diastereomer as a white solid and 15 mg as a white solid. A second diastereomer of g was obtained.

[0245] The diastereomers from the first isolation peak 1: 12 mg and peak 2: 15 mg were divided Further separation into their enantiomers was performed using chiral HPLC [Method 7], and four We obtained isomers of the same substance.

[0246] Example 7 2 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 9.084 mins; [Chiral analysis method 4] LCMS Rt=1.477 min;MS m / z, 384.05[M+H]+;[Method 2] 1 ¹H NMR (400 MHz, 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 A 4 mg second eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 10.439 mins; [Chiral Analysis Method 4] LCMS Rt=1.477 min;MS m / z, 384.2[M+H]+;[Method 2] 1 ¹H NMR (400 MHz, methanol-d4) δ 7.37-7.23 (m, 1H) ,7.10-7.02(m,1H),6.92(dd,J=11.4,8.1Hz,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 A 4 mg third eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 12.453 mins; [Chiral analysis method 4] LCMS Rt=1.327 min;MS m / z, 384.2[M+H]+;[Method 2] 1 ¹H NMR (400 MHz, 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 0.67 (m, 2H), 2.45-2.22 (m, 2H).

[0249] Example 7d A 4 mg fourth eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 13.173 mins; [Chiral analysis method 4] LCMS Rt=1.33 min;MS m / z, 384.2[M+H]+;[Method 2] 1 ¹H NMR (400 MHz, methanol-d4) δ 7.40-7.25 (m, 1H) ,7.14-7.05(m,1H),6.93(dd,J=11.4,8.2Hz,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-fluoroeth Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Flo[3,4-b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl) Ethanol-1-ol [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (Step 1, fruit In Example 1, a 30g, 121.42 mmol THF (300 mL) solution was administered under a nitrogen atmosphere. It was cooled to -78°C under gas pressure. Then, n-butyllithium (58) in n-hexane solution. (0.3 mL, 2.5 M, 147.71 mmol) was added over 10 minutes, and the following was obtained. The mixture was stirred at -78°C for 1 hour. Acetaldehyde (6.42 g, 145.71 ml) (mol) was added, and the resulting mixture was stirred at -78°C for 1 hour. Reaction mixture Quench with saturated ammonium chloride solution (50 mL), then add ethyl acetate (2 × 100 mL). Extraction was performed using [method]. The combined organic phase was washed with water (50 mL) and brine (50 mL), and Na2 The material was dried on SO4. The solvent was removed under reduced pressure, and silica flash chromatography was performed. The title compound was obtained by purification of the crude product from ethyl acetate in petroleum ether (0-10%). This is 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane. -1-ol (15g) 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 Oxolan [ka] 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane-1 - All (from Step 1, 15g, 70.68 mmol) of dichloromethane (150m (L) Diethylaminosulfur trifluoride (19.3 mL, 141.37 mL) is dissolved in the solution at -78°C. The reaction mixture was then saturated. Quench with ammonium chloride (20 mL) at 0°C, then dilute with ethyl acetate (100 mL). The organic phase was separated, washed with brine, and dried over Na2SO4. The solvent was then reduced under reduced pressure. Remove below, and silica flash chromatography (ethyl acetate in petroleum ether, 0 → Purification of the crude product with 10% yielded the title compound 2-(3-fluoro-2-( Prepare 1-fluoroethyl)phenyl)-1,3-dioxolane (8.5g) as a colorless liquid. I obtained 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, 23.1Hz, 3H).

[0252] Step 3: 3-Fluoro-2-(1-Fluoroethyl)benzaldehyde [ka] 2-(3-difluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxola (Step 2, 8.5g, 69.38 mmol) of diethyl ether (150mL) ) 4N HCl (85 mL) was added to the solution at room temperature. The solution thus obtained was then added at room temperature. The mixture was stirred for 3 hours. Then, water (100 mL), saturated NaHCO3 solution (200 mL), Washed with brine and dried over Na2SO4. Removed the solvent under reduced pressure and the title compound was used. A certain 3-difluoro-2-(1-fluoroethyl)benzaldehyde (6.5g) is colorless. It was obtained as a liquid. (Note: The obtained 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-dihydropyryl Zin-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 3, 1 Synthesized using 0g and 58.76 mmol, 3-ethyl 5-methyl 2-(acetoxy Methyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-6-(fluoro (Methyl)-1,4-dihydropyridine-3,5-dicarboxylate diastereomer - A mixture (13g, crude product) was obtained. 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-tetrahydrofl[3,4-b]p Lysine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (a mixture of intermediates from step 4). (13.0 g, 28.54 mmol) was used to synthesize the title compound, methyl 4- (3-Fluoro-2-(1-Fluoroethyl)phenyl)-2-(Fluoromethyl)-5 -Oxo-1,4,5,7-tetrahydroflo[3,4-b]pyridine-3-carboxy The rate (5g, crude product) was obtained as an off-white solid. The diastereomer mixture was then prepared. Silica flash chromatography (ethyl acetate in hexane, 0 → 80%) Separate the first diastereomer (1.04 g) and the second diastereomer (1.45 g). I obtained it.

[0255] The diastereomers were collected in a chiral SFC column 2.1 × 25.0 cm, Chiralce l OX-H;CO2, co-solvent (solvent B) methanol, definitive composition method, 25% co-solvent, 80g Further separation was performed using a system pressure of 100 bar per minute.

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

[0257] Example 8b 38 mg as the second eluted stereoisomer LCMS Rt=1.95 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt = 1.52 mins; mobile phase: 20% MeOH (0.1% isopropyl) in CO2 Amine), 4 mL / min; Column: Chiralcel OX-H, 4.6 × 100 mm 1 H NMR:(400MHz,DMSO-d6)δ 10.12(d,J=3.3Hz ,1H),7.56-7.23(m,1H),7.25-6.94(m,2H),6.3 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 of the third eluted stereoisomer LCMS Rt=1.88 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt = 2.08 mins; mobile phase: 20% MeOH (0.1% isopropyl) in CO2 Amine), 4 mL / min; Column: Chiralcel OX-H, 4.6 × 100 mm 1 H NMR(400MHz,DMSO-d6)δ 10.13(d,J=3.3Hz, 1H),7.33(td,J=8.0,5.4Hz,1H),7.23-6.92(m, 2H),6.49(dd,J=44.7,6.8Hz,1H),5.68(d,J=47 .8Hz,2H),4.97(s,1H),4.83(s,2H),3.44(s,3H) ), 1.70(dd, J=22.7, 6.6Hz, 3H).

[0259] Example 8d 40 mg: As the fourth eluting stereoisomer LCMS Rt=1.88 min;MS m / z, 366.3[MH]-;[Method 4] SFC Rt=3.01 min; Mobile phase: 20% MeOH (0.1% isopropyl) in CO2 Amine), 4 mL / min; Column: Chiralcel OX-H, 4.6 × 100 mm 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-tetrahydrofluoro The stereochemistry of [3,4-b]pyridine-3-carboxylate was determined by single-crystal X-ray crystallography. This was determined, and this confirmed that the active enantiomer is the R-enantiomer. (Figure 8).

[0261] Example 9: Methyl(R)-4-(2-(difluoromethoxy)phenyl)-2-(fluoro (methyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine- 3-carboxylate [ka] Step 1: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoro Methoxyphenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5- Dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (2-(difluoromethoxy)bene Zualdehyde (350 mg, 2.033 mmol), Intermediate A (382.3 mg, 2.0 Using 33 mmol) and intermediate B (275.65 mg, 2.033 mmol) 3-ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(difluoromethyl) (Phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dical A 600 mg crude voxylate was obtained. Without analysis, it was moved to the next step. I surpassed it.

[0262] Step 2: Methyl 4-(2-(difluoromethoxy)phenyl)-2-(fluorometh (Lu)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4-b]pyridine-3-ca Lu Boxylate [ka] Crude intermediate from Step 1 in methanol (20 mL) (600 mg, 1.30 mmol) Potassium hydroxide (293.44 mg, 5.22 mmol) was added to (1). The resulting solution was stirred at 65°C for 30 minutes. Water was added to the reaction mixture, and the solid precipitated. The solid was washed with diethyl ether, collected, and dried under reduced pressure, but this The title compound is methyl 4-(2-(difluoromethoxy)phenyl)-2- (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]p Lysine-3-carboxylate (100 mg) was obtained.

[0263] The 90 mg racemic mixture was analyzed using chiral HPLC [Method 4] to determine its enantiomer It separated into two parts.

[0264] Example 9 40 mg of the first eluted 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=0.7Hz, 3H). No exchangeable NH protons were observed.

[0265] Example 9, Methyl(R)-4-(2-(difluoromethoxy)phenyl)-2-(full Olomethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine The stereochemistry of -3-carboxylate was determined by single-crystal X-ray crystallography, and thus We confirmed that the active enantiomer is the R-enantiomer (Figure 9).

[0266] Example 9b 38 mg of the second enantiomer was eluted as a white solid, in 42% yield. Chiral HPLC Rt = 10.303 mins; [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) (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ [3,4-b]pyridine-3-carboxylate [ka] Step 1: 1-Bromo-3,5-difluoro-2-(trifluoromethyl)benzene [ka] 3,5-Difluoro-2-(trifluoromethyl)aniline (10g, 50.735m Cool a 48% HBr / H2O (80 mL / 80 mL) aqueous solution of (mol) to -5°C, and then... Then, slowly add NaNO2 (8.74g, 126.83 mmol in 100mL of H2O) Add the mixture over a period of 5 minutes, then stir the resulting mixture at -5°C for 1 hour. The reaction mixture was gradually dissolved in CuBr (10.92g, 76.103 mmol) at -5°C. The reaction mixture was processed as follows. The reaction mixture was slowly allowed to rise to room temperature and stirred for 4 hours. Extraction was performed with hexane (3 × 200 mL). The organic phase was combined with saturated brine (100 mL). Washed in L) and dried over Na2SO4. Removed solvent under reduced pressure and in petroleum ether. Purification of the crude product by silica flash chromatography revealed the title compound. 1-Bromo-3,5-difluoro-2-(trifluoromethyl)benzene (8g) is colorless It 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 12.0 g, 45.99 mmol) and trifluoro(vinyl)-l4-borane In an isopropyl alcohol (120 mL) solution, add potassium salt (12.3 g, 91.98 mg) (mol) and triethylamine (19.16 mL, 137.98 mmol) were added. The resulting solution was purged with argon for 10 minutes, and then [1,1'-bis(diphthong) [Fenylphosphino)ferrocene]dichloropalladium(II)·DCM (3.75g, 4 (0.599 mmol) was added. The reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was c Filter through elite pads, wash with ethyl acetate (100 mL), and on Na2SO4... It was dried. The solvent was removed under reduced pressure, and silica flash chromatography was performed in petroleum ether. Purification of the crude product by Fee revealed the title compound, 1,5-difluoro-2-( 6.5 g of difluoromethyl-3-vinylbenzene 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, 6.5g, 31.23 mmol) and RuCl3·XH2O (647 mg, 3.1 (23 mmol) is used in a dip solution of diacetoxyiodobenzene (20 g, 62.46 mmol). Loromethane was added to a H2O (130 mL:30 mL) solution. The resulting solution was then added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a celite pad and then dichloromethyl ester. Washed with tan (200 mL) and dried on Na2SO4. Removed the solvent under reduced pressure. Rica flash chromatography (crude ethyl acetate in petroleum ether, 0-5%) Purification of the product revealed the title compound, 3,5-difluoro-2-(trifluoromethyl Benzaldehyde (3.0 g) was obtained as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 10.34(m,1H),7.82-7 0.52 (m, 1H), 7.22-7.07 (m, 1H).

[0270] Step 4: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(3,5-difluor Ro-2-(trifluoromethyl)phenyl)-6-(fluoromethyl)-1,4-dihydr Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (from step 3 of aldehyde (4 Synthesized using 00 mg, 1.903 mmol), 3-ethyl 5-methyl 2-(acetate Toxymethyl)-4-(3,5-difluoro-2-(trifluoromethyl)phenyl)- 6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (9 00 mg (crude product) was obtained. 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-tetrahydrofloxacin[3,4- b) Pyridine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 4 (900) Synthesized using (mg, 1.8 mmol). Silica flash chromatography ( The crude product obtained by converting ethyl acetate in petroleum ether (0-50%) yields the title compound. Methyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-2-(full Olomethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine -3-carboxylate (90 mg) was obtained as an off-white solid. Racemic mixture The compounds were separated into their enantiomers using chiral HPLC [Method 7].

[0272] Example 10 30 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 5.502 mins; [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 A 30 mg second eluted 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-fluoro (enyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[ [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) Example 1: A 7g (28.45 mmol) THF (70 mL) solution was placed under a nitrogen atmosphere. It was then cooled to -78°C. Next, n-butyllithium (13.66) was added to the n-hexane solution. Add (mL, 2.5M, 58.5 mmol) over 10 minutes, and the resulting mixture is then added. The mixture was stirred at -78°C for 45 minutes. DMF (2.5g, 34.15 mmol) was obtained as a result. The resulting mixture was added and stirred at -78°C for 1.15 hours. The reaction mixture was saturated ammonium chloride. Quenched with nium solution (50 mL) and extracted with ethyl acetate (2 × 100 mL). The prepared organic phase is washed with water (50 mL), followed by brine (50 mL), and then Na2SO4. 4. Dried on the surface. Remove the solvent under reduced pressure and perform silica flash chromatography (petroleum The title compound was obtained by purification of the crude product with ethyl acetate in ether (0-50%). 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5g) It was 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 ml) (1,3-dioxychloride), potassium iodide (11.85 g, 71.4 mmol) and 2-(1,3-dioxychloride). Solan-2-yl)-6-fluorobenzaldehyde (from Step 1, 7g, 35.7 A solution of mmol was heated to 70°C under a nitrogen atmosphere and stirred for 30 minutes. -Difluoro-2-(fluorosulfonyl)acetate (12g, 62.4mmol) 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 a further 3 hours, then cooled to room temperature, and diethyl It was diluted with ether. The precipitated solid was filtered and washed with diethyl ether (100 mL). The solvent was removed under reduced pressure, and silica flash chromatography (vinegar in petroleum ether) was performed. Purification of the crude product with ethyl acid (0-5%) revealed 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-dioxy Solan (from Step 2, 3g, 13.04 mmol) in ethyl acetate (60mL) Then, 10% Pd-C (1g) was added. The reaction mixture obtained in this way was shaken in Parr. - The reaction mixture was held at room temperature for 48 hours under a hydrogen atmosphere at a pressure of 60 psi. The filtrate was filtered on an elite pad and washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure. Furthermore, silica flash chromatography (ethyl acetate in petroleum ether, 0 → 30%) Purification of the crude product by the following method revealed the title compound, 2-(2-(2,2-difluoroeth (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-dioxy Solan (from Step 3, 3g, 12.93 mmol) diethyl ether (40mL) 5 mL of 6N HCl was added to the solution. The resulting solution was stirred at room temperature for 3 hours. Mix the ingredients together. Wash with water (50 mL), saturated NaHCO3 solution (100 mL), and brine. The samples were then dried on Na2SO4. The solvent was removed under reduced pressure, and silica flash chromatography was performed. By purifying the crude product with Raffy (ethyl acetate in petroleum ether, 0 → 5%), the table The compound in question is 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1 0.9g 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).

[0278] Step 5: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-di Fluoroethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihyde Ropyridine-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 4, 4 Synthesized using 00 mg and 2.12 mmol, the title compound 3-ethyl 5-methyl 2- (Acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3-fluorophenyl (L)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate A 1g (crude product) 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-tetrahydrofloxacin[3,4- b) Pyridine-3-carboxylate [ka] The title compound was prepared using step 2 of general procedure I (intermediate from step 5, 1g, Synthesized using 2.11 mmol. Crude product was analyzed by silica flash chromatography. - Purified by (ethyl acetate in petroleum ether, 0 → 50%), the title compound is methyaluronic acid. 4-(2-(2,2-difluoroethyl)-3-fluorophenyl)-2-(fluoro Methyl)-5-oxo-1,4,5,7-tetrahydroflo[3,4-b]pyridine-3 -Carboxylate (85 mg) was obtained as an off-white solid. The racemic mixture was The enantiomers were separated using chiral preparative HPLC [Method 6].

[0280] Example 11 30 mg of the first eluted enantiomer was 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 eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 8.402 mins; [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-difluoroethyl Olophenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Flo[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 (steppe) From 1 to Example 3, 5g, 18.94 mmol) and potassium vinyl trifluorovolt (5.8g, 37.89mmol), triethylamine (7.91mL, 56.82mg) A 50 mL solution of isopropyl alcohol (mol) was heated using argon gas for 10 minutes. Degassed, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( II) Add DCM (1.55 g, 1.89 mmol). The resulting solution was then prepared. The mixture was degassed again with argon gas for 10 minutes and stirred at 80°C for 5 hours. The reaction mixture was filtered, Washed with ethyl acetate (100 mL). Dissolve the filtrate in water (1 L) and ethyl acetate (2 L). Extraction was performed inside. siRNA was washed with brine and dried on Na2SO4. The solvent was Remove under reduced pressure, then silica flash chromatography (ethyl acetate in petroleum ether, Purification of the crude product by 0-10% yields the title compound 2-(3,5-difluoro (3.45g)-1,3-dioxolane (2-vinylphenyl) is obtained as a colorless liquid. Note: The compound is naturally volatile, and hexane is present in the 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(steppe) 2 to 5 g, 23.58 mmol) and ruthenium chloride XH2O (490 mg, 2. (Diacetoxide) is added to a solution of 35 mmol) dichloromethane (50 mL) and water (10 mL). Iodobenzene (11.4 g, 35.37 mmol) was added. The resulting solution was obtained in this manner. The solution was stirred at 30°C for 2 hours. The reaction mixture was filtered and washed with ethyl acetate (200 mL). The solution was purified. The filtrate was dissolved in water (200 mL), and the product was extracted in ethyl acetate (500 mL). The organic matter was washed with brine and dried on Na2SO4. The solvent was removed under reduced pressure. Furthermore, silica flash chromatography (ethyl acetate in petroleum ether, 0 → 10%) Purification of the crude product by the following method yielded the title compound 2-(1,3-dioxolane-2-i (Lu)-4,6-difluorobenzaldehyde (3g) was obtained as a colorless liquid. Note: Compound The substance is naturally occurring 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] In acetonitrile (4.5 mL), under a nitrogen atmosphere, triphenylphosphine (1.8 3g, 7.0 mmol), potassium iodide (775 mg, 4.66 mmol) and 2-1 ,3-Dioxolan-2-yl)-6-Fluorobenzaldehyde (Steps 3 to 5 (00 mg, 2.33 mmol) was added. The reaction mixture was stirred at 70°C for 30 minutes. Then , 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde (7 Add 83 mg (4.07 mmol) slowly over a period of 10 minutes (masking during addition). The mixture thus obtained (the color turned yellow) was stirred for a further 3 hours at 70°C. Next, the reaction mixture is cooled to room temperature, diluted with diethyl ether, and the precipitated solid is filtered. The sample was washed with diethyl ether (100 mL). The solvent was removed under reduced pressure, and silica flushing was performed. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0 → 5%) Therefore, the title compound is 2-(2-(2,2-difluorovinyl)-3,5-difluoro Olophenyl)-1,3-dioxolane (400 mg) 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) with ethyl acetate (10 ml) To the solution (L), 10% Pd-C (180 mg) was added. The reaction mixture thus obtained was The Parr shaker was held at a pressure of 60 psi at room temperature under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (30 mL). The filtrate is concentrated under reduced pressure and subjected to silica flash chromatography (acetic acid in petroleum ether). Purification of the crude product with ethyl acetate (0-30%) yielded 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) diethyl ether (1 To the 0 mL solution, 1 mL of 5 N HCl was added. The resulting solution was then left at room temperature. Stirred for 3 hours. This was then mixed with water (50 mL), saturated NaHCO3 solution (100 mL), and br Washed in the line and dried on Na2SO4. Removed the solvent under reduced pressure and then flushed with silica. Purification of the crude product by chromatography (ethyl acetate in petroleum ether, 0 → 5%) Therefore, the title compound, 2-(2,2-difluoroethyl)-3,5-difluoroethyl 250 mg of benzoaldehyde 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 0.73 (m, 1H), 3.79-3.56 (m, 2H).

[0287] Step 7: 3-Ethyl 5-methyl 2-(acetoxymethyl)-4-(2-(2,2-di 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 step 6 of aldehyde (2 The title compound 3-ethyl 5-methyl 2) was synthesized using 50 mg (1.21 mmol) of ethyl 5-methyl 2. -(acetoxymethyl)-4-(2-(2,2-difluoroethyl)-3,5-difluoro (lophenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarb Xylate (800 mg, crude product) 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-difluoroethyl (Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3 ,4-b]pyridine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 7, 800 The product was synthesized (using mg, 1.62 mmol). The crude product was subjected to silica flash chromatography. Purified with Raffy (ethyl acetate in petroleum ether, 0-50%), the title compound was obtained. Methyl 4-(2-(2,2-difluoroethyl)-3,5-difluorophenyl)-2 -(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofloo[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 eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 5.674 mins; [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 A 10 mg second eluted enantiomer was 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-tetrahydrofloxacin[3,4- b) Pyridine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-3,5-Difluorobenzaldehyde [ka] 2-Bromo-3,5-difluorobenzaldehyde (10g, 45.20 mmol) and Bicyclopropylboronic acid (4.67g, 54.2 mmol) in toluene (100mL) To the solution, add 2N K2CO3 (102 mL, 204 mmol) and [1,1'-bis(diphthol). [Fenylphosphino)ferrocene]dichloropalladium(II)·DCM (3.17g, 3 (0.88 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 in ethyl acetate (2 L). The OAc phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. Rica flash chromatography (crude ethyl acetate in petroleum ether, 0-1%) Purification of the product revealed the title compound, 2-cyclopropyl-3,5-difluorobene. 8g of zualdehyde 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-dihydropyridyl n-3,5-dicarboxylate [ka] The title compound was prepared using General Step 1 of General Procedure I (Aldehyde from Step 1) (using 1.8g, 9.88mmol) it is synthesized, and 3-ethyl 5-methyl 2-(acetate Toxymethyl)-4-(2-cyclopropyl-3,5-difluorophenyl)-6-(F Luoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (4.61g) (A crude product was obtained.) 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-tetrahydrofl[3,4-b]pyri Zin-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 2, 4.6). Synthesized using 1 g, 9.871 mmol. Crude product was subjected to silica flash chromatography. It was purified by Graphy (ethyl acetate in petroleum ether, 0 → 50%), but this The compound in question is methyl 4-(2-cyclopropyl-3,5-difluorophenyl )-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4 -b] Pyridine-3-carboxylate (350 mg) is obtained as an off-white solid. Ta.

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

[0295] Example 13 135 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 5.33 mins; [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] In the solution of aldehyde (from Step 1 to Example 13, 300 mg, 1.64 mmol) methyl(Z)-3-amino-4-fluorobuta-2-enoe in ethanol (5 mL) (Intermediate B, 220 mg, 1.64 mmol) and cyclopentan-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 obtain the crude compound. The crude product was then subjected to silica flash chromatography. The compound is purified using ethyl acetate in petroleum ether (0-70%), and the title compound is obtained. Tyl 4-(2-cyclopropyl-3,5-difluorophenyl)-2-(fluoromethyl )-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine- 3-carboxylate (55 mg) was obtained as an off-white solid. The racemic mixture was The enantiomers were then separated using chiral preparative HPLC [Method 3].

[0297] Example 14 17 mg of the first eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 8.588 mins; [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 A 17 mg second eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 11.651 mins; [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-tetrahydrofloxacin[3,4- b) Pyridine-3-carboxylate [ka] Step 1: 2-(difluoromethyl)-1-fluoro-3-vinylbenzene [ka] 1-Bromo-2-(difluoromethyl)-3-fluorobenzene (2.0g, 8.88 Potassium vinyl truffles in isopropyl alcohol (20 mL) in a 9 mmol solution Luoroborate (2.38 g, 17.78 mmol) and triethylamine (3.7 mL) (26.66 mmol) was added. The solution thus obtained was filtered by argon for 10 minutes. Purge 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 mixture was stirred for 6 hours. The reaction mixture was filtered through a celite pad and ethyl acetate (10 Washed with 0 mL of water and dried on Na2SO4. Removed the solvent under reduced pressure and dried with petroleum ether. Purification of the crude product by silica flash chromatography revealed the title compound. A certain 2-(difluoromethyl)-1-fluoro-3-vinylbenzene (1.2g) is colorless. It 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 (0.2g, 6.970 mmol) solution with dichloromethane:H2O (20mL:6mL) The contents include RuCl3·XH2O (145 mg, 0.697 mmol) and diacetoxyiodine. Benzene (6.73 g, 20.91 mmol) was added. The resulting solution was left at room temperature. The mixture was stirred for 2 hours. The reaction mixture was filtered through a celite pad and dichloromethane was removed. Washed with (200 mL) and dried on Na2SO4. Removed the solvent under reduced pressure and dried on silica. Crude production by flash chromatography (ethyl acetate in petroleum ether, 0-5%) Through purification of the substance, the title compound 2-(difluoromethyl)-3-fluorobenzal is obtained. Ludehyde (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 (fluoromethyl)-3-fluorophenyl)-6-(fluoromethyl)-1,4-dihydropyryl Zin-3,5-dicarboxylate [ka] The title compound was prepared using step 1 of general procedure I (aldehyde from step 2, 5 Synthesized using 00 mg and 2.871 mmol, 3-ethyl 5-methyl 2-(aceto Xymethyl)-4-(2-(difluoromethyl)-3-fluorophenyl)-6-(Fur Oromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.5g, crude) (The 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-tetrahydrofl[3,4-b]pyri Zin-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 3, 1.0 Synthesized using g, 2.177 mmol. Silica flash chromatography ( The title compound was obtained by purification of the crude product from ethyl acetate in petroleum ether (0-50%). This is methyl 4-(2-(difluoromethyl)-3-fluorophenyl)-2-(fluoro (methyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine- 3-carboxylate (280 mg) was obtained as an off-white solid. Racemic mixture The enantiomers were separated using chiral preparative HPLC [Method 5].

[0303] Example 15 90 mg of the first eluted enantiomer was 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 A 90 mg second eluted enantiomer was obtained as a white solid. Chiral HPLC Rt = 12.05 mins; [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 -Tetrahydroflo[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. Synthesize 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-diflu Olophenyl)trimethylsilane [ka] 2-(2-bromo-3,5-difluorophenyl)-1,3-dioxolane (steppe) A freshly distilled THF (150 mL) solution containing 15.0 g (56.59 mmol) of 1 part THF. In an inert atmosphere, lithium diisopropylamide (31.1 mL, 2 in hexane) Add 0M trimethyl chloride (62.25 mmol) at -78°C and stir for 30 minutes. Add lyl (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 extracted phase was placed in a 2x500mL container. The combined ¼ phase was then placed in a brine solution (250mL). Washed with L) and dried on Na2SO4. Removed the solvent under reduced pressure and dried with petroleum ether (1 Purification of the crude product by silica flash chromatography in 00% of the title Compound (3-bromo-4-(1,3-dioxolan-2-yl)-2,6-difluoro 9.0 g of phenyl(trimethylsilane) 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-dioxolanic-2-yl)-2,6-difluorophenicol (L) Trimethylsilane (from step 2, 5.0g, 14.961 mmol) fresh steam To the distilled THF (50 mL) solution, n-butyllithium (6.0 mL) was added under an inert atmosphere. 2.5 M (14.961 mmol) of hexane was slowly added at -78°C. Next... Then, ethyl 2,2-difluoroacetate (3.1 g, 29.9 mmol) was added to the reaction mixture. In addition, the mixture was stirred at -78°C for 1 hour. The reaction mixture was then mixed with saturated NH4Cl solution (250 mL). The mixture was entrenched and extracted in ethyl acetate (2 x 200 mL). The combined alkyl phase was then mixed. Washed with In solution (50 mL) and dried on Na2SO4. Removed the solvent under reduced pressure. Silica flash chromatography (ethyl acetate in petroleum ether, 0 → 10%) By purification of the crude product, the title compound 1-(6-(1,3-dioxolane-2- (Iyl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2-fluoroeth N-1-ONE (2.5g) 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-(trimethicone) (Cylsilyl)phenyl)-2-fluoroethane-1-one (from step 3, 2.5g) 7.854 mmol) methanol (20 mL) solution, sodium borohydride (59 4.2 mg (15.70 mmol) was added gradually at 0°C. The temperature was slowly increased to room temperature. The mixture was then raised for 1 hour and stirred at room temperature for a further 2 hours. The reaction mixture was saturated ammonium chloride. The solution was quenched with 50 mL of nitrium solution and extracted in 200 mL of ethyl acetate. OAc was washed with brine solution (50 mL) and dried over Na2SO4. The solvent was then reduced under reduced pressure. Remove below, and silica flash chromatography (ethyl acetate in petroleum ether, 0 → Purification of the crude product with 30% yielded the title compound 1-(6-(1,3-dioxy Solan-2-yl)-2,4-difluoro-3-(trimethylsilyl)phenyl)-2- Fluoroethane-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 0.8Hz, 1H), 0.36(s, 9H).

[0309] Step 5: (3-(1,2-difluoroethyl)-4-(1,3-dioxolane-2- Il-2,6-difluorophenyl)trimethylsilane [ka] 1-(6-(1,3-dioxolan-2-yl)-2,4-difluoro-3-(trimethicone) (Cylsilyl)phenyl)-2-fluoroethane-1-ol (from step 4, 2.0g) Diethylamino trifluoride (6.24 mmol) dichloromethane (20 mL) solution Yellow (DAST) (1.24 mL, 9.36 mmol) was added at 0°C. The reaction mixture was allowed to cool to room temperature. The mixture was heated and stirred for 1 hour. Water (50 mL) was added to the reaction mixture, and the product was converted into dichloromethane ( Extraction was performed in 3 × 50 mL. Combined with the DCM phase and saturated NaHCO3 solution (50 mL). Washed with brine and dried on Na2SO4. Removed the solvent under reduced pressure and dried in silica filament. Crude product obtained by sch chromatography (ethyl acetate in petroleum ether, 0 → 2%) Through purification, the title compound (3-(1,2-difluoroethyl)-4-(1,3-dioxyethyl) Solan-2-yl)-2,6-difluorophenyl)trimethylsilane (1.1g) It was 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-(trimethic Lucilyl benzaldehyde [ka] (3-(1,2-difluoroethyl)-4-(1,3-dioxolan-2-yl)-2 ,6-difluorophenyl)trimethylsilane (from step 5, 1.1g, 3.41m) To a solution of (mol) diethyl ether (10 mL), 6N HCl (11 mL) was added. The resulting solution was stirred at room temperature for 3 hours. This was then mixed with water (50 mL) and saturated NaH. Washed with CO3 solution (100 mL) and brine, and dried on Na2SO4. Solvent Remove under reduced pressure to obtain the title compound 2-(1,2-difluoroethyl)-3,5-difluoroethyl Luoro-4-(trimethylsilyl)benzaldehyde (900 mg) as a colorless liquid The product was obtained. Without further purification or analysis, the product was used for the next step.

[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) THF (20 Add TBAF (8.0 mL, 1.0 M in THF, 8.08 mmol) to the solution. The solution obtained in this way was stirred at room temperature for 1 hour. Reaction mixture .''(50 Dilute (mL) and add water (50mL), saturated NaHCO3 solution (100mL), and b Washed in the line and dried on Na2SO4. Removed the solvent under reduced pressure and then flushed with silica. Purification of crude product by chromatography (ethyl acetate in petroleum ether, 5 → 10%) Depending on the manufacturing process, the title compound is 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-di 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 Synthesized using 90 mg, 2.377 mmol, 3-ethyl 5-methyl 2-(aceto Xymethyl)-4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl )-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (1.0 g, crude product) was obtained. Without further purification and analysis, the product was taken to the next step. It was used for the purpose of [something].

[0313] Step 9: Methyl 4-(2-(1,2-difluoroethyl)-3,5-difluoroethyl (Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3 ,4-b]pyridine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 8, 1.0 Synthesized using g, 2.03 mmol. Silica flash chromatography (stone The crude product obtained by ethyl acetate in oil ether (0-50%) yields the title compound, M Tyl 4-(2-(1,2-difluoroethyl)-3,5-difluorophenyl)-2-( Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyri Zin-3-carboxylate (1.0 g, crude product) was obtained as an off-white solid. Diastereomer mixtures were analyzed using silica flash chromatography (0-80%). The two isomers were then separated, and 70 mg of the first diastereomer was obtained as a white solid. And 50 mg of the second diastereomer was obtained as a white solid. First separation peak Diastereomer from Peak 1: 70 mg and diastereomer from Peak 2: 50 mg They were further separated into their enantiomers using preparative chiral SFCs [Method 8], and 4 Two isomers were obtained.

[0314] Example 16 25 mg of the second eluted 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 eluted 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 15 mg of the third eluted enantiomer as a white solid. Chiral HPLC Rt = 14.54 mins; [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 eluted enantiomer as a white solid. Chiral HPLC Rt = 18.97 mins; [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-tetrahydrofluoro[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-dihydropyryl Zin-3,5-dicarboxylate [ka] The title compound was prepared using general procedure I (commercially available 3-fluoro-2-(trifluoromethyl) (Using benzaldehyde, 1.4g, 7.28mmol) synthesized 3-ethyl 5 -methyl 2-(acetoxymethyl)-4-(3-fluoro-2-(trifluoromethyl) Phenyl)-6-(fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxy Silate (2g, crude) was obtained. Without further purification and analysis, the product was determined to be the following: I used it for the step.

[0319] Step 2: Methyl 4-(3-fluoro-2-(trifluoromethyl)phenyl)-2- (fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]p 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 (ethy acetate in petroleum ether) By purification of the crude product using a 0-70% solution, the title compound methyl 4-(3-F) was obtained. Luoro-2-(trifluoromethyl)phenyl)-2-(fluoromethyl)-5-oxo -1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate ( 240 mg was obtained as an off-white solid. The racemic mixture was subjected to preparative chiral HPLC. The enantiomers were separated using [Method 5].

[0320] Example 17 80 mg of the first eluted enantiomer as a white solid, 33% yield. Chiral HPLC Rt = 7.549 mins; [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 = 5.1 Hz, 2 H), 3.47 (s, 3 H).

[0321] Example 18: Methyl(R)-4-(2-(difluoromethyl)-3,5-difluoromethyl (Nyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[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. Synthesized according to the same procedure as in Step 1 of Example 1, 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 Synthesized using ran, following the same procedure as in Step 2 of Example 1, 2-(3,5-diph Luoro-2-vinylphenyl)-1,3-dioxolane (3.0 g) was obtained. 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 following the same procedure as in Step 1 of Example 5, and 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 following the same procedure as in step 3 of Example 5, and 2-(2-(diph Luoromethyl)-3,5-difluorophenyl)-1,3-dioxolane (570 mg) I obtained it. 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 = 1.2 Hz, 1 H), 4.30-3.86 (m, 4 H).

[0325] Step 5: 2-(difluoromethyl)-3,5-difluorobenzaldehyde [ka] 2-(2-(difluoromethyl)-3,5-difluorophenyl)-1,3-dioxo Ran (from Step 4, 570 mg, 2.41 mmol) diethyl ether (10 mL) ) 6N HCl (10 mL) was added to the solution at 0°C. The reaction mixture thus obtained The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted in diethyl ether (50 mL). Washed with water (30 mL). The organic phase was treated with saturated NaHCO3 solution (30 mL) and brine (3 mL). Washed with 0 mL of solvent and dried on Na2SO4. Removed the solvent under reduced pressure, and the crude compound was 2- (Difluoromethyl)-3,5-difluorobenzaldehyde (360 mg) is a colorless liquid. It was brought forth as a physical 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 Synthesized using 60 mg and 1.87 mmol, 3-ethyl 5-methyl 2-(acetoxide) 2-(difluoromethyl)-4-(2-(difluoromethyl)-3,5-difluorophenyl)-6-( Fluoromethyl)-1,4-dihydropyridine-3,5-dicarboxylate (720ml) g (crude product) was obtained. 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-tetrahydrofluoro[3,4-b Pyridine-3-carboxylate [ka] The title compound is prepared using step 2 of general procedure I (intermediate from step 6, 720 Synthesized using mg, 1.50 mmol. Silica flash chromatography ( The title compound was obtained by purification of the crude product from ethyl acetate in petroleum ether (0-70%). Methyl 4-(2-(difluoromethyl)-3,5-difluorophenyl)-2-( Fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyri Zin-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 eluted enantiomer was obtained as a white solid, in 25% yield. Chiral HPLC Rt = 17.629 mins; [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 eluted enantiomer was obtained as a white solid, in 30% yield. Chiral HPLC Rt = 19.634 mins; [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-tetrahydrofluoro[3,4 -b]pyridine-3-carboxylate [ka] The title compound is a commercially available 2-(difluoromethoxy)-3-fluorobenzaldehyde ( Prepared using the general procedure II with 249 mg (1.311 mmol). Crude product. This is eluted on a 24gSi column with a 0-100% gradient of acetate in heptane. Purified by flash column chromatography, followed by mass-based reverse-phase preparative chromatography. Further generated by graphics; conditions: Xbridge C18OBD, 30x50 mm, 5um, column ACN / H2O w / NH3OH, 5 mL / min, 1.5 mL injection. Racemic compounds are transported via chiral SFC (mobile phase: 5-25% MeOH in CO2, 80 g / min). ;Column: (RR)Whelk-O1, 21×250mm) used for its individual enant It separated into thiomers.

[0331] Example 19 8.6 mg second dissolving enantiomer (4%) Chiral SFC Rt=2.61 min (Mobile phase: 5-55% MeOH, Column: (RR)Wh) (ELK-O1, 4.6 x 100 mm, 5 μm column; 6-minute operation) LCMS Rt=1.94 min;MS m / z, 388.2[M+H]+;[Method 4] 1 ¹H NMR (400 MHz, methylene chloride -d2) δ 7.46 (d, J=6.8 Hz) ,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 the first eluted enantiomer (4%) Chiral SFC Rt=2.41 min (Mobile phase: 5-55% MeOH, Column: (RR)Wh) (ELK-O1, 4.6 x 100 mm, 5 μm column; 6-minute operation) LCMS Rt=1.90 min;MS m / z, 388.2[M+H]+;[Method 4] 1 ¹H NMR (400 MHz, methylene chloride -d2) δ 7.46 (d, J=6.8 Hz) ,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-tetrahydrofluoro[3,4 -b]pyridine-3-carboxylate [ka] The title compound is a commercially available 2-(difluoromethoxy)-5-fluorobenzaldehyde ( Prepared using the general procedure II with 229 mg (1.206 mmol). Crude product. This is eluted on a 24gSi column with a 0-100% gradient of acetate in heptane. Purified by flash column chromatography, followed by mass-based reverse-phase preparative chromatography. Further refined using graphics; conditions: Xbridge C18OBD, 30x50 mm, 5um column, ACN / H2O w / NH3OH, 5 mL / min, 1.5 mL injection. Racemic compounds are processed using chiral SFC (mobile phase: 5-25% MeOH in CO2, 80 g / min). Column: (RR)Whelk-O1, 21×250mm) used for its individual enant It separated into Omar.

[0334] Example 20 10 mg second dissolving enantiomer Chiral SFC Rt=2.51 min (Mobile phase: 5-55% MeOH, Column: (RR)Wh) (ELK-O1, 4.6 x 100 mm, 5 μm column; 6-minute operation) 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 12 mg first dissolution enantiomer Chiral SFC Rt=2.31 min (Mobile phase: 5-55% MeOH, Column: (RR)Wh) (ELK-O1, 4.6 x 100 mm, 5 μm column; 6-minute operation) 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-tetrahydrofl[3,4-b]p Lysine-3-carboxylate [ka] Step 1: 2-Cyclopropyl-5-Fluorobenzaldehyde [ka] Degassed 2-bromo-5-fluorobenzaldehyde (2.03g, 10.00mmo) l) Cyclopropaneboronic acid (1.031 g, 12.00 mmol), and PdCl2 (dppf)-CH2Cl2 adduct (0.817g, 1.000 mmol) dioxane (20 mL) solution, and 2.0 M K2CO3 aqueous solution (10.00 mL, 20.00 mL) The mixture (mol) was stirred and heated to 80°C. Once complete, the reaction mixture was cooled to room temperature, and then... The organic phase was then partitioned into water and ethyl acetate. The organic phase was washed with water and brine, and then MgSO4. 4. The product was dried and concentrated. The crude product was subjected to silica flash chromatography [in heptane]. The compound was purified with 0-20% ethyl acetate to obtain 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 (methyl)-5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine- 3-carboxylate [ka] The compound in the title is ethyl 4-chloro-3-oxobutanoate (346 mg, 2.10 mg). (mol), 2-cyclopropyl-5-fluorobenzaldehyde prepared in step 1 Hydro (345 mg, 2.10 mmol), and methyl(Z)-3-amino-4-fluoro From porcine-2-enoate (intermediate B, 280 mg, 2.10 mmol) to general procedure II Therefore, it was prepared. Racemic methyl 4-(2-cyclopropyl-5-fluorophenyl)- 2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4-b Pyridine-3-carboxylate is a chiral SFC (mobile phase: 0.2% NH4OH / C 25% methanol with O2, 80 g / min; Column: (SS)Whelk-O1, 4.6 The enantiomers were separated using a 100mm x 100mm (×) filter.

[0338] Example 21 21.4 mg of the first eluted enantiomer (5.6%) was obtained as a white solid. Chiral SFC Rt=2.41 min (Mobile phase: 5-55% MeOH w / 10mM NH4) OH / CO2, 5 mL / 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 CH group of benzyl on chloropropyl is hidden beneath the DMSO peak.

[0339] Example 21b 10.3 mg of the second eluted enantiomer (2.7%) was obtained as a white solid. Chiral SFC Rt=2.69 min (Mobile phase: 5-55% MeOH w / 10mM NH4) OH / CO2, 5 mL / 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 (Lu)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4-b]pyridine-3-ca Lu Boxylate [ka] Step 1: 2-Cyclopropylbenzaldehyde [ka] Degassed 2-bromobenzaldehyde (1g, 5.40 mmol), cyclopropane Ronic acid (0.557g, 6.49mmol), with PdCl2 (dppf) and CH2Cl2. A solution of the added (0.441 g, 0.540 mmol) dioxane (15 mL), and 2.0 Stir the M K2CO3 aqueous solution (5.40 mL, 10.81 mmol) and heat to 80°C. The reaction mixture was then cooled to room temperature and partitioned into water and ethyl acetate. The phase was washed with water and brine, then dried on MgSO4 and concentrated. The crude product was Purification by silica flash chromatography [0-20% ethyl acetate in heptane] The product was prepared to yield 420 mg of the title compound (53% yield). The crude product was further purified. They accepted it without question.

[0341] Step 2: Methyl 4-(2-cyclopropylphenyl)-2-(fluoromethyl)-5 -Oxo-1,4,5,7-tetrahydroflo[3,4-b]pyridine-3-carboxy rate [ka] The title compound is ethyl 4-chloro-3-oxobutanoate (0.204 mL, 1.5 (00 mmol), 2-cyclopropylbenzaldehyde (219 mg, 1.5 mmol) (Prepared in Step 1) and methyl(Z)-3-amino-4-fluorobuta-2-e Prepared from Noate (intermediate B, 200 mg, 1.50 mmol) by general procedure II. Racemic methyl-4-(2-cyclopropylphenyl)-2-(fluoromethyl)- 5-Oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboc Silate carboxylate is a chiral SFC (mobile phase: 10 mM NH4OH / CO2) Accompanied by 5-55% methanol, 3 mL / min; Column: (SS)WHO; 1 4.6 × 100 It was separated into its enantiomers using (mm)

[0342] Example 22 The first eluted enantiomer was 7.9 mg (3.0%) as a white solid. Chiral SFC Rt=2.77 minutes LCMS Rt=0.93 min; MS m / z, 344.5[M+H]+; [Method 4]. 1 ¹H NMR (400 MHz, 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 eluted enantiomer (2.9%) was obtained as a white solid. Chiral SFC Rt=3.19 minutes LCMS Rt=0.93 min; MS m / z, 344.5[M+H]+; [Method 4]. 1¹H NMR (400 MHz, 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-tetrahydrofluoro[3,4 -b]pyridine-3-carboxylate [ka] The title compound is 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 2-enoate (intermediate B, 312 mg, 2.342 mmol) by general procedure II Prepared as: Racemic methyl 4-(5-fluoro-2-(trifluoromethyl)phenyl )-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydrofluoro[3,4 -b] Pyridine-3-carboxylate is a chiral SFC (mobile phase: 0.2% ammonium hydroxide). 15% methanol with monoium / CO2, 80 g / min; column: 2.0 × 25.0 cm² It was isolated to its enantiomer using ChromegaChiral CC4. .

[0345] Example 23 12.2 mg of the first eluted enantiomer (2.7%) was obtained as a white solid. Chiral SFC Rt=1.29 min (Column: 4.6 × 100 mm, Chiralcel) OZ-H; Fixed composition: 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 eluted enantiomer (3.0%) was obtained as a white solid. Chiral SFC Rt=1.74 min (Column: 4.6 × 100 mm, Chiralcel) OZ-H; Fixed composition: 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-(trif Luoromethyl)phenyl)-1,4,5,7-tetrahydrofl[3,4-b]pyridine -3-carboxylate [ka] The title compound is 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-fluorobuta-2-enoate (intermediate) Prepared from B (280 mg, 2.10 mmol) according to general procedure II. Racemic meth 2-(fluoromethyl)-5-oxo-4-(2-(trifluoromethyl)phenyl) -1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate is , chiral SFC (mobile phase: 20% methanol with 0.2% ammonium hydroxide, 80g) / min; Column: 2.0 × 25.0 cm, using ChromegaChiral CC4) It then separated into its enantiomer.

[0348] Example 24 The first eluted enantiomer (2.0%) was 7.9 mg 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 eluted enantiomer (2.4%) was obtained as a white solid. Chiral SFC Rt = 1.72 mins (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-trifluoroeth (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 (60g, 295.56 mmol) and E Diethylene glycol (65.4 mL, 1182.2 mmol) dissolved in toluene (600 mL) Add p-toluenesulfonic acid monohydrate (28.11 g, 147.78 mmol) to the solution. The solution thus obtained was then incubated at 120°C for 24 hours using a Dean-Stark apparatus. The mixture was stirred. The solvent was added to water (2 L) and extracted in butyl (3 L). Washed with saturated NaHCO3 solution (1 L) and brine, and dried over Na2SO4. Solvent Remove under reduced pressure, and perform silica flash chromatography (ethyl acetate in petroleum ether). By purifying the crude product using 0→10%), the title compound 2-(2-bromo-3) was obtained. 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, 1st hour), 4.19-4.09 (m, 4th hour).

[0351] Step 2: 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (from Step 1) A 70 mL solution of 7 g (28.45 mmol) of THF was incubated at -78°C under a nitrogen atmosphere. It was then cooled. Next, n-butyllithium (13.66 mL, 2. A 5M solution (58.5 mmol) was added over 10 minutes. The resulting mixture was then heated to -78°C. Stir for 45 minutes, then add DMF (2.5g, 34.15 mmol), and the results and The resulting mixture was stirred at -78°C for 1.15 hours. The reaction mixture was saturated with ammonium chloride. Quenched with um solution (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 Na2SO4 It was dried above. The solvent was removed under reduced pressure, and silica flash chromatography (petroleum fluoride) was performed. The title compound was obtained by purification of the crude product with ethyl acetate in ethyl acetate (0-50%). 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (5g) It was obtained as a colored liquid. 1 ¹H NMR (300 MHz, 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] In a 65 mL solution of acetonitrile, under a nitrogen atmosphere, triphenylphosphine (2 (8.1g, 107.1 mmol), potassium iodide (11.85g, 71.4 mmol) and 2-(1,3-dioxolan-2-yl)-6-fluorobenzaldehyde (Ste From step 2, 7g (35.7 mmol) was added. The reaction mixture was stirred at 70°C for 30 minutes, and then... Then, methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (12g, 6 (2.4 mmol) was slowly added over a period of 10 minutes (the mascara turned yellow during the addition). The resulting mixture was stirred at 70°C for a further 3 hours, and then left at room temperature. Cool, dilute with diethyl ether, remove the precipitated solid by filtration, and diethyl ether Washed with 100 mL of solvent. The resulting solvent was removed under reduced pressure, and silica was removed. Crude product obtained by Rush chromatography (ethyl acetate in petroleum ether, 0-5%) By purification, the title compound 2-(2-(2,2-difluorovinyl)-3-fur Olophenyl)-1,3-dioxolane (6.9 g) was obtained as a pale yellow liquid. 1 ¹H NMR (300 MHz, 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-dioxy Solan (from Step 3, 2.7g, 11.73 mmol) and tetrabutylane fluoride A solution of monoum in THF (13.7g, 1M, 13.7 mmol) is heated to 70°C in a closed system. The mixture was heated for 2 hours. The reaction mixture was cooled and diluted with diethyl ether, and then diluted with water (50 mL). Wash with saturated NaHCO3 solution (100 mL) and brine, then dry on Na2SO4. The solvent was removed under reduced pressure, and silica flash chromatography (in petroleum ether) was performed. Purification of the crude product with ethyl acetate (0-10%) revealed the title compound 2-(3- Fluoro-2-(2,2,2-trifluoroethyl)phenyl)-1,3-dioxolane (1.2g) was obtained as a colorless liquid. 1 ¹H NMR (300 MHz, chloroform-d) δ 7.49-7.42 (m, 1H) ,7.35(m,1H),7.17-7.05(m,1H),6.03(s,1H),4 0.25-3.90 (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, 2g, 8.0 mmol) in diethyl ether (40mL) 5 mL of 6N HCl was added to the solution. The resulting solution was left at room temperature for 3 hours. The mixture was stirred. It was then washed with water (50 mL), saturated NaHCO3 solution (100 mL), and brine. The solution was purified and dried on Na2SO4. The solvent was removed under reduced pressure, and silica flash chromatography was performed. By purifying the crude product using graphi (ethyl acetate in petroleum ether, 0 → 5%), The title compound is 3-fluoro-2-(2,2,2-trifluoroethyl)benzaldehyde. Hyd (1.2g) was obtained as a colorless liquid. The crude product was then used for the next step without further purification. It was used as a step in itself.

[0355] Step 6: 3-Ethoxycyclopenta-2-en-1-one [ka] Stirred cyclopentane-1,3-dione (5.0 g, 50.96 mmol) Add pTSA (193 mg, 1.019 mmol) and EtOH (2) to a 70 mL solution. 2.61 ml (387.35 mmol) was added at room temperature. The resulting mixture was then obtained. 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 subjected to silica flash chromatography (ethyl acetate in petroleum ether, Purified by 0-50%, the title compound is 3-ethoxycyclopenta-2-ene 1-ONE (4.3g) 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-aminocyclopenta-2-en-1-one [ka] Stirred 3-ethoxycyclopenta-2-en-1-one (from step 6, 4.3g) Mix ammonium hydroxide solution (2) in ethanol (50 mL) solution (34.08 mmol). 5 mL (387.35 mmol) was added at room temperature. The resulting mixture was then heated to 85°C. The mixture was stirred for 16 hours. By removing the solvent under reduced pressure, the title compound, 3-aminosine, was obtained. Chlopenta-2-en-1-one (3.2g) 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) methyl 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-flu Oro-3-oxobutanoate (Method 2 of Intermediate B, Step 1, 130 mg, 0.97 In a 2 mL solution of 0.8 mmol EtOH, add 3-aminocyclopenta-2-ene-1- ON (from step 7, 94 mg, 0.9708 mmol) was added. Reaction reaction 80 The mixture was stirred at °C for 18 hours. The solvent was removed under reduced pressure. The crude product was subjected to silica flash chromatography. Purified by tography (ethyl acetate in petroleum ether, 0 → 70%), the title compound The result was obtained as an off-white solid. The racemic mixture was subjected to chiral preparative HPLC [Method 6]. It was used to separate the enantiomer.

[0358] Example 25 The second eluted 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 The first eluted enantiomer (24 mg) is presented 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-fluoro (enyl)-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-dioxy Solan (Example 25, from step 3, 3g, 13.04 mmol) ethyl acetate (60 To the solution (mL), 10% Pd-C (1g) was added. The reaction mixture obtained in this way was Pa The mixture was held in an RR shaker under a hydrogen atmosphere at room temperature at a pressure of 60 psi for 48 hours. The mixture was filtered through a celite pad and washed with ethyl acetate (30 mL). filtrate The solution is concentrated under reduced pressure and subjected to silica flash chromatography (ethyl acetate in petroleum ether). By purification of the crude product using 0→30%), the title compound 2-(2-(2,2- Difluoroethyl)-3-fluorophenyl)-1,3-dioxolane (3g) is colorless It was 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-dioxy Solan (Step 1, 3g, 12.93 mmol) in diethyl ether (40mL) 5 mL of 6N HCl was added to the solution. The resulting solution was stirred at room temperature for 3 hours. Mixed. This was then mixed with water (50 mL), saturated NaHCO3 solution (100 mL), and brine. Washed and dried on Na2SO4. Removed the solvent under reduced pressure and subjected to silica flash chromatography. Purification of the crude product by tography (ethyl acetate in petroleum ether, 0 → 5%) , the title compound is 2-(2,2-difluoroethyl)-3-fluorobenzaldehyde (1.9g) 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-fluoro (enyl)-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-cal Boxylate [ka] Aldehyde (from Step 2, 200 mg, 1.063 mmol), methyl-4-fluorine Ro-3-oxobutanoate (Method 2 of Intermediate B, Step 1, 142 mg, 1.063 mg) 3-aminocyclopenta-2-en-1-one in a 2 mL EtOH solution of mmol) (Example 25, Step 7, 103 mg, 1.063 mmol) was added. The reaction mixture was then prepared. The mixture was stirred at 80°C for 18 hours. The solvent was removed under reduced pressure to obtain the crude compound. The crude product was then silicified. By caffeh chromatography (ethyl acetate in petroleum ether, 0 → 70%) The compound was purified to obtain the title compound as an off-white solid (100 mg). The racemic mixture was The enantiomers were then separated using chiral preparative HPLC [Method 6].

[0363] Example 26 The first eluted 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 eluted 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-fluoro (Tyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydr Ro-1H-cyclopenta[b]pyridine-3-carboxylate [ka] Step 1: 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl) Ethanol-1-ol [ka] 2-(2-bromo-3-fluorophenyl)-1,3-dioxolane (Example 25, S Step 1: In a 300 mL solution of 121.42 mmol THF, under a nitrogen atmosphere... n-BuLi (58.3 mL, 2.5 M) in n-hexane solution at -78°C under ambient air. 147.71 mmol was added dropwise over 10 minutes. The mixture thus obtained was then added. Stir at 78°C for 1 hour, then add acetaldehyde (6.42g, 145.71mmo Add (1) and stir the reaction mixture at -78°C for 1 hour. The reaction mixture was saturated with ammonium chloride. Quenched with solution (50 mL) and extracted with ethyl acetate (2 × 100 mL). Combined Wash the phase with water (50 mL), wash with brine (50 mL), and dry on Na2SO4. The solvent was removed under reduced pressure, and silica flash chromatography (in petroleum ether) was performed. By purification of the crude product with ethyl acetate (0-10%), the title compound 1-(2 -(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane-1-ol( 15g 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 Oxolan [ka] 1-(2-(1,3-dioxolan-2-yl)-6-fluorophenyl)ethane-1 - All (from Step 1, 15g, 70.68 mmol) of dichloromethane (150m (L) Diethylaminosulfur trifluoride (19.3 mL, 141.37 mL) is dissolved in the solution at -78°C. (mol) was added. The resulting solution was heated to RT and stirred for 1 hour. Reaction mixture Quench with saturated ammonium chloride (20 mL) at 0°C, then add ethyl acetate (100 mL). Diluted with [a specific solvent]. The organic layer was separated, washed with brine, and dried over Na2SO4. Remove under reduced pressure, then silica flash chromatography (ethyl acetate in petroleum ether, Purification of the crude product by 0-10% filtration yields the title compound 2-(3-fluoro-2 -(1-fluoroethyl)phenyl)-1,3-dioxolane (8.5g) in a colorless liquid It was obtained as such. 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, 23.1Hz, 3H).

[0367] Step 3: 3-Fluoro-2-(1-Fluoroethyl)benzaldehyde [ka] 2-(3-fluoro-2-(1-fluoroethyl)phenyl)-1,3-dioxolane (Step 2: 8.5g, 69.38 mmol) of diethyl ether (150mL) 4N HCl (85 mL) was added to the solution at room temperature. The resulting solution was then left at room temperature. It was stirred for 3 hours. This was then mixed with water (100 mL), saturated NaHCO3 solution (200 mL), and Washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the title compound was extracted. 3-Fluoro-2-(1-Fluoroethyl)benzaldehyde (6.5g) is colorless. It was obtained as a liquid. (Note: The obtained aldehyde is naturally volatile.)

[0368] Step 4: Methyl 4-(3-fluoro-2-((R or S)-1-fluoroethyl) (enyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Cyclopenta[b]pyridine-3-carboxylate [ka] Aldehyde (from Step 3, 1g, 5.876 mmol), methyl 4-fluoro-3 - Oxobutanoate (Method 2 of Intermediate B, Step 1, 780 mg, 5.876 mmol) l) Add 3-aminocyclopenta-2-en-1-one (actual) to EtOH (10 mL) solution Example 25, Step 7, 570 mg (5.876 mmol) was added. The reaction mixture was 80 The mixture was stirred at °C for 18 hours. The solvent was removed under reduced pressure, and the crude product was subjected to silica flash chromatography. The title compound was purified by Graph (ethyl acetate in petroleum ether, 0 → 70%). Methyl 4-(3-fluoro-2-(1-fluoroethyl) phosphate is an off-white solid. (enyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetrahydro-1H -Diastereomer mixture of cyclopenta[b]pyridine-3-carboxylate (22 It was obtained as 0 mg.

[0369] The diastereomer mixture was separated into its two isomers using chiral preparative purification [Method 2]. It separated from it.

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

[0371] Example 27 The second eluted enantiomer (55 mg) was obtained as a white solid. Chiral HPLC Rt = 5.729 mins; [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 eluted enantiomer (55 mg) was obtained as a white solid. Chiral HPLC Rt = 5.678 mins; [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 diastereomer separation was obtained using chiral preparative purification [Method 10]. The enantiomers were separated into peaks 3 and 4.

[0374] Example 27c The third eluted enantiomer (10 mg) is a white solid. Chiral HPLC Rt = 8.702 mins; [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 The fourth eluted enantiomer (10 mg) is a white solid. 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 (15g, 73.88mmol) and cyclamate Toluene (160 mL) solution of propylboronic acid (7.61 g, 88.66 mmol) In addition, 2N K2CO3 (25.5 mL, 182.16 mmol) and [1,1'-bis( Diphenylphosphinosenoferrocene]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 solution was purified. The filtrate was added to water (500 mL), and the product was extracted in ethyl acetate (2 L). The æşe 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%) By purifying the crude product, the title compound, 2-cyclopropyl-3-fluorobenz Aldehyde (11.2g) 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 (methyl)-5-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[b] Lysine-3-carboxylate [ka] Aldehyde (from Step 1, 900 mg, 5.481 mmol), Methyl(Z)-3 -Amino-4-fluorobuta-2-enoate (intermediate B, 537.76 mg, 5.48 In a 1 mmol (5 mL) ethanol solution, add cyclopentan-1,3-dione (875 (0.68161 mg, 5.481 mmol) was added. The reaction mixture was stirred at 80°C for 16 hours. Mixed. Remove the solvent under reduced pressure, and the crude product was subjected to silica flash chromatography (petroleum The title compound, methyl-4- (2-Cyclopropyl-3-Fluorophenyl)-2-(Fluoromethyl)-5-Oxo -4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carboxy Rate (130 mg) was obtained as an off-white solid. The racemic mixture was chiral preparatively separated. The enantiomers were separated using HPLC [Method 11].

[0378] Example 28 The first eluted enantiomer (46 mg) was obtained as a white solid. Chiral HPLC Rt = 10.37 mins; [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 eluted enantiomer (48 mg) was obtained as a white solid. Chiral HPLC Rt = 15.216 mins; [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-flu Oroethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-teto Lahydro-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) Step 2 from, 5g, 23.58 mmol) and ruthenium chloride XH2O (490 Dichloromethane (50 mL) and water (10 mL) solution of mg, 2.35 mmol) Acetoxyiodobenzene (11.4 g, 35.37 mmol) was added. The prepared solution was stirred at 30°C for 2 hours. The reaction mixture was filtered and ethyl acetate (200 mL) was added. Washed with ) The filtrate was dissolved in water (200 mL) and extracted in ethyl acetate (500 mL). The sample was dried on Na2SO4. The solvent was removed under reduced pressure, and silica flash chromatography was performed. By purifying the crude product with Raffy (ethyl acetate in petroleum ether, 0 → 10%), The title compound is 2-(1,3-dioxolan-2-yl)-4,6-difluorobenz Aldehyde (3g) 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-dioxolalan-2-yl)-4,6-difluorophen Nylethane-1-ol [ka] 2-(1,3-dioxolan-2-yl)-4,6-difluorobenzaldehyde(s Step 1: Dissolve 1.0 g (4.67 mmol) of dry tetrahydrofuran in 10 mL of water. Add methylmagnesium bromide (2.33 mL, 3 M in ether, 4.67 mL) to the solution at 0°C. The reaction mixture was then saturated. Quench with ammonium chloride (10 mL) at 0°C, then dilute with ethyl acetate (100 mL). The mixture was separated. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure, and the mixture was prepared. The compound is 1-(2-(1,3-dioxolan-2-yl)-4,6-difluorophenyl (950 mg) ethane-1-ol was obtained as a colorless liquid. The crude compound was further refined. The process was postponed to the next step without being completed. 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 0.59 (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)ethanol N-1-ol (from step 2, 950 mg, 4.13 mmol) of dichloromethane ( (10 mL) Diethylaminosulfur trifluoride (1.0 g, 6.13 mm) is dissolved in the solution at -78°C. Add ol). The resulting solution was stirred at room temperature for 1 hour. Reaction mixture saturated. Quench with ammonium chloride (100 mL) at 0°C, then dilute with ethyl acetate (100 mL). The mixture was separated. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure, and the mixture was prepared. The compound is 2-(3,5-difluoro-2-(1-fluoroethyl)phenyl)-1,3 -Dioxolane (600 mg) was obtained as a thick yellow liquid. The crude compound was further purified. Without doing so, they moved on to the next step. 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-dioxy Solan (from Step 3, 600 mg, 2.58 mmol) diethyl ether (10 ml) To the solution (L), 2 mL of 4N HCl was added at room temperature. The resulting solution was then prepared at room temperature. The mixture was stirred for 3 hours. This was then mixed with water (50 mL) and saturated NaHCO3 solution (100 mL). Washed and dried on Na2SO4. The solvent was removed under reduced pressure, and the title compound 3,5 was obtained. -Difluoro-2-(1-fluoroethyl)benzaldehyde (200 mg) in a colorless liquid It was obtained as a substance. (Note: The obtained aldehyde 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).

[0384] Step 5: 3-Ethoxycyclopenta-2-en-1-one [ka] Stirred cyclopentane-1,3-dione (5.0 g, 50.96 mmol) Add pTSA (193 mg, 1.019 mmol) and EtOH (2) to a 70 mL solution. 2.61 ml (387.35 mmol) was added at room temperature. The resulting mixture was then obtained. The mixture was stirred at 120°C for 10 hours using a Dean-Stark apparatus. The solvent was removed under reduced pressure. The crude compound was obtained. The crude product was subjected to silica flash chromatography (in petroleum ether). The compound 3-ethoxycyclopene was purified by ethyl acetate (0-50%). TA-2-EN-1-ONE (4.3g) 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-aminocyclopenta-2-en-1-one [ka] Stirred 3-ethoxycyclopenta-2-en-1-one (from step 5, 4.3g) Mix ammonium hydroxide solution (2) in ethanol (50 mL) solution (34.08 mmol). 5 mL (387.35 mmol) was added at room temperature. The resulting mixture was then heated to 85°C. The mixture was stirred for 16 hours. By removing the solvent under reduced pressure, the title compound, 3-aminosine, was obtained. Chlopenta-2-en-1-one (3.2g) 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-flu Oro-3-oxobutanoate (Intermediate B, Step 1; Method 2, 598.73 mg, 4 0.4645 mmol) and 3-aminocyclopenta-2-en-1-one (step 6, Reaction: In a 15 mL solution of t-butanol (361.32 mg, 3.7204 mmol). The mixture was stirred at 80°C for 48 hours. The solvent was removed under reduced pressure to obtain the crude compound. Crude product Silica flash chromatography of the substance (ethyl acetate in petroleum ether, 0 → 50%) Purified by [method], the title compound is methyl 4-(3,5-difluoro-2-(1-fluorine Roethyl)phenyl)-2-(fluoromethyl)-5-oxo-4,5,6,7-tetra Hydro-1H-cyclopenta[b]pyridine-3-carboxylate (580 mg) As a white solid, and as a diastereomer and a first off-white solid Obtained as a mixture of diastereomers (320 mg, peak 1). Mixture (580 mg) The second ion was further purified by preparative HPLC (Method 8) to obtain an off-white solid. Astereomer (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 compounds were used to further separate them into their enantiomers, yielding the four isomers of Example 29.

[0388] Example 29 50 mg of the first eluted energy obtained as a white solid using chiral HPLC [Method 11] Nthiomar. LCMS RT=1.445 min;MS m / z, 382.1[MH]-;[Method 7] This was further purified by preparative HPLC [Method 9] to obtain an off-white solid (25 mg was obtained. Chiral HPLC: RT: 8.905 mins; [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 energy obtained as a white solid using chiral HPLC [Method 11] Nthiomar. Chiral HPLC: RT: 10.197 mins; [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 The third elution of 24.2 mg was obtained as a white solid using chiral HPLC [Method 11]. Enantiomer. Chiral HPLC: RT: 14.455 mins; [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 The fourth elution of 32.4 mg was obtained as a white solid using chiral HPLC [Method 11]. Enantiomer. Chiral HPLC: RT: 18.561 mins [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-tetrahydroflo[3,4-b]pyridine-3-carboxy rate [ka] Step 1: Methyl 4-(2-ethylphenyl)-2-(fluoromethyl)-5-oxo -1,4,5,7-tetrahydroflo[3,4-b]pyridine-3-carboxylate [ka] The title compound was prepared using General Method I (2-ethylbenzaldehyde, 0.2g, 1. Synthesized using 44 mmol. Crude product was analyzed by silica column chromatography (D The compound was purified using 2-3% methanol in CM, which resulted in the title compound becoming cream-colored. It was obtained as a solid: methylmethyl 4-(2-ethylphenyl)-2-(fluoromethyl) -5-oxo-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carb Xylate (0.165g, 43%). LCMS Rt=1.506 min; MS m / z. 331.85[M+H]+;[Method 10]

[0393] Racemic samples are subjected to chiral HPLC (column: LUX CELLULOSE-4, (250) MM × 21.2MM × 5 microns); Mobile phase: N-hexane(A)EtOH:MeOH, The enantiomers were separated by a 1:1 ratio (B, flow rate: 15 mL).

[0394] Example 30 The first eluted enantiomer, 30 mg as a pale yellow solid. Chiral HPLC Rt=5.952 min (Column: LUX CELLULOSE-4 (15 0 × 4.6 mm × 5 μm); 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 The second eluted enantiomer, 29 mg as a pale yellow solid. Chiral HPLC Rt=7.581 min (Column: LUX CELLULOSE-4 (15 0 × 4.6 mm × 5 μm); 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-tetraethyl Droflo[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 (2.0g, 11.35 mmol), 3-fluoro-2-(1-fluoroethyl)benzaldehyde (Example 27 From step 3, 1.93g (11.35 mmol) and ethyl(Z)-3-aminobutyric acid A solution of -2-enoate (1.46 g, 11.35 mmol) in ethanol (20 mL) The mixture was heated to 90°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude compound was converted into a brown liquid. The crude compound was obtained by silica flash chromatography (9-10% acetic acid in hexane). The title compound was purified with ethyl(5-ethyl3-) Methyl 2-(dimethoxymethyl)-4-(3-fluoro-2-(1-fluoroethyl) (1.6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (1. 7g, 34%).

[0397] The compound was received directly as a crude product without further analysis.

[0398] Step 2: 3-ethyl 5-methyl 4-(3-fluoro-2-(1-fluoroethyl) Enyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxy 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-Dicarboxylate (from Step 1, 1.7g, 3.86 mmol) A 10.0 mL solution of Sun was cooled to 0°C. A 15.0 mL solution of 6N hydrochloric acid was cooled to 0°C. The reaction mixture was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the product was prepared. The mixture was extracted in ethyl acetate. The combined organic layers were washed with a saturated solution of sodium bicarbonate. The crude compound was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Purified by flash chromatography (12-15% ethyl acetate in hexane). , diastereomer 1 (400 mg, 26%) and diastereomer 2 (3) of the title compound A 00 mg, 20% solution was obtained as a yellow, viscous 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) (Nyl)-6-formyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxy Diamethicone (from diastereoisomer 1 of step 2, 0.40 g, 1.01 mmol) A chloromethane (5.0 mL) solution was cooled to -78°C. Diethylaminosulfur trifluoride ( Add 0.16 mL (1.22 mmol) little by little at -78°C, and allow the reaction mixture to cool at room temperature. The mixture was stirred for 16 hours. The reaction mixture was quenched with ice-cold water, and the product was collected in dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution and then anhydrous sodium sulfate solution. Dry on a surface, filter, remove solvent under reduced pressure, and the title compound as a brown, viscous liquid. Obtained. 5-ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1 -Fluoroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarbonate Luboxylate (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-dihydropyrid n-3,5-dicarboxylate [ka] 5-Ethyl 3-methyl 2-(difluoromethyl)-4-(3-fluoro-2-(1-F (Oroethyl)phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarb Dichloromethane xylate (from step 3, 0.3g, 0.722 mmol) (5. The 0 mL solution was cooled to -78°C. Pyridinium tribromide (0.254 g, 0.794 mL) The mixture was added at -78°C and stirred at the same temperature for 1 hour. The reaction mixture was then left at room temperature. The mixture was stirred for 30 minutes. The reaction mixture was diluted with ice-cold water, and the product was extracted in dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Removed. Crude compound was subjected to silica flash chromatography (10-12% acetic acid in hexane). The title compound was obtained as a yellow, viscous liquid by purification with ethyl(3-ethyl5-) 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-fluorinated Roethyl)phenyl)-5-oxo-1,4,5,7-tetrahydrofl[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, 0.1g, 0.202 mmol) chloroform Add potassium hydroxide (0.005 g, 0.101 mmol) to 5.0 mL of solution at room temperature. It was added as follows. The reaction mixture was heated to 60°C and stirred for 8 hours. Tetra-n-butylan Add monium iodide (0.007 g, 0.020 mmol) at room temperature to the reaction mixture. The mixture was heated to 65°C for 12 hours. The reaction mixture was diluted with water, and the product was extracted in dichloromethane. The combined organic layers were washed with brine, dried on anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The crude product was separated by preparative HPLC (column: ZORBAX XDB( 250mm x 21.2mm), 5.0μ; Mobile phase: A=water, B=ACN; flow rate: 18ml The compound was purified by ( / min) to obtain the title compound as a cream-colored solid. Methyl 2-(diflu Oromethyl)-4-(3-fluoro-2-(1-fluoroethyl)phenyl)-5-Oxyl So-1,4,5,7-tetrahydrofl[3,4-b]pyridine-3-carboxylate (20 mg, 26%) LCMS Rt=1.503 min;MS m / z, 384.05[MH]-;[Method 10 ]

[0404] Racemic samples are subjected to chiral HPLC (column: CHIRALPAK IJ, 250mm x 4). 0.3 mm × 5 microns; Mobile phase: A = hexane, B = 0.1% HCOOH in MeOH: The enantiomers were separated using EtOH (1:1, flow rate: 5 mL).

[0405] Example 31: The first elution peak in chiral HPLC was 3.4 mg, which appeared as a creamy solid. Chiral HPLC Rt = 6.393 min (Column: CHIRAL PAK IJ (250×) 4.6 mm × 5 μm; 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 The second elution peak in chiral HPLC was observed, representing 3 mg of a cream-colored solid. Chiral HPLC Rt = 7.605 min (Column: CHIRAL PAK IJ (250×) 4.6 mm × 5 μm; 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 (XRPD) measurement XRPD is a nickel-filter monochromator and Cu-K alpha 1,2 irradiation LYNXEY with an open angle of 2.948° using a wavelength of 0.15419nm. The analysis was performed using a Bruker D8 Advance diffractometer equipped with an E (1D mode) detector. The diffractogram is calculated step by step in the angular range of 2° to 40° 2-theta under ambient conditions. Applying a step size of 0.0164° (2-theta value) in 0.3 seconds to 40kV pipe The voltage and tube current of 40 mA were recorded. The scan time was 768 seconds. (Diagram of 2-theta values) The precision is in the range of ±0.2°²theta, preferably ±0.1°²theta. For example, appearing at 10.4° 2-theta, for example, methyl(R)-4- (3-fluoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl (Lu)-5-oxo-1,4,5,7-tetrahydrofloxacin[3,4-b]pyridine-3-ca The diffraction peak of crystalline form A of the boxylate is, under standard conditions, shown in most X-ray diffractometers, ( 10.4-0.2)° to (10.4+0.2)° 2 theta, preferably (10.4- It can appear 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-tetrahydrofluoro[3,4 -b] Pyridine-3-carboxylate (130g, 0.35mol) in ethyl ether The mixture was slurryed in 520 ml at room temperature for 3 hours to obtain a suspension, which was then filtered. Then, the moist cake is dried under vacuum at 60°C for 72 hours, and methyl(R)-4-(3-F Luoro-2-((R)-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5 -Oxo-1,4,5,7-tetrahydroflo[3,4-b]pyridine-3-carboxy Rate form A (100g, 0.27mol) was obtained in 77% yield.

[0409] Crystal form B Crystal form B is obtained by dissolving 100 mg of form A in sufficient isopropyl acetate. The solution was prepared and obtained. Then, sufficient heptane was added at 55°C until a turbid suspension was obtained. In addition, the suspension was kept 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-tetrahydrof The presence of form B of [3,4-b]pyridine-3-carboxylate was confirmed.

[0410] Alternative 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 added. The resulting mixture, which was added to the vessel as a seed crystal at 55°C, was incubated at 55°C for 30 minutes. Equilibrium was reached. Then, a solution of isopropyl acetate in free form A was added to the syringe within 2 hours. The mixture was added dropwise to the reactor using a dipump. The resulting mixture was then heated at 55°C. The mixture was then allowed to equilibrate for 2 hours. The mixture was then cooled to 25°C within 6 hours, and then at 25°C. The mixture was then allowed to equilibrate for another 10 hours. Next, the suspension was filtered, and the moist cake was heated under vacuum at 50°C. It was dried for 4 hours. Approximately 21 g of the final product was obtained, which was converted to morphology B by XRPD. It was confirmed that the solution was effective. The water content measured by KF was 0.3%.

[0411] Crystal form C Approximately 100 mg of methyl(R)-4-(3-fluoro-2-((R)-1-fluoroeth Phenyl)-2-(fluoromethyl)-5-oxo-1,4,5,7-tetrahydro Flo[3,4-b]pyridine-3-carboxylate and various stoichiometric amounts of citrate ( (Base:acid ratios of 4:1, 3:1, 2:1, or 1:1) tert-butyl methyl ether It crystallized inside. The resulting solid form is methyl(R)-4-(3-fluoro-2-((R )-1-fluoroethyl)phenyl)-2-(fluoromethyl)-5-oxo-1,4, Corresponds to form C of 5,7-tetrahydroflo[3,4-b]pyridine-3-carboxylate. did.

[0412] Alternative synthesis: Add 40 mL of heptane 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 Seed crystals of form C were added to the reactor at 25°C. The resulting mixture was then heated at 25°C. Equilibration was performed for 30 minutes. A solution of free form A isopropyl acetate was dispensed using a syringe pump. The mixture was then added dropwise to the reactor over a period of 2 hours. The mixture was equilibrated at °C for 2 hours. The in-process control showed a mixture of form C and hydrate A. Next, the solid material was dissolved in 10 mL of isopropyl acetate / heptane (1 / 7) for 2 days. - The suspension was then filtered and dried at 40°C for 18 hours. The final product was XR PD corresponded to morphology C. The water content, as determined by KF, was 0.3%.

[0413] Crystalline form hydrate A Weigh 1.97 g of Form A into a 100 mL EasyMax glass vial, and 35 Disperse in mL of water, and heat the suspension at 300 rpm overhead stirring at a temperature below 50°C for 3 minutes. Stir for a while, then cool to 25°C at approximately 0.07°C / min over 6 hours, and then to 25°C The mixture was stirred for 24 hours. The solid material was isolated by filtration. The solid form of XRPD was then removed from the water. It corresponds to Japanese item A.

[0414] Alternative synthesis: Hydrate A can be, for example, acetone, acetonitrile / water (99.5:0.5) The hydrate was obtained by evaporation and crystallization of a clear saturated solution of crystalline form B in ethyl acetate or water. A shows a mass loss of approximately 4.1% due to TGA, which is due to the monohydrate (4.7%) It is close to the calculated water content. Hydrate A is slightly hygroscopic. Water absorption of 10%~95%RH. The humidity is approximately 0.2% at 25°C.

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

[0416] Alternative synthesis: Hydrate B was obtained by air drying of crystalline form B in methanol solvate. Hydrate B shows a mass loss of approximately 4.4% by TGA, but this is also the case for monohydrate ( It is close to the calculated water content of 4.7%. Hydrate B begins to dehydrate below 20% RH, and 0% RH It loses about 4.4% of its water content. Due to the subsequent rise in relative humidity, this is about 3% at 25°C. It absorbs only % of the water.

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

[0418] Biological data Many known calcium channel activators are Ca V The complex mechanism that activates 1.2 As shown above, these molecules not only increase the peak current, but also, for example, the voltage of the channel By shifting pressure sensitivity to a more negative membrane potential, intracellular calcium concentration is increased. It has a further mechanism. Figure 6 shows the simulated myocardial action potential from the epicardial environment. The Ca2+10 V 1.2 The activation voltage is more negative for the film voltage These further mechanisms are illustrated by demonstrating the effect of shifting to a certain position. Further mechanisms include cardiovascular effects, such as increased blood pressure, changes in heart rate or contractility, and This can promote or exacerbate arrhythmias due to / or QT prolongation. For example, O'Hara-Rudy Using the model, Ca for action potential duration and arrhythmia trend V 1.2 Effects of Adjustment This was investigated. A hyperpolarity shift of >12mV in the activation curve corresponds to >15% QT extension and It was identified that this could potentially lead to an increased risk of arrhythmias. Therefore, voltage sensitivity Minimizing the shift in degree is a compound that reduces the risk of QT prolongation and cardiac arrhythmias. It can bring things.

[0419] The compound of formula (I) is a biophysical compound that minimizes cardiovascular risk as outlined above. Highly strong Ca with rofil V 1.2 It is an activating substance. Firstly, the chemical formula (I) The composite minimizes the hyperpolarization shift to <9mV, thereby reducing their voltage sensitivity. It limits the effect and reduces the possibility of arrhythmia. Secondly, the compound of formula (I) is Ca V 1.2 The peak current is increased by at most 2.5 times, thereby limiting channel overactivation. Thirdly, the compound of formula (I) is the underlying pathophysiological factor behind the cardiac symptoms of Timothy syndrome. Ca, the mechanism V 1.2 Do not delay channel inactivation. Furthermore, compounds of formula (I) It is designed to maximize brain exposure by not showing significant outflow in the brain. .

[0420] Ca V Generation and maintenance of the 1,2-HEK293(AUX) cell line Monoclonal Ca V The 1.2-HEK293(AUX) cell line is human Ca V 1.2 Al It constitutively expresses the α1C (α1C) subunit (CACNA1C), and alpha 2-delta (α2△2) auxiliary subunit (CACNA2D2) and beta-2 (β2) auxiliary It exhibits doxycycline-inducible expression of the subunit (CACNB2). It generates a cell line. To achieve this, the expression vector pcDNA5.0 / FRT-TO-CACNA2D2-FCS -P2A-CACNB2 and pCMV6-entry-CACNA1C are used in gene synthesis and This was established by cloning. Here, the pcDNA5.0 / FRT-TO plasmid was used. It is from Invitrogen, and the pCMV6 entry is from Origene. FCS represents the furin cleavage site, and P2A is due to porcine tesshou virus-1. The resulting peptide self-cleavage sequence is FRT, which is the Flippase recognition target site. Next, the parent lineage Flp-In(trademark)293T-Rex(Invitrogen) is converted to pcD NA5.0 / FRT-TO-CACNA2D2-FCS-P2A-CACNB2 and Fl Transfect with ippase vector pOG44 (Invitrogen), Fl CACNA to a pre-operated FRT site in p-In(trademark) 293T-Rex Target integration of the 2D2-FCS-P2A-CACNB2 expression cassette was established. Subsequently, The intermediate cell line was transfected with pCMV6-entry-CACNA1C, and a stable cell line was obtained. CACNA1C expression was established. Clonal isolation was achieved under neomycin selection. Cell cloning accompanied by voltage-dependent barium current (see electrophysiological methods below) 2-19B) Ca V 1.2 Selected for characterization of the activating substance.

[0421] To maintain the cell line, the cells were passaged twice a week. Each passage was administered using the growth medium (Table 6). Remove all traces of the cells and soak them in 10 ml of D-PBS and 5 ml of warm TrypLE (trademark). Rinsed sequentially with Express enzyme (Gibco). D-PBS and TrypLE Both (trademark) Express enzymes were removed immediately after rinsing. Then the plate was The cells were left at room temperature for 3-5 minutes. Next, 10 mL of warm 37°C complete medium was added, and the cells were allowed to breathe. The growing surface was run over and dissociated cells were collected. The cells were counted, and the T175cm 2 Each flask 2-3 x 10 6 The cells were seeded into a new flask, targeting a specific cell density.

[0422] [Table 6]

[0423] Ca V Ca using 1.2-HEK293(AUX) cell line and QPatch V 1.2 Determination of the electrophysiological properties of activating substances Add doxycycline (1 μg / ml) to the growth medium 24 hours before the electrophysiology experiment. (Table 6), simultaneous application of 25 μM verapamil was performed, which was caused by calcium influx. This prevented cell death. Cell density should reach 70%-80% immediately before the experiment.

[0424] (For example, T175cm) 2 To collect the cells (from the flask), completely remove the growth medium. Removed and rinsed the cells with 10 mL of D-PBS. D-PBS was aspirated and 10 mL of D Add etachin (Genlantis) and place the plate in a 37°C incubator. The cells were placed in a 15 mL conical tube and heated at 1000 rpm for 2 minutes. Spinned. Remove the supernatant and transfer the cells to QPatch complete medium. 150 per QPatch operation. The cells were resuspended to the desired cell density of approximately 3 million cells (Table 7). Each experimental procedure was performed as described in 1.5 Use mL of cells.

[0425] The Sophion QPatch platform uses whole-cell voltage clamping to apply cell suspension. Take a foam and place Ca on single-hole QPlates. V 1.2 Conduction through variu The current was measured. Extracellular and intracellular patch-clamp solutions were measured in Tables 7 and 8, respectively. The following will be described. Using the dose-response assay protocol, the inward peak current of each compound ( Emax) and effectiveness (EC 50The maximum multiple change of ) was determined. The protocol involved eight liquid phases. There was a period of time. The first liquid period was to stabilize the current amplitude, which was -80m Monitor using repeated 200ms voltage pulses that gradually change from V to 0mV. The second liquid period was a single 20ms electrical current that changed stepwise from -80mV to 0mV. By using pressure pulses to determine the baseline current amplitude in the presence of a vehicle control, Yes, it was. Using the third to eighth liquid periods, and also gradually changing from -80mV to 0mV. A single 20ms voltage pulse was used to confirm the dose response to compound processing. . EC 50 This is given by the following equation I concentration =I base +( I full -I base ) * c n / (XC 50 n +c n (In the formula, c is the concentration and n is Hil I obtained using the constant coefficient l. full This is the maximum achievable current, and I ba se The value is 0. Using a channel biophysical assay protocol, the current-voltage relationship is examined. (IV curve), intermediate channel activation voltage (V 1 / 2 ), the rate of channel inactivation (tau) The channel gate switching characteristics, including the amplitude of the tail current, were determined. Among these, V 1 / 2 The equation G(V) = G Vmin +(G Vmax -G Vmin ) / (1+exp(- (V-V1 / 2) / V slope ))(In the formula, G represents conductance, G Vmin is equal to 0, G VmaxV is the maximum conductance. slope is a slope It originated from fitting the factor. G(V) is each experimentally The equation G(V) = I(V) is given for the applied depolarization potential (V) and the corresponding current amplitude (I(V)). The calculation was done in advance using (V) / (V-0.06), but the 0.06 in the equation is the actual value at Bolt. The reverse potential was determined experimentally. The protocol had four liquid periods. First liquid period The purpose was to stabilize the current amplitude, which was to gradually reduce it from -80mV to 0mV. The voltage was monitored using a changing, repeating 200ms voltage pulse. To stabilize the current amplitude... Therefore, the deactivation tau is obtained by a single exponential fit of the deactivation phase of the current trace. Baseline values ​​were determined for the second liquid period under the presence of a vehicle control. The third liquid period involves measuring the baseline values ​​that make up the voltage curve, and the current voltage The objective was to measure the effect of the compound on the curve during each of these two liquid periods. During this time, each cell receives an increment of -80mV to -55mV to +35mV. Ten 20ms voltage pulses were applied, gradually changing in increment size (10mV). During the liquid period of 4, a 200ms voltage pulse of -80mV to 0mV is sent again to inactivate the system. The effect of compounds on tau in the chemical reaction was measured.

[0426] [Table 7]

[0427] [Table 8]

[0428] [Table 9]

[0429] [Table 10]

[0430] Assessment of compound exposure – cFos induction (PK-PD) relationship in wild-type mice Animal care and ethics. All animals are kept in a controlled temperature and light cycle (22°C, 12 hours). With intermittent light / 12-hour dark cycles, and unrestricted access to food and water. They were taken into custody. All animal experiments are conducted by Novartis Institutes for Biology. oMedical Research, Inc. (Cambridge, MA, US) A) Regarding the management and use of laboratory animals approved by the Animal Experimentation Committee (IACUC) This was done in accordance with the facility guidelines.

[0431] Compound administration and brain tissue collection. Wild-type C57BL / 6J male mice were used in the Jackson 2000 chemochemistry. Obtained from laboratories (Bar Harbor, ME). Ca of this disclosure V 1.2 The acute single-dose effect of activating substances was evaluated in 8-week-old male mice (n=6 mice per compound). The compounds were evaluated in a mixture of 10% PEG300 and 10% Solutol. Dissolve the compound in 10% Cremophore EL and 70% phosphate buffer solution. It was administered intraperitoneally (IP) at concentrations ranging from 1 mg / kg to 30 mg / kg. One hour after administration of the drug, the animals were euthanized by total blood collection under deep anesthesia. Drug level Blood was collected in an EDTA tube for downstream analysis. The brain was quickly removed from the skull. The cerebral cortex and cerebellum were then dissected locally. The cerebellar sample was snap-frozen in liquid nitrogen and then chemically treated. Compound exposure was assessed. 500 μl of cortical sample was used for cFos assessment. Place the sample in NAlater solution (ThermoFisher) to check the integrity of the RNA in the sample. The sample was kept in RNAlater at 4°C for at least 24 hours, and then processed. It was stored at -80°C before use.

[0432] Quantification of cFos mRNA induction. TissueLyse for 96-well plates. Tissue homogenization was performed using the r system (Qiagen). First, the frozen cortical sample was prepared. Thaw the sample, remove it from RNAlater, and use buffer RLT containing 0.5% reagent DX. and one 5mm TissueLyser metal bead along with TissueLyser I put it inside the tube. TissueLyser tubes into TissueLyser II set. Three rounds were loaded into the homogenizer for homogenization, but each round was 30Hz. The beading continued for 5 minutes. RNeasy96Plus kit (Qiagen The total RNA was purified from the homogenate using ) and the RNA concentration and A260 / A280 ratio were determined. The quantification was performed using Nanodrop (ThermoFisher), and all samples were measured in 10°C. The concentration was normalized to 0 ng / μL. Superscript III First-st Using the RAND synthesis SuperMix kit (ThermoFisher), RNA The RNA was reverse transcribed into cDNA. For each sample, 6 μL of RNA (total 600 ng) was added to 1 μL of cDNA. Mix Oligo dT with 1 μl of annealing buffer and heat to 65°C for 5 minutes. Next, 10 μL of 2×First-Strand reaction mix and 2 μL of enzyme mix were added. After adding the sucrose, a total reaction volume of 20 μL was achieved. The sample was heated to 50°C for 50 minutes, and then... The cDNA synthesis was completed by heating to 85°C for 5 minutes.

[0433] Quantitative PCR is performed in a 384-well assay format. Multiplex RT-PCR kit (Qiagen) used on cDNA samples The procedure was performed. Each PCR well contained 2 μl of cDNA (60 ng total) and 10 μl of RT-PCR. mastermix, 1 μL cFos FAM Taqman probe (Mm004 87425_m1(FAM)#4351368), 1μL of GAPDH VIC Taq man probe (Mm99999915-g1(VIC)#4448486), 0.2μ Contains 1 μl of Multiplex RT mix and 5.8 μl of RNase-free water. On the ViiA7 real-time PCR system (ThermoFisher), the sample was processed 9 times. Heat to 5°C for 15 minutes, then heat at 94°C for 45 seconds and 60°C for 45 seconds for 45 seconds. The cycle was performed over several cycles. The cFos Ct value was exported, and the GAPDH Ct value was also exported. Standardized to express the relative multiple change using the delta-delta Ct relative quantification method. The conversion was performed. The change in the cFos factor between compound treatment and vehicle was analyzed using one-way ANOVA, and This was followed by an analysis using Tukey post-hoc comparisons.

[0434] Quantification of compound exposure. Cerebellar tissue samples were treated with 4 ml of 20% acetonitrile per 1 g of tissue. And homogenized in 80% phosphate-buffered saline (5× dilution). The following three methods Either method was used to homogenize the tissue: a handheld probe system, 30 minutes for 4 minutes. s -1TissueLyser system with 5mm steel beads at the specified frequency, Alternatively, depending on the tissue type, OMNI Bead Ruptor Elixir for 30 seconds to 1 minute. e-homogenizer. Add tissue sample to 96-well plate (12.5 μL of sample), mass The data was processed for quantification using analytical methods.

[0435] result

[0436] [Table 11]

[0437] [Table 12]

[0438] Comparative Example Other Ca V 1.2 Although the activators are well known, these compounds also affect the cardiovascular system. Dangers include, for example, increased blood pressure, changes in heart rate or systolicity, and / or QT prolongation. Minimizing pulse regulation, while not being too strong, and / or activating channels, and sufficient It lacks the desirable biophysical properties required for brain exposure.

[0439] [Table 13]

[0440] [Table 14] The invention described in the original claims of this application is listed below. [1] Compounds according to formula (I) or pharmaceutically acceptable salts or solvates thereof [ka] (In the formula: A is O or CH 2 and; R 1 is either H or F; R 2 is either H or F; R 3 Each of these is replaced by 1 to 3 F's at will, OCHF 2 (It is methyl, ethyl, or cyclopropyl.) [2] The compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, as described in [1].

change

change

[10] R 3 The compound according to [4], wherein the compound is an ethyl methyl molecule substituted with one or two fluorine atoms, or an unsubstituted or cyclopropyl molecule substituted with two fluorine atoms.

[11] A, CH 2 The compound described in any of [1] to [3].

[12] R 2 However, the compound described in

[11] is F.

[13] R 3 The compounds described in

[11] or

[12] , wherein the ethyl compound is substituted with 1 to 3 F atoms.

[14] Compounds according to formula (III) or pharmaceutically acceptable salts or solvates thereof

change

[15] The compound described in

[14] , wherein A is O.

[16] R 2 However, the compound described in

[15] is F.

[17] R 2 The compound described in

[15] , which is H.

[18] R 3 However, OCHF 2 The compound described in

[15] .

[19] R 3 The compounds described in

[15] , wherein each is optionally substituted with 1 to 3 F atoms, and is methyl, ethyl, or cyclopropyl.

[20] R 3 However, CHF 2 or CF 3 The compound described in

[15] .

[21] R 3 The compound according to

[15] , wherein the compound is an ethyl atom optionally substituted with one or two F atoms, or an unsubstituted or cyclopropyl atom substituted with two F atoms.

[22] R 3 The compound described in

[15] is ethyl.

[23] R 4 However, the compound described in

[15] is F.

[24] R 4 The compound described in

[15] , which is H.

[25] A, CH 2 The compound described in

[14] .

[26] R 2 However, the compound described in

[23] is F.

[27] R 3 However, the compounds described in

[23] are ethyl compounds substituted with 1 to 3 F atoms.

[28] R 4 However, the compound described in

[23] is F.

[29] R 4 The compound described in

[23] , which is H.

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

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

[32] The compound described in

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

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

[34] The crystal form described in

[33] , which is form A.

[35] The crystal form described in

[33] , which is form B.

[36] The crystal form described in

[33] , which is form C.

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

[38] Hydrate A, the crystalline hydrate form described in

[37] .

[39] Hydrate B, the crystalline hydrated form described in

[37] . A pharmaceutical composition comprising any of the compounds described in

[40] [1] to

[32] , and a pharmaceutically acceptable additive.

[41] A method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, QT shortening syndrome, or early repolarization syndrome, comprising administering an effective amount of any of the compounds described in [1] to

[32] or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[42] A method for the treatment of schizophrenia, bipolar disorder, major depressive disorder, substance use disorder, ADHD, Phelan-McDermid syndrome, autism spectrum disorder, multiple sclerosis, frontotemporal dementia, Alzheimer's disease, Brugada syndrome, QT shortening syndrome, or early repolarization syndrome, comprising administering to a patient in need of such treatment a compound or a pharmaceutically acceptable salt thereof described in any of [1] to

[32] .

Claims

1. A pharmaceutical composition in the form of a tablet or gelatin capsule, comprising a compound represented by the following structural formula and a pharmaceutically acceptable additive. 【Chemistry 1】

2. A pharmaceutical composition in the form of a tablet or gelatin capsule comprising a compound represented by the following structural formula or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive. 【Chemistry 2】

3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable additive comprises one or more selected from the following: a) Excipients selected from the group consisting of lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and glycine; b) A lubricant selected from the group consisting of silica, talc powder, stearic acid, its magnesium or calcium salt, and polyethylene glycol; c) A binder selected from the group consisting of magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone; d) Disintegrants selected from the group consisting of starch, agar, alginic acid or its sodium salt, and effervescent mixtures; and e) Additives selected from the group consisting of absorbents, colorants, flavoring agents, and sweeteners.

4. A pharmaceutical composition according to any one of claims 1 to 3, formulated for oral administration.

5. A pharmaceutical composition according to any one of claims 1 to 4 for treating schizophrenia, bipolar disorder, or Alzheimer's disease.

6. A pharmaceutical composition according to any one of claims 1 to 5 for treating schizophrenia.

7. A pharmaceutical composition according to any one of claims 1 to 5 for treating bipolar disorder.

8. A pharmaceutical composition according to any one of claims 1 to 5 for treating Alzheimer's disease.

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