Alcohol derivatives as KV7 potassium channel openers

Abstract

To provide compounds, pharmaceutical compositions, and uses thereof for activating Kv7 potassium channels and treating related disorders.SOLUTION: Compounds selected from the group consisting of (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; and pharmaceutically acceptable salts thereof are provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to a novel compound that activates the Kv7 potassium channel. The embodiment includes a pharmaceutical composition containing the compound and a response to activation of the Kv7 potassium channel. This relates to the use of compounds for treating diseases. [Background technology]

[0002] Voltage-gated potassium (Kv) channels respond to changes in membrane potential by releasing potassium throughout the cell membrane. Muion (K + ) conducts, thereby regulating (increasing or decreasing) the electrical activity of cells. This allows for the control of cellular excitability. Functional Kv channels have four α It exists as a multimeric structure formed by the association of a subunit and four β-subunits. The α subunit includes six transmembrane regions, a pore-forming loop, and a voltage sensor. They are arranged symmetrically around the central hole. β or auxiliary subunits are α subunits. It interacts with the t, and the electrophysiological or biophysical properties of the channel, expression level, Alternatively, changes in the expression pattern may occur, but are not limited to, any modification of the channel complex's characteristics. It can be questioned.

[0003] A family of nine Kv channel α subunits has been identified, namely Kv1-Kv9. It is referred to as such. Therefore, the functionality of the Kv channel includes numerous subfamilies and subfaculties. Formation of both homologous and heterogeneous subunits within Millie, as well as β subunit There is a vast diversity that arises as a result of the additional effects of the meeting with (Christi e,25 Clinical and Experimental Pharmacol ogy and physiology,1995,22,944-951).

[0004] The Kv7 channel family includes Kv7.1, Kv7.2, Kv7.3, Kv7.4, and K Mammalian channels of v7.5, and any mammalian or non-mammalian equivalents or mutants thereof ( It consists of at least five members, including one or more of the Price variants. The members of this family are, respectively, named KCNQ1, KCNQ2, and KCNQ 3. Also known as KCNQ4 and KCNQ5 (Dalby-Brown, et al.) Current Topics in Medicinal Chemistry,20 06,6,9991023).

[0005] As mentioned above, the Kv7 potassium channel in nerve cells plays a role in regulating nerve cell excitation. It plays a role. The Kv7 channel, especially the Kv7.2 / Kv7.3 heterodimer, is M This forms the basis of electric current (Wang et al Science. 1998 Dec 4;282(5395):1890-3). M current is a membrane current that responds to multiple excitatory stimuli. It possesses characteristic time and voltage dependencies that lead to stabilization of the position.

[0006] Thus, M current is involved in the control of neuronal excitability (Delmas&Br). (own, Nature, 2005, 6, 850-862). M currents are found in many neuronal cell types. This is a non-inactivated potassium current found in each cell type. In each cell type, this is the initiation of an action potential. By being the only sustained current within the range, it controls membrane excitability (Marri on,Annual Review Physiology 1997,59,483- 504).

[0007] Retigabin (N-(2-amino-4-(4-fluorobenzylamino)-phenyl) (Wu) is a compound that binds to the Kv7 potassium channel. ttke,et al.,Molecular Pharmacology,2005, 67, 1009-1017). Retigabin is a K in nerve cells. + Activating the electric current, this induce The pharmacology of the electromotive force is Kv7.2 / 3 + M-channels correlated with heteromultimers of channels This shows consistency with the published pharmacology of the channel, which indicates the activity of the Kv7.2 / 3 channel. This suggests that the chemical reaction is responsible for at least part of the anticonvulsant effect of this drug (Wicken). den,et al.,Molecular Pharmacology 2000,5 (8,591-600). Retigabin reduces the incidence of epileptic seizures in epilepsy patients. It is effective in this regard (Bialer, et al., Epilepsy Research) (2002, 51, 31-71). Retigabine has a broad spectrum and strong anticonvulsant effect. It has the following properties: It was administered orally and intraperitoneally to rats and mice in various anticonvulsant tests. Effective after (Rostock, et al., Epilepsy Research) (h 1996, 23, 211-223).

[0008] The five members of this family of ion channels have different expression patterns. The expression of v7.1 is limited to the heart, peripheral epithelium, and smooth muscle, but Kv7.2 and Kv7.3 are also expressed. Expression of Kv7.4 and Kv7.5 is observed in the hippocampus, cerebral cortex, ventral tegmental region, and dorsal root nerves. It appears to be dominant in the nervous system, including ganglion neurons (Greene & Hoshi). ,Cellular and Molecular Life Sciences,20 See 17,74(3),495-508 for reference.

[0009] The KCNQ2 and KCNQ3 genes are associated with epilepsy, also known as benign familial neonatal seizures. It is thought that mutations occur within the genotype (Rogawski, Trends in Ne Urosciences 2000, 23, 393-398). KCNQ2 and KCNQ Proteins encoded by 3 genes are associated with the onset and transmission of epileptic seizures in the brain. It is localized in the pyramidal neurons of the human cerebral cortex and hippocampus (Cooper et al.). al., Proceedings National Academy of Sci. ence USA 2000,97,4914-4919).

[0010] Furthermore, in addition to Kv7.2 mRNA, Kv7.3 and Kv7.5 mRNA are also present in glial astrocytes. It is expressed in cells and glial cells. Therefore, Kv7.2, Kv7.3, and Kv7.5 The channel helps regulate synaptic activity in the CNS, and KCNQ channel openers are effective in the nervous system. It can contribute to protective action (Noda, et al., Society for N Euroscience Abstracts 2003, 53.9), this is Alzheimer's disease. This includes, but is not limited to, Hymer's disease, Parkinson's disease, and Huntington's disease. It will be suitable for the treatment of neurodegenerative diseases.

[0011] mRNA of the Kv7.2 and Kv7.3 subunits is associated with conditions such as depression and bipolar disorder. Brain regions associated with behavioral and emotional behavior, such as the hippocampus, ventral tegmental area, and amygdala, are found to be involved. (Published by Saganich, et al. Journal of Neuroscience) ce 2001,21,4609-4624;Friedman et al.,Nat Commun.2016;7:11671.), Retigabin is an animal model of anxiety-like behavior. It has been reported to be effective in (Korsgaard et al. J Pha rmacol Exp Ther.2005 Jul;314(1):282-92.E (pub 2005 Apr 6.). For this reason, the Kv7 channel is used in bipolar depression, and This includes, but is not limited to, mood disorders, anxiety, suicidal thoughts, anxiety attacks, and social phobias. It is appropriate for treating related diseases.

[0012] The Kv7.2 / 3 channel has also been reported to be upregulated in models of neuropathic pain. (Wickenden, et al., Society for Neuros) Science Abstracts 2002, 454.7), potassium channel regulators It is hypothesized that this is effective for both neuropathic pain and epilepsy. roder,et al.,Neuropharmacology 2001,40,8 88-898). In addition to its role in neuropathic pain, the trigeminal ganglion and dorsal root ganglion, The expression of Kv7.2-5 mRNA in the trigeminal nerve nucleus tail indicates that these channels are openers. This means it can also affect the sensory processing in migraines (Goldstein, et al. l.Society for Neuroscience Abstracts 200 3.53.8). In summary, this evidence suggests that the treatment of chronic pain and neurological disorders is not effective. This demonstrates the validity of KCNQ channel openers.

[0013] International Publication No. 07 / 90409 is a pamphlet on the treatment of schizophrenia using the Kv7 channel. Regarding the use of Kv7 channel openers. Kv7 channel openers modulate the function of the dopaminergic system. Therefore (Friedman et al., Nat Commun. 2016; Scot ty et al J Pharmacol Exp Ther.2009 Mar;3 28(3):951-62.doi:10.1124 / jpet.108.146944 .Epub 2008 Dec 19;Koyama et al.,J Neurop hysiol.2006 Aug;96(2):535-43.Epub 2006 J an 4;Li et al Br J Pharmacol.2017 Dec;17 4(23):4277-4294.doi:10.1111 / bph.14026.Ep ub 2017 Oct 19.;Hansen et al J Pharmacol Exp Ther.2006 Sep;318(3):1006-19.Epub 2 (June 14, 2006), psychosis, mania, stress-related disorders, acute stress reaction, attention deficit ADHD, post-traumatic stress disorder, obsessive-compulsive disorder, impulsivity disorder, personality disorder, schizophrenia These include schizotypical disorder, aggression, and autism spectrum disorder. Appropriate for the treatment of mental illnesses, not limited to those listed above. International Publication No. 01 / 96540 Pamphlet The t is a regulator of the M current formed by the expression of the KCNQ2 and KCNQ3 genes. The use for insomnia is disclosed, and International Publication No. 01 / 092526 states: This publication discloses that the regulator of Kv7.5 may be used in the treatment of sleep disorders. Pamphlet No. 09 / 015667 discusses the use of Kv7 mouth openers in the treatment of sexual dysfunction. It is disclosed.

[0014] Patients suffering from the above-mentioned diseases may have available treatment options, but these options Many of the options lack the desired efficacy and also have undesirable side effects. Therefore, There is an unmet need for novel therapies to treat the aforementioned diseases.

[0015] In an attempt to identify new treatment methods, the inventors have identified a series of novel methods represented by Formula I. A compound was identified. Therefore, the present invention relates to the regulation by KCNQ potassium channels. To provide novel compounds as pharmaceuticals for treating diseases. [Overview of the Initiative]

[0016] This invention relates to formula I [ka] Regarding the compound, In the formula, R1 is C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3- Selected from the group consisting of C8 cycloalkyls, wherein one C3-C8 cycloalkyl is present. Alternatively, it may be substituted with two C1-C3 alkyl groups, F, CHF2, or CF3, and Beauty R2 is H, C1-C6 alkyl or CF3; or R1 and R2 bond together (together with the carbon atoms to which they are bonded), one or two F, CHF 2、 Or form a C3-C5 cycloalkyl group optionally substituted with CF3; and to R3 is C1-C3 alkyl or CH2O-C 1~3 Alkyl, and the C1-C3 Alkyl or CH2O-C 1~3 Alkyls are C≡N, 3F, or C3-C5 cycloalkyls. It has been replaced with 'ru'; R4 is selected from the group consisting of OCF3 or OCHF2.

[0017] According to another aspect of the present invention, the present invention relates to a novel compound of the present invention.

[0018] The present invention further comprises the compound of the present invention and a pharmaceutically acceptable carrier or excipient. Regarding pharmaceutical compositions.

[0019] Furthermore, the present invention is for treating patients as described in the claims and embodiments. Regarding the method, this includes administering a therapeutically effective amount of the compound of the present invention to the subject. This includes the treatment of patients with epilepsy, bipolar disorder, migraines, and schizophrenia. [Modes for carrying out the invention]

[0020] Detailed description of the invention According to one embodiment, the compound of formula I may have an R4 group which is OCF3 or OCHF2. ru.

[0021] According to other embodiments, the compound according to formula I is CH2-O-CF3,CH2O-cyclo It may have an R3 group selected from the group including propyl and CH2-C≡N.

[0022] According to a further embodiment, the compound according to formula I contains one or two C1-C3 alkyl groups, The R1 group is a C3-C4 cycloalkyl group that can be optionally substituted with F, CHF2, or CF3. It is possible to have.

[0023] In yet another embodiment, any compound according to formula I has R1 and R2 groups As a result, the R1 and R2 groups are bonded and optionally substituted with one or two F atoms in a cyclob It forms a chill, and R4 is either OCF3 or OCHF2.

[0024] According to a particular embodiment of the present invention, the Compound according to the present invention (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phen Nyl(ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(triflu Oromethoxyethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trif Luoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl) (Tyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)p Ropyr-3-hydroxy-4,4-dimethylpentanamide; (R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl) Ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl) (Tyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (Difluoromethoxy)phenyl)-2-(Trifluoromethoxy)ethyl)acetamine Do; or (S)-N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)- 2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide, or The group consists of pharmaceutically acceptable salts of any of these compounds.

[0025] Other aspects of the present invention include: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2- Trifluoroethoxy(phenyl)ethyl(pentanamide); R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-to (Lifluoroethoxy)phenyl)ethyl)pentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclop Ropil (propanamide); (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclop Ropil (propanamide); (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (Phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl Ropil (propanamide); (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (Phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl Ropil (propanamide); (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro Toxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Panamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro Toxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Panamide (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro Toxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Lopanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro Toxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Lopanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(diflu Olomethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(diflu Olomethoxy)phenyl)butyl)-3-hydroxypropanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Mido; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Mido; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-Hy Droxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorophenyl Olobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-diflu Oropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-Hy Droxy-4,4-dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(diph (Oromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide ; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(diph (Oromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamine Do; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (Difluoromethoxy)phenyl)butyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (Difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (trifluoromethoxy)phenyl)propyl)acetamide; (S)-N-(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl) Ropyr)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane Mido; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane Mido; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Phenylethyl-3-(1-fluorocyclopropyl)-3-hydroxybutane Amido; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Phenylethyl-3-(1-fluorocyclopropyl)-3-hydroxybutane Amido; (R)-3-Cyclopropyl-N-((R)-2-(Difluoromethoxy)-1-(3- (Trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (S)-3-Cyclopropyl-N-((R)-2-(Difluoromethoxy)-1-(3- (Trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpenta Namido; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpenta Namido; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl(ethyl)-3-hydroxy-3,5-dimethylhexaneamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl(ethyl)-3-hydroxy-3,5-dimethylhexaneamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropane Namido; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropane Namido; (S)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3- (Difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3- (Difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methyl Toxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2 -Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide A compound selected from the group, or a pharmaceutically acceptable salt of any of these compounds. To relate to.

[0026] References to compounds included in this invention include racemic mixtures of compounds, and related This includes optical isomers of the compound, as well as tautomers of related compounds. The compounds of the present day may, in some cases, be in polymorphic and amorphous forms, or in pharmaceutical form with water, ethanol, etc. It may exist in both non-solvated and solvated forms with a generally acceptable solvent.

[0027] The present invention also includes isotopically labeled forms of the compounds of the present invention, such as deuterium. The compounds are acceptors. Positrons for medical imaging and positron emission tomography (PET) to determine the distribution of the body Emitted isotopes can also be incorporated. Suitable positron emission canotopes that can be incorporated into the compound of the present invention. The isotopes released are 11C, 13N, 15O, and 18F. The isotope-labeled compound of the present invention Generally, by conventional techniques known to those skilled in the art, or by appropriate alternatives to non-isotope labeling reagents, Manufactured using a topologically labeled reagent by a process similar to the process described in the attached embodiment. It is possible.

[0028] The compound of the present invention is a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier. It can exist within an object.

[0029] In one embodiment, the present invention relates to a compound of the present invention for use in therapeutic purposes.

[0030] In another embodiment, the present invention relates to a person suffering from epilepsy, bipolar disorder, migraine, or schizophrenia. a method for treating a patient in need of a treatment method, comprising a therapeutically effective amount of the compound of the present invention This relates to a method, including administering a substance to a target.

[0031] In yet another embodiment, the present invention involves administering a therapeutically effective amount of the compound of the present invention to a target. This includes psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, and major depression. Pathological disorders, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity Sexual disorders, personality disorders, schizophrenic disorders, aggression, chronic pain, neurological disorders, autism spectrum disorder He suffers from a disease such as Huntington's disease, sclerosis, multiple sclerosis, and Alzheimer's disease, and is undergoing treatment. Regarding methods for treating patients who require such methods.

[0032] According to one embodiment, the compound of the present invention is used in therapeutic purposes.

[0033] The use of the compounds of the present invention is for the treatment of epilepsy, bipolar disorder, migraine, or schizophrenia. This is for, or in another embodiment, psychosis, mania, stress-related disorders, acute Stress response, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders ADHD, PTSD, OCD, impulsivity disorder, personality disorder, schizophrenic disorder, aggression, chronic Sexual pain, neurological disorders, autism spectrum disorder, Huntington's disease, sclerosis, multiple sclerosis It is intended to treat Alzheimer's disease.

[0034] In other embodiments, the compounds of the present invention are used to treat epilepsy, fragile X syndrome, and Angelmann syndrome. For the manufacture of medicines for the treatment of syndromes, bipolar disorder, migraine, or schizophrenia, or In other embodiments, psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, Major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD Impulsivity disorder, personality disorder, schizophrenic disorder, aggression, chronic pain, neurological disorder, autism spectrum disorder Treating respiratory disorders, Huntington's disease, sclerosis, multiple sclerosis, and Alzheimer's disease. It is for manufacturing pharmaceuticals for the purpose of [doing something].

[0035] In the context of the present invention, "optionally substituted" means that the indicated portion is replaced. This means that substitution is not required, and if substitution occurs, it can be a single substitution or a double substitution. Therefore, if there is no substituent designated as the "optionally substituted" part, It will be understood that the position is maintained by the hydrogen atom.

[0036] The specified range is indicated by using either a dash ("~") or "to" interchangeably. It is possible, for example, the term "C 1~3 "Alkyl" is synonymous with alkyl groups from C1 to C3. That is the case.

[0037] The terms "C1-C3 alkyl" and "C1-C6 alkyl" refer to 1 to a maximum of 6 (1 and 6 are...). This refers to unbranched or branched saturated hydrocarbons having carbon atoms (including). Examples of such groups and For example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and Examples include, but are not limited to, t-butyl.

[0038] The term "C1-C3 alkoxy" refers to the -OR part of the formula, where R is defined above. It refers to C1-C3 alkyl groups.

[0039] Terms: "C3-C4 cycloalkyl", "C3-C5 cycloalkyl", "C3-C8 cycloalkyl "Cloalkyl" or "cyclopropyl" refers to a saturated monocyclic ring. Examples of such groups include For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl Examples include ru and cyclooctyl.

[0040] Route of administration: Pharmaceutical compositions containing the compounds of the present invention as defined above may be administered orally, rectally, nasally, orally, or sublingually. , via any preferred route such as transcutaneous and parenteral (e.g., subcutaneous, intramuscular, and intravenous) routes. Therefore, it can be formulated specifically for administration, and the oral route is preferred.

[0041] The route of administration depends on the patient's overall health and age, the nature of the disease being treated, and the active ingredient. It will be understood that it will change.

[0042] Pharmaceutical formulations and excipients: In the following, the terms "excipient" or "pharmaceutically acceptable excipient" refer to fillers, adhesives, etc. Antiadherents, binders, coating agents, dyes, disintegrants, fragrances, Examples include flow promoters, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles, and auxiliary agents. This refers to pharmaceutical excipients, but is not limited to these.

[0043] The present invention also includes the formulation of one of the compounds disclosed in the experimental section of this specification. The present invention provides a pharmaceutical composition containing a compound. The present invention also provides a pharmaceutical composition containing the compound of the present invention. The present invention provides a process for manufacturing. The pharmaceutical composition of the present invention is based on Remington's "Th eScience and Practice of Pharmacy”22th Disclosed in edition (2012) (edited by Allen, Loyd V., Jr.) It can be formulated using pharmaceutically acceptable excipients in accordance with conventional technologies.

[0044] Pharmaceutical compositions for oral administration include solid forms such as tablets, capsules, powders, and granules. Oral dosage forms, as well as liquid oral dosage forms such as solutions, emulsions, suspensions, and syrups, and suitable Examples include powders or granules that are dissolved or suspended in a fine liquid.

[0045] Each solid oral dosage form contains a predetermined amount of the active ingredient and preferably one or more suitable excipients. It may be provided as individual units containing (e.g., tablets or hard or soft capsules). Where appropriate, the solid dosage form may be enterically coated according to methods well known in the art. They may be prepared with coatings such as delayed release or sustained release. It may be formulated to provide a modified release of the sexual component. If appropriate, a solid agent. The form may be a dosage form that disintegrates in saliva, such as an orally dispersible tablet.

[0046] Examples of excipients suitable for solid oral formulations include microcrystalline cellulose, corn starch, and cellulose. Cactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclamate Rodextrin, talcum, gelatin, pectin, magnesium stearate, steary Examples include, but are not limited to, cellulose-based acids and lower alkyl ethers of cellulose. Similarly, the solid formulation may be glyceryl monostearate or hypromellose, etc. The solid material may contain excipients for delayed-release or sustained-release formulations known in the field. When used for oral administration, the formulation may, for example, involve mixing the active ingredient with a solid excipient. The mixture may then be prepared by compressing it in a conventional tablet forming machine, or, For example, the compound may be placed inside a hard capsule in the form of a powder, pellet, or small tablet. It may be used. The amount of solid excipients varies considerably, but typically, it is measured in dose units. Each unit contains approximately 25 mg to 1 g.

[0047] Liquid oral dosage forms include, for example, elixirs, syrups, and oral drops. ), or it may be provided as a liquid-filled capsule. The liquid oral dosage form may also be aqueous or non-aqueous. It may also be provided as a powder for solutions or suspensions in liquid. Suitable excipients for liquid oral formulations. Examples include ethanol, propylene glycol, glycerol, and polyethylene glycol. Calcium, poloxamer, sorbitol, polysorbate, mono and diglycerides, cyclodextrin Examples include, but are not limited to, string, coconut oil, palm oil, and water. Oral dosage forms are, for example, obtained by dissolving or suspending the active ingredient in an aqueous or non-aqueous solution. Alternatively, it can be prepared by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion. It is possible.

[0048] Further excipients such as colorants, flavorings, and preservatives are used in solid and liquid oral formulations. It is possible.

[0049] Pharmaceutical compositions for parenteral administration include sterile aqueous solutions and non-aqueous solutions, dispersions, injections, or injections. Suspensions or emulsions for use, concentrates for injection or infusion, and for use before injection or infusion Examples include sterile powders that are reconstituted in sterile solutions or dispersions. Suitable excipients for parenteral formulations. Examples of such preparations include solutions of water, coconut oil, palm oil, and cyclodextrin. However, these are not limited to these. Aqueous formulations should be properly buffered if necessary. The solution should be made isotonic using sufficient saline or glucose.

[0050] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, skin patches, and implants. Examples include formulations and formulations for oral or sublingual administration.

[0051] Excipients used in any pharmaceutical formulation should be administered according to the intended route of administration and in accordance with the active ingredient. Compatibility is absolutely essential.

[0052] dose: In one embodiment, the compound of the present invention is administered at a dose of approximately 0.001 mg / kg body weight to approximately 10 per day. It is administered at a dose of 0 mg / kg body weight. Specifically, the daily dose is 0.01 mg per day. The dosage may range from g / kg body weight to approximately 50 mg / kg body weight. The exact dosage depends on the frequency of administration. and method, sex, age, weight, general condition of the patient, nature and severity of the disease being treated, Depending on any complications being treated, the desired therapeutic effect, and other factors known to those skilled in the art To exist.

[0053] The typical oral dose for adults is within the range of 0.1 to 1000 mg / day of the compound of the present invention. For example, 1-500 mg / day, 1-100 mg / day, or 1-50 mg / day. In terms of convenience, the compound of the present invention contains approximately 0.1 to 500 mg of the compound in a unit dosage form containing the compound. g, for example, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg The compound of the present invention is administered in the amount specified above.

[0054] Heteromorphic and tautomeric types: If the compound of the present invention contains one or more chiral atoms, the reference to the compound is otherwise Unless otherwise specified, enantiomers or diastereoisomers of pure compounds, and any ratio This covers mixtures of enantiomers or diastereomers.

[0055] To represent the unknown stereochemistry of the compound of the present invention, MDL Extended Stereomorphism (MDL En (Hand-set stereo representation) is used. Therefore The label "or1" on the chiral carbon atom indicates that the absolute conformation of this atom is unknown. Used to indicate that, for example, the conformation of this carbon atom is (S) or (R It is one of the following.

[0056] Furthermore, carbon atoms labeled "or1" using an upward or downward wedge. Chiral bonds from are equivalent representations; for example, the two figures have the same meaning, and their meaning and The absolute conformation of the carbon atom labeled "or1" is unknown, and (S) Alternatively, it could be (R).

[0057] Therefore, upward wedge bonds and downward wedge bonds from atoms labeled "or1" The use of rust bonds shows different stereoisomers in the carbon ion labeled "or1". This is simply intended to provide a visual cue indicating that the conformation in the child is unknown.

[0058] Furthermore, some of the compounds of the present invention can exist in various tautomeristic forms. It is intended that any tautomers that the compound can form are included within the scope of the present invention. It can be done.

[0059] Therapeutic effective dose: In the context of this invention, the term "therapeutic effective dose" of a compound means a therapeutic dose including the administration of the compound. In therapeutic interventions, reduce, prevent, or partially prevent the clinical signs of a given disease and its complications. This means a sufficient amount to remove or delay the treatment. It is defined as the "effective dose for each purpose." The effective dose for each purpose depends on the severity of the disease or injury, and It depends on the weight and overall condition of the subject. Determining the appropriate dosage is done using routine experiments and values This is achieved by constructing a matrix and testing various points within that matrix. It is possible, and it will be understood that this is all within the normal range of skill for a skilled physician. .

[0060] Treatment and the act of treating: In the context of the present invention, "treatment" or "treating" "Aging" means reducing, preventing, partially preventing, eliminating, or delaying the progression of clinical signs of a disease. It is intended to refer to the management and care of patients with the aim of achieving a certain condition. Preferably a mammal, specifically a human.

[0061] All references cited herein, including publications, patent applications, and patents, are referenced by... By doing so, the entirety is incorporated into this specification, and as if each reference were by reference... When incorporated, it is indicated individually and specifically, to the same extent as when the whole is described (Law (To the maximum extent permitted by law) incorporated herein.

[0062] Use in epilepsy, epileptic syndromes, epileptic symptoms, or epileptic seizures. In other embodiments, the present invention relates to epilepsy, epileptic syndromes, epileptic symptoms, and treatment resistance. Patients suffering from or intractable anti-epileptic or refractory epilepsy, or epileptic seizures, who require such treatment. A method of treatment comprising administering a therapeutically effective amount of the compound according to the present invention to a target. Regarding the method.

[0063] In yet another embodiment, the present invention relates to focal (partial) epilepsy with simple partial seizures, and multiple Focal (partial) epilepsy with mixed partial seizures, idiopathic generalized epilepsy, grand mal seizure epilepsy, seizures Status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), and benign familial neonatosis. Seizures, and other epileptic syndromes (severe myoclonic epilepsy in infancy, slow-wave sleep onset) Epilepsy with persistent spike-and-wave seizures, West syndrome, Lennox-Gastaut syndrome, and other conditions. Behavior syndrome and early myoclonic encephalopathy, Ohtahara syndrome, etc., or stress, hormones Changes, drugs (such as amphetamines or cocaine), alcohol, infections, or metabolic disorders Patients suffering from epileptic seizures associated with harm (such as hyponatremia) or those who require treatment. Methods for treating those with Alzheimer's disease, Lewy body dementia, early-onset Huntington's disease, or frontal lobe disease. It is used in the treatment of epileptic symptoms as part of neurodegenerative diseases such as temporal lobar degeneration. A method comprising administering a therapeutically effective amount of the compound of the present invention to a target. .

[0064] The use of the compounds according to the present invention is for focal (partial) epilepsy with simple partial seizures, and complex partial epilepsy. Focal (partial) epilepsy with seizures, idiopathic generalized epilepsy, grand mal seizure epilepsy, status epilepticus neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), and benign familial neonatal seizures. Also, other epileptic syndromes (severe myoclonic epilepsy in infancy, persistent seizures during slow-wave sleep) Epilepsy with spinous slow waves, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome (and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or stress, hormonal changes, Drugs, alcohol, infections, traumatic brain injury, stroke, brain tumors, autism spectrum disorder, etc. Or use in the treatment of epileptic seizures associated with metabolic disorders (such as hyponatremia). Including, or Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, frontotemporal lobar degeneration Used in the treatment of epilepsy as part of neurodegenerative diseases such as Therefore, it is used.

[0065] In other embodiments, the compounds of the present invention are used to treat epilepsy, epileptic syndromes, and epileptic symptoms. Treatment-resistant or refractory epilepsy, or focal (partial) epilepsy with simple partial seizures, complex Focal (partial) epilepsy with partial seizures, idiopathic generalized epilepsy, grand mal seizure epilepsy, epilepsy Status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), and benign familial neonatal syndrome. Seizures, and other epileptic syndromes (severe myoclonic epilepsy in infancy, slow-wave sleep onset) Epilepsy with persistent spike-and-wave seizures, West syndrome, Lennox-Gastaut syndrome, and other conditions. (e.g., Beh syndrome and early myoclonic encephalopathy, Ohtahara syndrome), or stress, hormones Changes in brain function, drugs, alcohol, infections, traumatic brain injury, stroke, brain tumors, autism spectrum disorder For the treatment of epileptic seizures associated with thyroid disorders or metabolic disorders (such as hyponatremia) or Alzheimer's disease, Lewy body dementia, early-onset Huntington's disease, frontotemporal lobar degeneration, etc. To manufacture pharmaceuticals used to treat epileptic symptoms as part of any neurodegenerative disease It is a compound.

[0066] The classification of epilepsy is based on ICD - 10 (published by WHO in 2016) and is described in Sections G40 and G41, and is included in the treatment of epilepsy according to the present invention. G40.0 Local - related (focal) (partial) idiopathic epilepsy and epilepsy syndrome with locally - occurring epileptic seizures G40.1 Local - related (focal) (partial) symptomatic epilepsy and epilepsy syndrome with simple partial seizures G40.2 Local - related (focal) (partial) symptomatic epilepsy and epilepsy syndrome with complex partial seizures G40.3 Idiopathic general epilepsy and epilepsy syndrome G40.4 Other general epilepsy and epilepsy syndrome G40.5 Special epilepsy syndrome G40.6 Grand mal epilepsy, details unknown (with or without petit mal) G40.7 Petit mal, details unknown, without grand mal G40.8 Other epilepsy G40.9 Epilepsy, details unknown G41 Status epilepticus

[0067] Treatment of epileptic seizures An epileptic seizure is a sudden, uncontrolled electrical disorder in the brain. It can cause changes in behavior, movement or emotion, and level of consciousness. When a person has two or more epileptic seizures, or has a tendency to have recurrent epileptic seizures, it is diagnosed as epilepsy. <000091​​​​​​​​​​​

[0069] Focal seizures Focal seizures result from abnormal electrical activity in one area of ​​the brain. Focal seizures are accompanied by consciousness. It can occur without losing consciousness. • Focal seizures accompanied by impaired consciousness. These epileptic seizures involve changes or loss of consciousness or awareness. This includes: The person stares at the space, usually without reacting to the environment, or rubs their hands together, chews. They may perform repetitive movements such as swallowing or walking in circles. • Focal seizures without loss of consciousness. These epileptic seizures may alter emotions, or The person may lose consciousness, but their perception of sight, smell, senses, taste, or hearing may be altered. No. These epileptic seizures are characterized by involuntary spasms of body parts such as arms or legs, and stabbing pain. Spontaneous sensory symptoms such as dizziness and flashes of light may also occur.

[0070] Generalized seizures Epileptic seizures that appear to involve all areas of the brain are called generalized seizures. The following are examples of typical seizures: Absence seizures. Absence seizures, traditionally known as minor seizures, occur most frequently in children. This includes staring into space, or making subtle bodily movements such as blinking or clicking one's lips. These are signs. These epileptic seizures can occur as a single event, and a brief loss of consciousness may occur. It can happen. • Tonic seizures. Tonic seizures cause muscle rigidity. These epileptic seizures usually involve the back, It affects the muscles in the arms and legs. • Atonic seizures. Also known as falling seizures, atonic seizures result in a loss of muscle control. This could cause it to suddenly collapse or fall over. • Clonic seizures. Clonic seizures are characterized by recurrent or rhythmic muscle spasms. These epileptic seizures The seizures usually affect the head, face, and arms. · Myoclonic seizures. Myoclonic seizures usually appear as sudden, brief jerks of the arms and legs or as single contractions. · Tonic-clonic seizures. Tonic-clonic seizures, previously known as grand mal seizures, are the most dramatic type of seizure, involving sudden loss of consciousness, body stiffness and shaking, and sometimes loss of bladder control or tongue biting. Often, seizures are associated with or caused by:

[0071] high fever associated with infections such as meningitis sleep deprivation low blood sodium (hyponatremia) that can occur with diuretic treatment drug applications such as certain analgesics, antidepressants, or smoking cessation treatments that lower the seizure threshold head trauma that causes bleeding areas in the brain stroke brain tumor drugs such as amphetamines or cocaine alcohol and are associated with or caused by these.

[0072] The title and subtitle are used in this specification for convenience only and should in no way be construed as limiting the present invention.

[0073] The use of any examples or exemplary language in this specification (including "for instance", "for example", "e.g.", and " as such") is intended merely to illustrate the present invention better, unless otherwise specified, and does not limit the scope of the present invention.

[0074] The citation and incorporation of patent documents in this specification are for convenience only and There are no opinions regarding the validity, patentability, and / or legal enforceability of such patent documents. The solution is not reflected either.

[0075] The present invention includes all modifications and equivalents of the subject matter referenced in the claims appended herein, as permitted by applicable law. The present invention may include the following embodiments. [1] Equation I [ka] (In the formula, R1 is C 1 ~C 6 Alkyl, CF 3 CH 2 CF 3 , CF 2 CHF 2 、C 3 ~C 8 Selected from the group consisting of cycloalkyls, the C 3 ~C 8 Cycloalkyl is C 1 ~C 3 Alkyl, F, CHF 2 and CF 3 They may be substituted with one or two substituents selected from the group consisting of and R2 is H, C 1 ~C 6 Alkyl or CF 3 is; or R1 and R2 combine to form one or two F and CHF molecules. 2 , or C optionally replaced with CF3 3 ~C 5 Forming cycloalkyl groups; and R3 is C 1 ~C 3 Alkyl or CH 2 OC 1~3 Alkyl, and the C 1 ~C 3 Alkyl or CH 2 OC 1 ~C 3 C≡N, 3F, or C 3 ~C 5 It is an alkyl group substituted with a cycloalkyl group; R4 is OCF 3 , or OCHF 2 A compound selected from the group consisting of the following, or a pharmaceutically acceptable salt of any of these compounds. [2] R4 is OCF 3 or OCHF 2 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [3] R3, CH 2 O-CF 3 CH 2 O-cyclopropyl, CH 2 A compound selected from the group consisting of -C≡N, according to any one of the prior claims, or a pharmaceutically acceptable salt thereof. [4] R1 is one or two C 1 ~C 3 Alkyl, F, CHF 2 or CF 3 C arbitrarily replaced by 3 ~C 4 A cycloalkyl compound as described in any one of the prior claims, or a pharmaceutically acceptable salt thereof. [5] R1 and R2 combine to form cyclobutyl which is optionally substituted with one or two F atoms, and R4 is OCF 3 or OCHF 2 A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof. [6] (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide; or (S)-N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide A compound according to claim 1, selected from the group consisting of the following, or a pharmaceutically acceptable salt of any of these compounds. [7] (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide; (S)-N-(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (S)-3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexaneamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexaneamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide; (S)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide A compound selected from the group consisting of the above, or a pharmaceutically acceptable salt of any of these compounds. [8] A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [9] A method for treating a patient in need of treatment for epilepsy, bipolar disorder, migraine, or schizophrenia, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

[10] A method for treating a patient in need of treatment who suffers from or is in need of treatment for psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity disorder, personality disorders, schizotypal disorders, aggression, chronic pain, neurological disorders, autism spectrum disorder, Huntington's disease, sclerosis, multiple sclerosis, or Alzheimer's disease, comprising administering to the subject a therapeutically effective amount of any compound described in any of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

[11] Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in a therapeutic method.

[12] Use of the compounds according to claims 1 to 7 or pharmaceutically acceptable salts thereof for the treatment of epilepsy, bipolar disorder, migraine, or schizophrenia.

[13] Use of the compounds described in claims 1 to 7 or pharmaceutically acceptable salts thereof for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity disorder, personality disorders, schizotypal disorders, aggression, chronic pain, neurological disorders, autism spectrum disorder, Huntington's disease, sclerosis, multiple sclerosis, and Alzheimer's disease.

[14] A compound according to claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine, or schizophrenia.

[15] A compound according to claims 1 to 7 or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity disorder, personality disorders, schizotypal disorders, aggression, chronic pain, neurological disorders, autism spectrum disorder, Huntington's disease, sclerosis, multiple sclerosis, and Alzheimer's disease.

[16] A compound according to claims 1 to 7 or a pharmaceutically active salt thereof, or a pharmaceutical composition according to claim 16, for use in the treatment of epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures.

[17] A compound or a pharmaceutically active salt thereof, or a pharmaceutical composition, according to claim 16, for use in the treatment of epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or metabolic disorders (such as hyponatremia), for use in the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), and benign familial neonatal seizures, and other epileptic syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with persistent spike-and-wave seizures during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy, Ohtahara syndrome, etc.).

[18] A compound according to claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, and frontotemporal lobar degeneration.

[19] A method for treating a patient who is suffering from or in need of epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

[20] Focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), and benign familial neonatal seizures, and other epileptic syndromes (severe myoclonic epilepsy in infancy, epilepsy with persistent spike-and-wave seizures during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy, Ohtahara syndrome, etc., or stress, hormonal changes, drugs, A method for treating patients who are in need of treatment for epileptic seizures associated with alcohol, infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or metabolic disorders (such as hyponatremia), or for use in the treatment of epileptic symptoms as part of a neurodegenerative disease such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, or frontotemporal lobar degeneration, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

[21] Use of the compounds according to claims 1 to 7 or pharmaceutically acceptable salts thereof for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures.

[22] Use of the compounds described in claims 1 to 7 or pharmaceutically acceptable salts thereof for use in the treatment of epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infections, or metabolic disorders (such as hyponatremia), or for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, frontotemporal dementia, and other epileptic syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with persistent spike-and-wave seizures during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy, Ohtahara syndrome), or stress, hormonal changes, drugs, alcohol, infections, or metabolic disorders (such as hyponatremia, or for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, and frontotemporal lobar degeneration).

[23] Compounds according to claims 1 to 7, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures.

[24] Compounds according to claims 1 to 7, or pharmaceutically acceptable salts thereof, for the manufacture of drugs for use in the manufacture of drugs for focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), benign familial neonatal seizures, and other epilepsy syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with persistent spike-and-wave seizures during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, and frontotemporal lobar degeneration.

[0076] Experiment section Biological evaluation: Cell culture The P2A sequence codes encoding human Kv7.3 and human Kv7.2. The resulting cDNA fragment was processed using the BamHI and XhoI restriction sites for pcDNA5 / FRT / T It was inserted into an O vector. Subsequently, the structure was modified using Lipofectamine2000. HEK Flp-In was transfected into 293 cells. The cells were placed in DMEM containing 10% (v / v) FBS and 1% PenStrep. After growing for 48 hours, the cells were incubated in humid air at 37°C and 5% CO2 with 10% (v / v) F Contains BS, 1% PenStrep, and 200 μg / mL Hygromycin B. The selected state was maintained within the available DMEM. The obtained stable hKv7.2 / hKv7. Three cell lines (HEK-hKv7.2 / hKv7.3) were subjected to automated whole-cell patch clamp testing. When tested, it is sensitive to XE991 and enhanced by retigabine. It showed a typical Kv7 current.

[0077] Thallium inflow assay FLIPR Potassium Assay Kit (Molecular Devi Using the published procedure (CDWeaver, et al., J Bio), Potassium channels (similar to mol Screen 2004,9,671-677) An activation thallium influx assay was performed on HEK-hKv7.2 / hKv7.3 cells. , 96-well culture dish with black walls and a transparent bottom (Corning, Acton, MA, US A) If the cells are assayed the following day, use 80,000 cells / well (100 μl). The density (per well), or 40,000 cells if the assay is performed 2 days after seeding. Seeds were sown at a density of 100 μl / well.

[0078] On the day of the assay, the medium was removed, and then the sample was placed in HBSS containing 20 mM HEPES. 50 μL / well of the test compound diluted to twice the final concentration and 50 μL / well of the 2-fold dye loading buffer were added. Subsequently, the cells were incubated for 60 minutes in the dark at room temperature. Chloride-free stimulation buffer containing 5-fold the final concentration of Tl and K + (5-fold concentration: 5 mM in both cases) and the test compound at 1-fold the final concentration were prepared during the incubation. Subsequently, the cells were assayed in the FDSS7000EX Functional Drug Screening System (Hamamatsu). Following baseline fluorescence signal readings for 60 seconds at 0.1 Hz and 10 seconds at 1 Hz, 25 μL / well of the stimulation buffer was added, and the fluorescence was measured continuously for 50 seconds at 1 Hz and then for 4 minutes at 0.1 Hz. The effect of the compound was quantified using AUC as the readout and normalized to the reference compound included on each plate. + (5-fold concentration: 5 mM in both cases) was included in the chloride-free stimulation buffer, and the test compound at 1-fold the final concentration was prepared during the incubation. Subsequently, the cells were assayed in the FDSS7000EX Functional Drug Screening System (Hamamatsu). Following baseline fluorescence signal readings for 60 seconds at 0.1 Hz and 10 seconds at 1 Hz, 25 μL / well of the stimulation buffer was added, and the fluorescence was measured continuously for 50 seconds at 1 Hz and then for 4 minutes at 0.1 Hz. The effect of the compound was quantified using AUC as the readout and normalized to the reference compound included on each plate. to the FDSS7000EX Functional Drug S creening System (Hamamatsu). After baseline fluorescence signal readings for 60 seconds at 0.1 Hz and 10 seconds at 1 Hz, 25 μL / well of the stimulation buffer was added, and the fluorescence was measured continuously for 50 seconds at 1 Hz and then for 4 minutes at 0.1 Hz. The effect of the compound was quantified using AUC as the readout and normalized to the reference compound included on each plate. at 0.1 Hz for 60 seconds and at 1 Hz for 10 seconds, 25 μL / well of the stimulation buffer was added, and the fluorescence was measured continuously for 50 seconds at 1 Hz and then for 4 minutes at 0.1 Hz. The effect of the compound was quantified using AUC as the readout and normalized to the reference compound included on each plate. [[ID=1--9]] in the chloride-free stimulation buffer, and the test compound at 1-fold the final concentration was prepared during the incubation. Subsequently, the cells were assayed in the FDSS7000EX Functional Drug Screening System (Hamamatsu). After baseline fluorescence signal readings for 60 seconds at 0.1 Hz and 10 seconds at 1 Hz, 25 μL / well of the stimulation buffer was added, and the fluorescence was measured continuously for 50 seconds at [[ID=11--18]] 1 Hz and then for 4 minutes at 0.1 Hz. The effect of the compound was quantified using AUC as the readout and normalized to the reference compound included on each plate. using AUC as the readout and normalized to the reference compound included on each plate.

[0079] Effect of the compound In the assay described above, the compounds of the present invention had the following biological activities.

[0080] [[ID=-----]]

Table 1

[0081]

Table 2

[0082] Synthesis of the compounds of the present invention: General method: The general procedure for the synthesis of the intermediates and compounds of general formula I is described in Reaction Scheme 1 and is specifically exemplified in the preparation section and the examples. Variations known to those skilled in the art of the procedures described are also within the scope of the present invention. to the preparation section and the examples. Variations known to those skilled in the art of the procedures described are also within the scope of the present invention. It falls within the scope of "brightness".

[0083] The compounds of the present invention are prepared as described in Scheme 1. Among the compounds of general formula I The compound contains two chiral carbon atoms and is formed as a mixture of diastereomers. In this case, the diastereomers can be separated to obtain single stereoisomers Ia and Ib. can.

[0084] Scheme 1 [ka] Scheme I shows the preparation of compounds of general formula I by two general routes. The first route is , via methods well known in the art for converting acids and amines to amides, Compounds of formula I are obtained by the reaction of an enantiomerically pure amine of formula II with an acid of general formula III. This is a synthesis. This method involves activated esters and reactive mixed anhydrides, but these... A reactive derivative of an acid of formula III (not limited to) is formed, followed by condensation with an amine of general formula II. This includes the following: One such method involves using a solvent such as dichloromethane (DCM), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] Pyridinium 3-oxide hexafluorophosphate (HATU) and diisopropyl The condensation is carried out in the presence of a suitable base such as ethylamine (DIPEA).

[0085] Alternatively, R 2 If is H, the compound of general formula I is prepared via the second general route. This can be done, and here the intermediate of general formula V can be NaB in a suitable solvent such as methanol. It is treated with a suitable reducing agent such as H4. The intermediate of formula V is an enantiomer of the general formula II. It can be obtained from pure amines and carboxylic acids of general formula IV (R=H). This conversion The reaction strips for condensing II and III to form I are similar to those described above. This can be achieved using [the item].

[0086] A variation of this procedure involves a chiral amine of general formula II and a carboxylic acid ester of general formula IV. This is a direct coupling reaction (R=Me, Et). This reaction is suitable for DIPEA and other suitable compounds. In the presence of a base and a catalytic amount of a suitable catalyst such as 4-dimethylaminopyridine (DMAP), The reaction is carried out by heating the reactants under reflux in a suitable solvent such as toluene in the presence of a medium. It is possible.

[0087] Optically active amines of general formula II can be prepared as outlined in scheme 2a. Cut. Scheme 2a [ka] Aldehydes of general formula VI are desiccants such as titanium(IV) isopropoxide or copper sulfate. In the presence of (R)-2-methylpropane-2-s in a suitable solvent such as dichloroethane, It can be condensed with sulfinamide. The formed sulfinylimine XV is TH In a suitable inert solvent such as F, R 3 Processed with MgBr, and the corresponding substitution (R)- 2-Methyl-N-((S)-1-aryl-alkyl)propan-2-sulfinamide (VII) is obtained and treated with a suitable acid in a suitable solvent such as HCl in MeOH. This converts it to a compound of general formula II.

[0088] In a modified form of this procedure, R having a functional group3 The substituents are further used by chemists in the field of this art. It can be modified by known standard functional group transformation methodologies. An example of the operation is shown in Scheme 2b. General formula VII (where R 3 (= an allele) intermediate Form from XV and allyl-MgBr, and in a suitable solvent such as ethyl acetate, Pd / C etc. Using H2(g) in the presence of a suitable catalyst, R 3 =Catalytic reduction to n-propyl This can be done. Alternatively, in the presence of a suitable base such as 2,6-lutidine, Furthermore, in a suitable solvent such as dioxane / H2O, suitable solvents such as K2OsO4 and NaIO4 By treating with a suitable catalyst, the general formula VII (wherein R) 3 (= an allele) intermediate It is subjected to dihydroxylation, followed by oxidative cleavage, R 3 =Acetaldehyde Intermixture VII is obtained. The resulting aldehyde can be further converted; for example, to a suitable DCM. By treating with a suitable reagent such as diethylaminosulfur trifluoride (DAST) in a solvent, Then, it is subjected to oxygen exchange for two fluorine atoms. In the final step, the chiral amine It can be obtained by the hydrolysis described above.

[0089] As another embodiment, general formula XVI (wherein R 3 The intermediate is CuCl and (is acetic acid). Ethyl 2-bromoacetate in a suitable solvent such as THF in the presence of activated Zn It can be formed from XV in the reaction with [another substance]. By transformation known to chemists in the art The ester group can be further derivatized. For example, in a suitable solvent such as THF. By treating it with a suitable reducing agent such as LiAlH4, the ester can be converted to a primary aluminum alloy. It can be reduced to kohl. The resulting alcohol can also be converted by a method known to those skilled in the art. And it can be further derivatized. For example, an alcohol can be derivatized in a suitable solvent such as DCM. Activated with a reagent such as mesyl chloride in the presence of a suitable base such as ethylamine (TEA). This can be converted into a leaving group. The resulting mesylate can be processed into an appropriate form such as DMSO. It can be reacted with a suitable nucleophile such as potassium cyanide in a solvent.

[0090] Scheme 2b: [ka]

[0091] Aldehydes of general formula VI can also be categorized into general formula I by alternative means, as shown in scheme 2c. It can be converted to a chiral amine of I. Scheme 2c: [ka] Following this procedure, using the Wittig methodology known to chemists in the art, appropriately The substituted benzaldehyde VI is converted to the corresponding appropriately substituted styrene. These intermediates can be subjected to alkylation-oxidation reactions to form keto intermediate XVI. I can be formed. The intermediate of general formula XVII can be formed in a suitable solvent such as dichloroethane. In the presence of a suitable desiccant such as titanium(IV) ethoxide, (R)-2-methylpropane It can condense with n-2-sulfinamide. The resulting sulfinylimine is In a suitable inert solvent such as THF, suitable solvents such as L-selectride Reduced with a suitable reducing agent, the corresponding appropriately substituted (R)-2-methyl-N-((S) -1-aryl-alkyl)propan-2-sulfinamide is formed in MeOH By treating with an appropriate acid in a suitable solvent such as HCl, the chiral ammonium compound of general formula II can be obtained. It can be converted into n.

[0092] Those skilled in the art will know that other transformations are possible from each of the intermediates; the present invention provides for such alternative transformations It should be recognized that this is intended to include...

[0093] The aldehyde of formula VI used to prepare the compound of the present invention is commercially available, or It can also be prepared as described in the literature (Journal of Medici See nal Chemistry, 45(18), 3891-3904; 2002. sea ​​bream).

[0094] In other procedures, reagents such as L-selectlide are used as shown in scheme 3a. The intermediate sulf obtained from the reaction with (R)-2-methylpropane-2-sulfinamide By the hydride reduction of ynylimines, the chiral amine of formula II is obtained from aryl ketones. It is possible.

[0095] Scheme 3a [ka] A variation of this procedure is shown in scheme 3b. In this procedure, a further ether is added. R 3 The substituents are typical α-brominates obtained by the bromination of appropriately substituted acetophenone. It is incorporated from moacetophenone intermediate XI. Examples include, but are not limited to, R 3 year One example is the introduction of a fluoroalkylmethylene ether group. Therefore, this methodology Using Finkelstein conditions, dimethylacet In a suitable solvent such as an amide (DMA), appropriately substituted bromoacetophenone is thawed. Fluoromethyltrifluoromethanesulfonate and fluoroalkoxy donors such as KF By reacting it with the body, intermediate XII is obtained, and as described above, it is further converted into a chiral amine. It can be replaced. Other examples include, but are not limited to, R 3 Alkylmethylene as One possible method is the introduction of ether. Therefore, the appropriately substituted bromoacetophenone is A suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) In the presence of and in a suitable solvent such as THF, 4-methyl-N'-(p-trisulfone By reacting with nyl)benzenesulfonohydrazide, acyldiazo intermediate XI is produced. It can be converted to II. Intermediate XIII can be converted in a suitable solvent such as toluene. By treating with a suitable solvent such as cindium triflate, the carbene formation reaction can be carried out. It is possible. The formed carbene can be captured in situ by the appropriate alcohol. , alkoxykete intermediate XIV may be formed. From intermediate XIV, the chiral amine of formula II can be formed. n is obtained by the standard operation described above.

[0096] Scheme 3b: [ka] The appropriately substituted ketones or acetophenones used in the production of the compounds of the present invention are, It can be sold or manufactured by methods known to those skilled in the art.

[0097] Those skilled in the art will know that other transformations are possible from intermediates of general formula XI, and that the present invention provides for such alternative transformations It will be recognized that the intention is to include exchange.

[0098] General formula II (wherein, R 3 Other suitable procedures for obtaining chiral amines (which are ethers) This will be outlined in Scheme 4. Scheme 4: [ka] In this procedure, as described in Japanese Patent Publication No. 2017-095366, the Grio During the condensation reaction between xylic acid ester and (R)-2-methylpropane-2-sulfinamide The sulfinylimine glyoxylate formed therein is used in a suitable solvent such as dioxane. Bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoro It can be reacted with a suitably substituted boronic acid using a suitable catalyst such as borate. The obtained intermediate VIII is hydrolyzed and a suitable protecting group such as Boc is added under standard conditions. Reprotect and subject to esterification reduction under appropriate conditions such as LiAlH4 in THF, generally An alcohol intermediate of formula IX can be obtained. The intermediate of formula IX can be further derivatized to obtain the desired Target R 3 A substituent can be obtained. For example, the alcohol group in intermediate IX is acetate. Under conditions such as CuI activation in a suitable solvent such as tonitrile, 2,2-difluoro- It can be difluoromethylated using a suitable reagent such as 2-(fluorosulfonyl)acetic acid. Alternatively, the alcohol group in IX is THF in the presence of a suitable base such as NaH. In any suitable solvent, use simple alkyl halides such as methyl iodide It can be converted to DCM in the presence of a suitable base such as TEA. Intermediate IX can be produced by activating it in a suitable solvent using a reagent such as mesyl chloride. The alcohol can be converted into a leaving group. The resulting mesylate can be treated with appropriate solvents such as DMSO. It can be reacted with a suitable nucleophile, such as potassium cyanide, in a solvent.

[0099] Those skilled in the art will acknowledge that other transformations are also possible from the intermediates of general formula IX. This invention is intended to encompass such alternative transformations.

[0100] Carboxylic acids of general formula III can be prepared as outlined in Scheme 5. . Scheme 5 [ka] Ketones of general formula X are, for example, alkali of bromoacetic acid activated with Zn and iodine. It reacts with chyl esters to produce the corresponding aldol adducts. In alternative procedures... Bromoacetate esters are activated using Zn and TMSCl (trimethylsilyl chloride). This can be done. In the final step, the hydrolysis of the alkyl ester is carried out in a suitable solvent such as water. Then, treat with a suitable base such as NaOH or LiOH, or with alcohol in water. This is achieved by subsequently acidifying the compound with a suitable acid to obtain the compound of formula III.

[0101] Carboxylate esters of general formula IV (R=Me, Et) are commercially available, or scheme It can be manufactured as outlined in section 6. Scheme 6 [ka] The appropriately substituted carboxylic acid is activated using a suitable reagent such as CDI, and MgCl In the presence of 2, it condenses with potassium 3-ethoxy-3-oxo-propanoate, generally An intermediate of equation IV can be obtained.

[0102] Using a Bruker Avance III400 instrument at 400.13MHz, or Br Using a uker Avance300 device at 300.13MHz, 1 H NMR spectrum This was recorded. Dimethyl sulfoxide deuterated or chloroform deuterated was used as the solvent. Tetramethylsilane was used as the internal reference standard. The chemical shift values ​​were obtained from tetramethylsilane. It is expressed as a ppm value relative to the run. The following abbreviations are used in relation to the multiplicity of NMR signals. There are: s=singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=septet , dd=double doublet, ddd=double doublet, dt=double triplet, dq=double quartet, tt = triple triplet, m = multiplet, and brs = broad singlet.

[0103] For evaluating chemical purity (LCMS method) and chiral purity (SFC and HPLC method) The chromatographic system and method are described below.

[0104] LCMS Method 1: Apparatus: Agilent 1200 LCMS system equipped with ELS detector .

[0105] [Table 3]

[0106] LCMS Method 2: Equipment: Agilent 1200 LCMS system with ELS detector .

[0107] [Table 4]

[0108] LCMS Method 3: Equipment: Agilent 1200 LCMS system with ELS detector .

[0109] [Table 5]

[0110] LCMS Method 4: Apparatus: Shimadzu LC20ADXR LC with ESI detector MS system.

[0111] [Table 6]

[0112] Chiral analysis method: SFC method 1: Equipment: Waters UPC2

[0113] [Table 7]

[0114] SFC method 2: Equipment: Agilent 1260

[0115] [Table 8]

[0116] SFC method 3: Equipment: Agilent 1260

[0117] [Table 9]

[0118] SFC Method 4: Device: Agilent 1260

[0119] Table 10

[0120] SFC Method 5: Device: Agilent 1260

[0121] Table 11

[0122] SFC Method 6: Device: Agilent 1260

[0123] Table 12

[0124] SFC Method 7: Device: Waters UPC2

[0125] Table 13

[0126] SFC Method 8: Device: Waters UPC2

[0127] Table 14

[0128] SFC Method 9: Device: Waters UPC2

[0129] Table 15

[0130] SFC Method 10: Device: Agilent 1260

[0131] Table 16

[0132] SFC Method 11: Device: Agilent 1260

[0133] Table 17

[0134] SFC Method 12: Device: Waters UPC2

[0135] Table 18

[0136] SFC Method 13: Device: Waters UPC2

[0137] Table 19

[0138] SFC Method 14: Device: Waters UPC2

[0139] Table 20

[0140] SFC Method 15: Device: Waters UPC2

[0141] Table 21

[0142] SFC Method 16: Device: Waters UPC2

[0143] Table 22

[0144] SFC Method 17: Device: Waters UPC2

[0145] Table 23

[0146] SFC Method 18: Device: Agilent

[0147] Table 24

[0148] SFC Method 19: Device: Agilent

[0149] Table 25

[0150] SFC Method 20: Device: Waters UPC2

[0151] Table 26

[0152] SFC Method 21: Device: Waters UPC2

[0153] Table 27

[0154] SFC Method 22: Apparatus: Agilent 1260

[0155] Table 28

[0156] Korra HPLC method 1: Apparatus: SHIMADZU LC-20AB

[0157] [Table 29]

[0158] Chiral HPLC method 2: Apparatus: SHIMADZU LC-20AB

[0159] [Table 30]

[0160] Chiral HPLC method 3: Apparatus: SHIMADZU LC-20AB

[0161] [Table 31]

[0162] Chiral HPLC method 4: Apparatus: SHIMADZU LC-20AB

[0163] [Table 32]

[0164] Preparation of intermediates: IIb:((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Phenyl)ethane-1-amine [ka] Step 1: Preparation of ethyl 2-[(R)-tert-butylsulfinyl]iminoacetate [ka] Ethyl 2-oxoacetate (7.5g, 36.7mmol) in DCM (150mL) ) and (R)-2-methylpropane-2-sulfinamide (4.9g, 40.4 mmol) Add CuSO4 (12.9g, 80.8mmol) to the solution with ) and reaction mixture 2 The mixture was stirred at 5°C for 24 hours. The solids were filtered off and washed with ethyl acetate (50 mL) to obtain the organic phase. The mixture was concentrated using a combination of these. The resulting residue was then subjected to column chromatography (silica gel, petroleum ester). The solution was purified by ethyl acetate (5 / 1) to obtain the desired product (5.1 g, yield 6). 7.6%).

[0165] Step 2: Ethyl(2R)-2-[[(R)-tert-butylsulfinyl]amino]- Preparation of 2-[3-(trifluoromethoxy)phenyl]acetate [ka] Ethyl-2-[(R)-tert-butylsulfinyl in dioxane (100 mL) [Iminoacetate (7g, 34.1mmol) and [3-(trifluoromethoxy)phenate In a solution with [nylboronic acid (8.4g, 40.9mmol)], add [Rh(COD)(MeC Add N)2]BF4 (1.3g, 3.4 mmol) and incubate the mixture at 80°C for 16 hours. The mixture was stirred. The product was analyzed by silica gel chromatography (petroleum ether:ethyl acetate = 5:1). After purification, 9.8 g (78%) was obtained.

[0166] Step 3: Ethyl(2R)-2-amino-2-[3-(trifluoro-methoxy)phenyl Preparation of acetate hydrochloride [ka] Ethyl (2R)-2-[[(R)-tert-butylsulfate in MeOH (100 mL) [Phenyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate (9. To a solution of 8g (26.7 mmol), add HCl / MeOH (4M, 100mL). This mixture is stirred at 25°C for 2 hours, then concentrated to obtain ethyl(2R)-2-amino-2 -[3-(trifluoromethoxy)phenyl]acetate (7.8 g, crude product) was obtained.

[0167] Step 4: Ethyl(R)-2-((tert-butoxycarbonyl)amino)-2-(3- Preparation of (difluoromethoxy)phenyl)acetate [ka] Ethyl (2R)-2-amino-2-[3-(trifluoromethyl)methyl ester in THF (150 mL) A mixture of toxy)phenyl acetate hydrochloride (6g) and Boc2O (8.7g) NaHCO3 (1.7g) was added and stirred at 25°C for 16 hours. The mixture was concentrated and silicified. Purified by chromatography (petroleum ether:ethyl acetate = 10:1) and produced I obtained something (7.2g).

[0168] Step 5: tert-butyl(R)-(1-(3-(difluoromethoxy)phenyl)-2 Preparation of hydroxyethyl carbamates [ka] To a suspension of LiAlH4 (1.7g) in THF (200mL), add TH while keeping it cold. (R)-2-((tert-butoxycarbonyl)amino)-2-( 3-(difluoromethoxy)phenyl)acetate (4g) was added. The reaction was carried out at 25°C. The mixture was heated and stirred for 2 hours. Anhydrous magnesium sulfate was added, followed by a drop of water and ethyl acetate. The following substances were added in succession. Insoluble substances were filtered by passing the mixture through a Celite pad. The filtrate was concentrated and then processed. Refined by chromatography on Rica (petroleum ether:ethyl acetate = 5:1) (2 (0.1g).

[0169] Step 6: tert-butyl(R)-(2-(difluoromethoxy)-1-(3-(trif Preparation of oromethoxyphenyl ethyl carbamate [ka] tert-butyl(R)-(1-(3-(difluoromethoxy) in MeCN (20 mL) In a solution of (1.5g) phenyl-2-hydroxyethyl carbamate, CuI( 360 mg was added and stirred at 25°C under an N2 atmosphere for 30 minutes. Subsequently, MeCN A solution of 2,2-difluoro-2-fluorosulfonylacetic acid (1.7g) in 5mL The mixture was added over 30 minutes at 45°C, and the reaction was stirred at 45°C for 1 hour. Then, the mixture was diluted with ethyl acetate (100 mL), filtered, and concentrated to obtain the desired product. (1.5g, crude product).

[0170] Step 7: (R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Preparation of phenyl)ethane-1-amine [ka] tert-butyl(R)-(2-(difluoromethoxy)- in MeOH (15 mL) Dissolve 1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1.5g) Add HCl / MeOH (4M in MeOH, 30 mL) to the solution at 25°C and proceed with the reaction at 25°C. The mixture was stirred for 30 minutes. Ammonium hydroxide (30%) was added to adjust the pH to 9, and this solution was then prepared. The solution is concentrated and chromatographed on silica (petroleum ether:ethyl acetate = 2:1) Purified, (R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) 700 mg of phenyl)ethane-1-amine was obtained.

[0171] IIa:(R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)fe Nyl)ethane-1-amine hydrochloride [ka] Prepared using appropriate reagents as described for IIb.

[0172] IIc:(R)-2-Cyclopropoxy-1-(3-(difluoromethoxy)phenyl) Ethane-1-amine hydrochloride [ka] Step 1: Preparation of 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydrazide [ka] 4-methylbenzenesulfonhydrazide (70g) and 4-methylbenzenesulfonyl DCM (400 mL) was added to a mixture of loride (93 g). The mixture was then cooled to 0°C. Instead, pyridine (38.65g) was added drop by drop, and the reaction mixture was left at 0°C for 1 hour, then at 20°C. The mixture was stirred for 7 hours. Water (200 mL) and methyl-tert-butyl ether ( METB (200 mL) was added and filtered. The filtered cake was then put METB (200 mL) Wash and dry, then 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydr I obtained radid (125g). 1 H NMR(DMSO-d6 400MHz):δ9.55(s,2H),7.61( d,4H), 7.35(d,4H), 2.36(s,6H).

[0173] Step 2: 2-bromo-1-(3-(difluoromethoxy)phenyl)ethane-1-one preparation [ka] 1-[3-(difluoromethoxy)phenyl]ethanone in dioxane (100 mL) To the (10g) solution, add the solution of Br2 (8.58g) in dioxane (100mL). The resulting mixture was stirred at 20°C for 2 hours. (50 mL of saturated NaHCO3 aqueous solution) H2O (100 mL) was added, and the aqueous phase was extracted with SiO2O (200 mL x 2). The organic phase was washed with brine (200 mL), dried with Na2SO4, concentrated, and 2-brine. Romo-1-[3-(difluoromethoxy)phenyl]ethanone (17g) was obtained. 1 H NMR(CDCl3400MHz):δ7.81(d,1H),7.72(s, 1H),7.49(t,1H),7.37(d,1H),6.56(t,1H),4.4 1(s,2H).

[0174] Step 3: 1-(3-(difluoromethoxy)phenyl)-2-iminoethane-1-one preparation [ka] 2-bromo-1-[3-(difluoromethoxy)phenyl] in THF (100 mL) Ethanone (5.6g) and 4-methyl-N'-(p-trisulfonyl)benzenesulfon To a solution of hydrazide (11.51 g), add DBU (12.87 g) drop by drop at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then at 20°C for 4 hours. Saturated aqueous solution of NaHCO3 (2 Quench the mixture with 00 mL, dilute with water (200 mL), then acetyl (20 mL) Extraction was performed using 0 mL x 2. The organic layer was washed with brine (100 mL) and dried with Na2SO4. The crude product was dried and concentrated. The crude product was subjected to column chromatography on silica gel (20 in petroleum ether). Purified by % HCl, 1-(3-(difluoromethoxy)phenyl)-2-I Minoethane-1-one (6.4g) was obtained. 1 H NMR(CDCl3,400MHz):δ7.57(dt,1H),7.55(s ,1H),7.46(t,1H),7.31(dd,1H),6.56(t,1H),5 .90 (s, 1H).

[0175] Step 4: 2-Cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethane- 1-ON preparation [ka] Cyclopropanol (1.75 g) and 2-diazo-1-[ in toluene (50 mL) In a solution of 3-(difluoromethoxy)phenyl]ethanone (3.2g), indium (I II) Triflate (1.7 g) was added under N2 conditions. The resulting mixture was incubated at 20°C for 16 minutes. The mixture was stirred for a certain amount of time. The mixture was quenched with a saturated aqueous solution of NaHCO3 (100 mL) and H2O( Diluted with 50 mL, then extracted with ethyl(100 × 2). The organic layer was brined ( Washed with 200 mL x 2, dried with Na2SO4, and concentrated. The crude product was placed on silica gel. Purified by column chromatography (5% HCl in petroleum ether), and 2-cyclo Propoxy-1-(3-(difluoromethoxy)phenyl)ethane-1-one (6.1g) ) was obtained. 1 H NMR(CDCl3,400MHz):δ7.76(d,1H),7.68(s, 1H),7.47(t,1H),7.34(d,1H),6.55(t,1H),4.7 4(s,1H),3.55-3.50(m,1H),0.70-0.66(m,2H), 0.53-0.49 (m, 2H).

[0176] Step 5: (R,Z)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy) Preparation of phenyl(ethylidene)-2-methylpropane-2-sulfinamide [ka] 2-(cyclopropoxy)-1-[3-(difluoromethoxy) in THF (100 mL) (C)phenyl]ethanone (6.1g) and (R)-2-methylpropane-2-sulfine Ti(OEt)4 (11.5g) was added to a solution of amide (4.6g). The mixture was stirred at 60°C for 8 hours and then used directly in the next step.

[0177] Step 6: (R)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy Preparation of phenylethyl-2-methylpropane-2-sulfinamide [ka] (R,Z)-N-(2-cyclopropoxy- 1-(3-(difluoromethoxy)phenyl)ethylidene)-2-methylpropane-2- Add a solution of L-selectlide (1 M in THF, 50.36 mL) to a sulfinamide solution. ) was added dropwise at -45°C. The mixture was stirred at -45°C for 1 hour and MeOH(10 Quenched with 0 mL of H2O (100 mL) and filtered on Celite. The filtrate was EtO Extract with Ac (200 mL x 2), wash the organic layer with brine (200 mL x 2), and then Na The crude product was dried with 2SO4 and concentrated. The crude product was then subjected to column chromatography (petroleum fluoride) on silica gel. Purified by 30-50% ethyl acetate in a methyl group, (R)-N-((R)-2-cyclo Propoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane 2.4 g of 2-2-sulfinamide was obtained.

[0178] Step 7: (R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl) Preparation of ethane-1-amine hydrochloride [ka] (R)-N-((R)-2-cyclopropoxy-1-(3- (Difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide To a solution of (0.46 g) of HCl / MeOH (10 mL) was added. The resulting mixture Stir at 20°C for 1 hour, concentrate, and (1R)-2-(cyclopropoxy)-1-[3- (Difluoromethoxy)phenyl]ethanamine hydrochloride (0.46 g, crude product) was obtained.

[0179] IId:(R)-2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl ) Ethane-1-amine hydrochloride [ka] Using 1-[3-(trifluoromethoxy)phenyl]ethanone as a starting material, Preparation for IIc was carried out as described.

[0180] IIe:(R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxyphenyl) Toxy)ethane-1-amine hydrochloride [ka] Step 1: Preparation of 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone [ka] 1-[3-(difluoromethoxy)phenyl]ethanone in dioxane (50 mL) To the solution of 5g of dioxane, add the solution of Br2 (4.29g) in 50mL of dioxane at 20°C. It was added. This mixture was stirred at 20°C for 1 hour, diluted with toluene (200 mL), and water. Washed with (100 mL x 3). The organic phase was dried with anhydrous Na2SO4 and concentrated. Residual A chromatographic column on silica gel (petroleum ether: SiO₂ = 10:1) Purified by 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone ( 5g was obtained.

[0181] Step 2: 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy) Preparation of ethane-1-one [ka] A solution of KF (712 mg) in DMA (20 mL) is mixed with trifluoromethyltrifluoride. Lomethanesulfonate (4.11 g) was added at 0°C. The reaction mixture was stored in a sealed tube. Stir for 1 hour, then 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanol Add 2.5g (9.43 mmol) and KI (157 mg) to this solution at 0°C. The mixture was stirred for 16 hours at 20°C. Diluted the mixture with EtAOc (100 mL) and water (5 The solution was washed with 0 mL x 3. The organic phase was concentrated to obtain the product, which was then subjected to acidic preparative HPLC. It was purified (1.4g). 1 H NMR(CDCl3400MHz):δ7.72(d,1H),7.66(s, 1H),7.51(t,1H),7.40(d,1H),6.56(t1H),5.13 (s, 2H). 19FNMR(CDCl3400MHz):δ-61.11,-81.52,-81. 71.

[0182] Step 3: (R)-N-(1-(3-(difluoromethoxy)phenyl)-2-(triflu Preparation of Olomethoxy)ethylidene)-2-methylpropane-2-sulfinamide [ka] 1-(3-(difluoromethoxy)phenyl)-2-(trif) in THF (50 mL) Luoromethoxy)ethane-1-one (900mg), (R)-2-methylpropane-2- Mixture of sulfinamide (606 mg) and Ti(OEt)4 (2.28 g) at 60°C The mixture was stirred under N2 for 16 hours. The product (1.2 g, crude) in THF (70 mL) was then... They obtained it and used it directly in the next step.

[0183] Step 4: (R)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-( Preparation of trifluoromethoxy(ethyl)-2-methylpropane-2-sulfinamide [ka] (R)-N-(1-(3-(difluoromethoxy)phenyl) in THF (70 mL) -2-(trifluoromethoxy)ethylidene)-2-methylpropane-2-sulfin Add L-selectride (1M in THF, 3.86mL) to a solution of mid (1.2g) -6 The mixture was added at 0°C. The mixture was stirred at -60°C for 0.5 hours, then toluene (100 mL) Diluted with ( ) and washed with water (50 mL x 3). The organic phase was dried, filtered, and concentrated. Crude The product was analyzed by chromatography on silica gel (petroleum ether / ethyl acetate = 5:1). (R)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2- (Trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide (60 0 mg was obtained. 1 H NMR(CDCl3400MHz):δ7.37(t,1H),7.20(d, 1H),7.12-7.09(m,2H),6.50(t,1H),4.75-4.72 (m,1H),4.20-4.16(m,1H),4.14-4.05(m,1H),3 .87 (s, 1H), 1.21 (s, 9H).

[0184] Step 5: (R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethyl) Preparation of Toxy)ethane-1-amine hydrochloride [ka] (R)-N-((R)-1-(3-(difluoromethoxy) in MeOH (10 mL) Phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulf In a solution of vinamide (600 mg), add HCl / MeOH (4M in MeOH, 8.0 mL). The following was added. This mixture was stirred at 15°C for 1 hour, then concentrated to ((R)-1-(3 -(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethane-1-amine We obtained 500 mg of hydroxypropyl hydrochloride (crude product). 1 H NMR(CDCl3400MHz):δ9.17(s,3H),7.40-7. 31(m,4H),6.55(t,1H),4.58(s,1H),4.46-4.42 (m,1H), 4.33-4.29(m,1H).

[0185] IIf:(R)-2-(trifluoromethoxy)-1-(3-(trifluoromethoxy) Phenyl)ethane-1-amine hydrochloride [ka] Using 1-[3-(trifluoromethoxy)phenyl]ethanone as a starting material, It was prepared as described for IIe. 1 H NMR(CDCl3400MHz):δ9.18(s,3H),7.19-7. 47(m,1H),7.19-7.38(m,2H),7.27(s,1H),4.65 (s,1H),4.47-4.42(m,1H),4.32-4.30(m,1H).

[0186] IIg: (S)-1-(3-(difluoromethoxy)phenyl)butane-1-amine hydrochloride salt [ka] Step 1: (R)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane Preparation of n-2-sulfinamide [ka] 3-(difluoromethoxy)benzaldehyde (3g) and in DCE (120mL) (R)-2-methylpropane-2-sulfinamide (2.54g) is dissolved in CuSO4. 4 (13.91 g) was added. The mixture was stirred at 55°C for 16 hours. The reaction mixture was filtered. The filtrate was concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate) was performed. The residue was purified using a ratio of 100 / 1 to 10:1 to obtain the product (3g).

[0187] Step 2: (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)buto-3 Preparation of -en-1-yl)-2-methylpropan-2-sulfinamide [ka] (R)-N-(3-(difluoromethoxy)benzylidene)- in DCM (40 mL) A solution of 2-methylpropan-2-sulfinamide (1 g) is mixed with allyl in THF at 0°C. (Bromo)magnesium (1M solution in THF, 10.9 mL) was slowly added. The resulting mixture was stirred at 0°C for 1 hour and then at 25°C for 2 hours. Saturated NH4Cl(10) at 0°C Add (mL) and quench the reaction mixture, dilute with H2O (50mL), and DCM (4 Extraction was performed using 0 mL x 3. The combined organic phase was washed with H2O (40 mL) and Na2SO4 It was dried, filtered, and concentrated. Column chromatography (SiO2, petroleum ether / The residue is purified with ethyl acetate (100 / 1~1:2), and (R)-N-((S)-1 -(3-(difluoromethoxy)phenyl)buto-3-en-1-yl)-2-methylpropyl Ropan-2-sulfinamide (580 mg) was obtained. 1 H NMR(CDCl3400MHz):δ7.31(t,1H),7.15(d, 1H),7.08(s,1H),7.01(d,1H),6.48(t,1H),5.7 3-5.66(m,1H),5.19-5.15(m,2H),4.46(t,1H), 3.65(s,1H),2.59-2.54(m,1H),2.46-2.38(m,1 H), 1.19(s,9H).

[0188] Step 3: (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl) Preparation of 2-methylpropane-2-sulfinamide [ka] (R)-N-((S)-1-(3-(difluoromethoxy) in alkyl ethyl acetate (20 mL) )phenyl)buto-3-en-1-yl)-2-methylpropane-2-sulfinamide To a solution of (580 mg), Pd / C (0.4 g, purity 10%) was added under N2 conditions. The turbid liquid was degassed under vacuum and purged several times with H2. The mixture was then heated under H2 (18 psi) for 2 The mixture was stirred at 5°C for 0.5 hours. The reaction mixture was filtered and concentrated to obtain (R)-N-((S)-1 -(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulf I obtained vinamide (560 mg).

[0189] Step 4: (S)-1-(3-(difluoromethoxy)phenyl)butane-1-amine hydrochloride Salt preparation [ka] (R)-N-((S)-1-(3-(difluoromethoxy)f in MeOH (8 mL) In a solution of phenylbutyl-2-methylpropane-2-sulfinamide (580 mg) Then, HCl / MeOH (4M, 3.1 mL) was added. The mixture was stirred at 25°C for 3 hours. Next, concentrate the (1S)-1-[3-(difluoromethoxy)phenyl]butane-1- I obtained amine hydrochloride (250 mg).

[0190] IIh:(S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorob Tan-1-amine hydrochloride [ka] Step 1: Preparation of 1-(difluoromethoxy)-3-vinylbenzene [ka] Dissolution of methyltriphenylphosphonium iodide (7.05g) in DME (50mL) K2CO3 (2.41g) was added to the liquid. The resulting mixture was stirred at 20°C for 1 hour, and then... Then add 3-(difluoromethoxy)benzaldehyde (1.5g) and heat at 80°C for 1 The mixture was stirred continuously for 5 hours. The mixture was filtered, and the filtered cake was washed with petroleum ether (100 mL). The filtrate was concentrated and subjected to column chromatography (SiO2, petroleum ether / ethyl acetate). Purified by (1 / 0~10 / 1), 1-(difluoromethoxy)-3-vinylbene I obtained zen (1.4g). 1 H NMR(CDCl3400MHz):δ7.32(t,1H),7.25(d, 1H),7.16(s,1H),7.01(d,1H),6.70(t,1H),6.5 2(t,1H),5.77(d,1H),5.32(d,1H).

[0191] Step 2: 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutane-1 - ON adjustment [ka] 1,1-difluoro-2-iodoethane (1g) in ACN (20mL), 1-(di Fluoromethoxy)-3-vinyl-benzene (1.33g), bis[(Z)-1-methyl -3-oxobuto-1-enoxy]copper (273mg) and Ag2SO4 (325mg) In a solution of ), add Et3N (527 mg) and tert-butyl hydroperoxide (TBH P) (2.01 g, 70% in water) was added. The resulting mixture was stirred at 80°C for 24 hours. The reaction was quenched with a saturated aqueous solution of Na2S2O3, and extracted with DCM (10 mL x 3). The organic phase was combined, washed with brine (5 mL x 2), dried with Na2SO4, and concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) The residue is purified by 1-(3-(difluoromethoxy)phenyl)-4,4- Difluorobutan-1-one (300 mg) was obtained. 1 H NMR(CDCl3400MHz):δ7.82(d,1H),7.73(s, 1H),7.50(t,1H),7.36(d,1H),6.57(t,1H),6.0 2(tt,1H),3.18(t,2H),2.35-2.27(m,2H).

[0192] Step 3: (S,E)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-di Preparation of fluorobutylidene)-2-methylpropane-2-sulfinamide [ka] 1-(3-(difluoromethoxy)phenyl)-4,4-difluoromethylphenyl in THF (10 mL) Luolobutan-1-one (300 mg) and (R)-2-methylpropane-2-sulfite Ti(OEt)4 (547 mg) was added to a solution of naamide (218 mg). The mixture was stirred at 60°C for 6 hours. The reaction mixture was used directly in the next step.

[0193] Step 4: N-[(1S)-1-[3-(difluoromethoxy)phenyl]-4,4-diph Preparation of ruolo-butyl]-2-methylpropane-2-sulfinamide [ka] (S)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluoromethoxyphenyl in THF Fluorobutylidene)-2-methylpropane-2-sulfinamide (423 mg) L-selectlide (1M in THF, 3.59 mL) was added to a solution at 48°C. Reaction The mixture was stirred for 0.5 hours, then cooled to 0°C, and H2O (approximately 10 mL) was added. The mixture was extracted with ethyl acetate (35 mL x 2). The organic extract was then treated with brine (10 mL). Extracted using SiO2, dried with Na2SO4 and concentrated. Column chromatography (SiO2, The residue is purified using petroleum ether / ethyl acetate (1 / 0~1 / 1), and N-[(1S) -1-[3-(difluoromethoxy)phenyl]-4,4-difluorobutyl]-2- Methyl-propane-2-sulfinamide (140 mg) was obtained.

[0194] Step 5: (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluoro Tan-1-amine hydrochloride [ka] N-[(1S)-1 in MeOH (10 mL) and HCl / MeOH (5 mL, 4 M) -[3-(difluoromethoxy)phenyl]-4,4-difluorobutyl]-2-methyl Ru-propan-2-sulfinamide (140 mg) was stirred at 20°C for 1 hour. Concentrate (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluoro Lobutan-1-amine hydrochloride (110 mg) was obtained.

[0195] IIi:(S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluorophenyl Ropan-1-amine hydrochloride [ka] Step 1: (S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methyl Preparation of Ropan-2-sulfinamide [ka] 3-(difluoromethoxy)benzaldehyde (5g) in DCE (150mL) and (R)-2-methylpropane-2-sulfinamide (4.22g) is dissolved in CuSO4. 4 (23g) was added. The reaction mixture was stirred at 55°C for 20 hours, filtered, and concentrated. Chromatography on Rica (SiO2, petroleum ether / ethyl acetate = 1 / 10 to 1 / 5) The crude product was purified by (S,E)-N-(3-(difluoromethoxy)benzyli Dene-2-methylpropane-2-sulfinamide (6.9 g) was obtained. 1 H NMR(CDCl3400MHz):δ8.55(s,1H),7.65(d, 1H),7.62(s,1H),7.47(t,1H),7.25(d,1H),6.5 5(t,1H), 1.25(s,9H).

[0196] Step 2: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)buto-3 Preparation of -en-1-yl)-2-methylpropan-2-sulfinamide [ka] (S,E)-N-(3-(difluoromethoxy)benzylidene in DCM (60 mL) In a solution of 2g of methylpropane-2-sulfinamide, add allyl (brom) at 0°C. Magnesium (1M solution in THF, 21.79 mL) was slowly added. The mixture was stirred at 0°C for 1 hour and then at 25°C for 2 hours. A saturated aqueous solution of NH4Cl at 0°C (10 ml) Add L) to quench the reaction, then dilute with H2O (50 mL) and DCM (40 mL). Extraction was performed using L×3. The combined organic phase was washed with H2O (40 mL) and dried with Na2SO4. The solution was dried, filtered, and concentrated. Chromatography (SiO2, petroleum ether / ethyl acetate) The residue is purified by 100 / 1~1 / 2), and (S)-N-((S)-1-(3-(di Fluoromethoxy)phenyl)buto-3-en-1-yl)-2-methylpropane-2- Sulfinamide (2.3g) was obtained. 1 H NMR(CDCl3400MHz):δ7.31(t,1H),7.15(d, 1H),7.08(s,1H),7.01(d,1H),6.49(t,1H),5.7 1-5.65(m,1H),5.19-5.15(m,2H),4.48-4.44(m ,1H),3.66(s,1H),2.59-2.54(m,1H),2.46-2.4 0 (m, 1H), 1.18 (s, 9H).

[0197] Step 3: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3-O Preparation of xopropyl)-2-methylpropane-2-sulfinamide [ka] S)-N-((S)-1-( 3-(difluoromethoxy)phenyl)buto-3-en-1-yl)-2-methylpropane n-2-sulfinamide (2.5g), 2,6-lutidine (1.69g), and periodon Potassium dioxide (dioxo)osmium in a stirred solution of sodium phosphate (5.05 g) A hydrated compound (276 mg) was added all at once. The reaction mixture was stirred at 20°C for 1 hour, and then... The solution was then diluted with DCM (100 mL) and water (20 mL). The aqueous layer was then mixed with DCM (25 mL x 2). Extraction was performed using the following method. The combined organic extracts were dried with Na2SO4. The crude reaction mixture was then processed as follows: I used it directly.

[0198] Step 4: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3 Preparation of (difluoropropyl)-2-methylpropane-2-sulfinamide [ka] (S)-N-((S)-1-(3-(difluoromethoxy) in DCM (200 mL) Phenyl-3-oxopropyl-2-methylpropane-2-sulfinamide (2g Add diethylaminosulfur trifluoride (DAST) (3.03g) to the solution of ) at -78°C. The mixture was added drop by drop. The reaction mixture was brought to 20°C and stirred for 2 hours. The solution was then prepared using NaHCO₃⁻. The solution was poured into a saturated aqueous solution (50 mL) and the organic phase was separated. This solution was dried with anhydrous Na2SO4. It was dried and concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate) The residue is purified by (5 / 1~1 / 1), and (S)-N-((S)-1-(3-(Diflu Olomethoxyphenyl)-3,3-difluoropropyl)-2-methylpropane-2- I obtained sulfinamide (500 mg).

[0199] Step 5: (1S)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoro Preparation of propane-1-amine hydrochloride [ka] (S)-N-((S)-1-(3-(difluoromethoxy) in MeOH (15 mL) Phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide Add HCl / MeOH (25 mL, 4 M) to the solution of (380 mg) at 0°C and react. The mixture was stirred for 0.5 hours and allowed to reach 25°C. The reaction mixture was concentrated and (1S)-1-[3 -(difluoromethoxy)phenyl]-3,3-difluoro-propane-1-amine hydrochloride Salt (300 mg, crude product, HCl salt) was obtained. It was used directly without further purification.

[0200] IIj:(S)-1-(3-(difluoromethoxy)phenyl)ethane-1-amine hydrochloride salt [ka] Step 1: ((S,E)-N-(3-(difluoro-methoxy)benzylidene)-2-meth Preparation of lupropan-2-sulfinamide [ka] 3-(difluoromethoxy)benzaldehyde (2g) and ( in DCE (60mL) A mixture of R)-2-methylpropane-2-sulfinamide (1.7g) and CuSO4 (9.3g) was added under N2 conditions at 55°C. The reaction mixture was stirred at 55°C for 12 hours. The solution was filtered and the filtrate was concentrated. Chromatography was performed on a silica gel column. The crude product is purified using roughe (petroleum ether / ethyl acetate = 20:1 to 10:1). ((S,E)-N-(3-(difluoro-methoxy)benzylidene)-2-methylpropane 4.5 g of 2-sulfinamide was obtained.

[0201] Step 2: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl) Preparation of 2-methylpropane-2-sulfinamide [ka] ((S,E)-N-(3-(difluoro-methoxy)benzyme in DCM (30 mL) In a solution of 2g of 2-methylpropane-2-sulfinamide, add bromo(methyl Magnesium (3M, 4.8 mL in Et2O) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour and then at 20°C for 16 hours. (10 mL of saturated NH4Cl aqueous solution) The reaction was quenched by [method], and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The extract was washed with brine (40 mL x 2), dried with anhydrous Na2SO4, and filtered. Concentrate and chromatograph on a silica gel column (petroleum ether / ethyl acetate = 5:1~ The crude product was purified by (S)-N-((S)-1-(3-(difluoro Methoxyphenylethyl-2-methylpropane-2-sulfinamide (960m g) was obtained.

[0202] Step 3: (S)-1-(3-(difluoromethoxy)phenyl)ethane-1-amine hydrochloride Salt preparation [ka] (S)-N-((S)-1-(3-(difluoromethoxy)f in MeOH (4 mL) In a solution of phenylethyl-2-methylpropane-2-sulfinamide (0.8g), HCl / MeOH (4M, 2 mL) was added. The resulting mixture was stirred at 25°C for 3 hours. Concentrated, (S)-1-(3-(difluoromethoxy)phenyl)ethane-1-amine Hydrochloride salt (1.6 g, crude product) was obtained.

[0203] IIk:(R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethane -1-amine hydrochloride [ka] Step 1: Ethyl(R,E)-2-((tert-butylsulfinyl)imino)acetate Preparation [ka] Ethyl 2-oxoacetate (7.5 g) and ( in DCM (150 mL) under nitrogen. In a solution of R)-2-methylpropane-2-sulfinamide (4.90g), add CuSO4 (12.9g) was added, and the reaction mixture was stirred at 25°C for 24 hours. The solid was filtered off, and vinegar was added. Washed with ethyl acid (50 mL), the organic layer was concentrated. Chromatography (SiO2, hex The residue was purified with ethyl(R,E)-2-((t) We obtained ert-butylsulfinyl imino acetate (5g).

[0204] Step 2: Ethyl(R)-2-(((S)-tert-butylsulfinyl)amino)-2 Preparation of (3-(trifluoromethoxy)phenyl)acetate [ka] Ethyl (R,E)-2-((tert-butylsulfini) in dioxane (80 mL) (5g) Limino) Acetate and [3-(trifluoromethoxy)phenyl]boron In a solution of acid (6.02 g), add bis(acetonitrile)(1,5-cyclooctadiene) Dium(I) tetrafluoroborate (CAS: 32679-02-0) (1.85g) The mixture was stirred at 80°C for 16 hours after adding the other ingredients. The solution was filtered, and the organic phase was concentrated. The residue was analyzed by chromatography (SiO2, petroleum ether: SiO2: SiO2 = 6:1). Purified, ethyl(R)-2-(((S)-tert-butylsulfinyl)amino)-2 -(3-(trifluoromethoxy)phenyl)acetate (5.1 g) was obtained.

[0205] Step 3: Ethyl(R)-2-amino-2-(3-(trifluoromethoxy)phenyl) Preparation of Cete [ka] Ethyl(R)-2-(((S)-tert-butyl sulfide in MeOH (30 mL) Nyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (4.6g HCl / MeOH (4M, 25.04 mL) was added to the solution of ) at 0°C. Reaction mixture Stir at 25°C for 1 hour, concentrate, and ethyl(R)-2-amino-2-(3-(triful Olomethoxyphenyl acetate was obtained as hydrochloride (3.3 g).

[0206] Step 4: Ethyl(R)-2-((tert-butoxycarbonyl)amino)-2-(3- Preparation of (trifluoromethoxy)phenyl)acetate [ka] Ethyl(R)-2-amino-2-(3-(trifluoromethyl) in THF (80 mL) A mixture of phenyl acetate hydrochloride (3.3g) and Boc2O (4.81g) NaHCO3 (925 mg) was added, and the reaction was stirred at 25°C for 16 hours. [Reaction mixture] The solution was concentrated, diluted with ELISA (20 mL), washed with water (20 mL), and then concentrated again. Chromatography (SiO2; petroleum ether: SiO2 = 10:1) determines the residue Purify the ethyl(R)-2-((tert-butoxycarbonyl)amino)-2-( 3.8 g of 3-(trifluoromethoxy)phenyl)acetate was obtained.

[0207] Step 5: tert-butyl(R)-(2-hydroxy-1-(3-(trifluoromethyl Preparation of phenylethyl carbamate [ka] A suspension of LiAlH4 (2.1g) in THF (200mL) is mixed with THF (20mL) The ethyl(R)-2-((tert-butoxycarbonyl)amino)-2-(3-(t Add 5g of difluoromethoxyphenyl acetate while cooling with ice, and mix 0 The mixture was stirred at ~25°C for 2 hours. Anhydrous magnesium sulfate was added, followed by water (5 mL) and vinegar. Ethyl acid (100 mL) was added sequentially, and insoluble substances were filtered using Celite. The filtrate was then... It was concentrated by chromatography (SiO2, petroleum ether:dimethyl = 5:1). The crude product was purified and tert-butyl(R)-(2-hydroxy-1-(3-(triflu Olomethoxyphenyl ethyl carbamate (3.37 g) was obtained.

[0208] Step 6: tert-butyl(R)-(2-ethoxy-1-(3-(trifluoromethoxy) Preparation of phenyl(ethyl)carbamates [ka] tert-butyl(R)-(2-hydroxy-1-(3-( A solution of trifluoromethoxyphenyl ethyl carbamate (1g) is mixed with ethyl sulfate. Na (960 mg), tetrabutylammonium chloride (TBAC) (87 mg), and Na A solution of OH (324 mg) and H2O (1.5 mL) was added. The resulting mixture was stored at 25°C. The mixture was stirred for 20 hours. The reaction mixture was diluted with dimethyl acetate (200 mL) and water (100 mL). Washed with ) and brine (100 mL), dried with Na2SO4, and concentrated. Chroma The crude product is refined by tography (SiO2, 10% ethyl acetate in petroleum ether). Prepared as tert-butyl(R)-(2-ethoxy-1-(3-(trifluoromethoxy) 5.9 g of phenylethyl carbamate was obtained.

[0209] Step 7: (R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethane Preparation of -1-amine hydrochloride [ka] tert-butyl(R)-(2-ethoxy-1-(3-( A solution of trifluoromethoxyphenyl ethyl carbamate (5.9g) is mixed with HCl. Add MeOH (4M, 63.33 mL) at 25°C, and incubate the mixture at 25°C for 16 hours. Stirring. This solution was concentrated and (R)-2-ethoxy-1-(3-(trifluorometh Xy)phenyl)ethane-1-amine hydrochloride (4.5 g) was obtained.

[0210] IIl:(S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine Hydrochloride [ka] Step 1: (S,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene) Preparation of propane-2-sulfinamide: [ka] 3-(trifluoromethoxy)benzaldehyde (10.0) in DCE (200 mL) g) (R)-2-methylpropane-2-sulfinamide (7.7g) and CuSO4 The mixture (12.6g) was stirred at 55°C for 16 hours. The mixture was filtered and filtered into a cake. The sample was washed with DCM (200 mL). The filtrate was concentrated. Chromatography (SiO2, 0 The residue is purified by a ~10% ethyl acetate / petroleum ether gradient, (S,E) -2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfur Finamide (12.6g) was obtained.

[0211] Step 2: (S)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phen Preparation of Nyl)propyl)propan-2-sulfinamide [ka] (S,E)-2-methyl-N-(3-(trifluoromethyl) in DCM (40 mL) at 0°C EtM gBr (3M in Et2O, 9.1 mL) was added dropwise. The resulting mixture was incubated at 0°C for 1 The mixture was stirred at 20°C for 3 hours. The mixture was cooled to 0°C and a saturated aqueous solution of NH4Cl (100%) was added. A mL of solution was added. The mixture was extracted with DCM (100 mL x 2) to separate the phases, and the organic layer was removed. Washed with brine (200 mL), dried with Na2SO4, and concentrated. Chromatography. The residue is purified by (SiO2, 0-50% ethyl acetate / petroleum ether gradient), The product (1.4g) was obtained.

[0212] Step 3: (S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine Preparation of hydrochloride [ka] (S)-2-methyl-N-((S)-1-(3-(triflu) in MeOH (40 mL) Dissolve Olomethoxy)phenyl)propyl)propan-2-sulfinamide (1.4g) HCl / MeOH (4M, 20 mL) was added to the solution. The resulting mixture was incubated at 30°C for 12 minutes. Stirring for a while, then concentrated, the crude product (S)-1-(3-(trifluoromethoxy)phen (1g) Propane-1-amine hydrochloride was obtained and used without further purification. ).

[0213] IIm:(S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propane Nitrile hydrochloride [ka] Step 1: tert-butyl(R)-(2-hydroxy-1-(3-(trifluoromethyl Preparation of phenylethyl carbamate This intermediate was prepared as described for intermediate IIk and steps 1-5.

[0214] Step 2: (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(tri Preparation of fluoromethoxy(phenyl)ethylmethanesulfonate [ka] DCM (20 mL) contains tert-butyl(R)-(2-hydroxy-1-(3-(t Et3N(7) 56 mg was added, followed by methanesulfonyl chloride (1.75 g) at 0°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was washed with a saturated aqueous solution of NH4Cl (15 mL). Purify, dry with Na2SO4, filter, concentrate, (R)-2-((tert-butoxy Carbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethylmethanes Obtain ruhonate (2.50g, crude product), and use it in the next step without purification. Ta.

[0215] Step 3: (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propane Preparation of nitrile hydrochloride [ka] (R)-2-((tert-butoxycarbonyl)amino)- in DMSO (5 mL) 2-(3-(trifluoromethoxy)phenyl)ethylmethanesulfonate (420mg) KCN (225 mg) was added to the solution at 20°C. The mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with 10% Na2CO3 solution (40 mL) and Depositphotos (30 mL). Extraction was performed using L×3. The combined organic extract was then diluted with water (50mL) and brine (50mL). The solution was washed, then dried with Na2SO4, filtered, and concentrated. Chromatography (SiO2SO4) 2. The residue is purified using petroleum ether / ethyl acetate (5 / 1 to 4 / 1), and then tert -Butyl(S)-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl I obtained carbamate (665 mg). 1 H NMR(400MHz,CDCl3):δ7.46(t,1H),7.33(d, 1H),7.24(m,2H),7.04(d,1H),5.31-5.38(m,1H ),3.73-3.71(m,1H),3.11-3.05(m,1H),2.84-2 .92(m,2H),2.49-2.43(m,1H),2.28-2.37(m,1H ), 0.93(s,9H).

[0216] tert-butyl(S)-(2-cyano-1-(3-(trif) in MeOH (8 mL) A solution of 400 mg of hydroxyphenyl ethyl carbamate is mixed with HCl / M eOH (4M, 4.00 mL) was added at 0°C. The mixture was stirred at 25°C for 16 hours. Next, the reaction mixture is concentrated and (S)-3-amino-3-(3-(trifluoromethyl) Phenylpropannitrile hydrochloride (280 mg, crude product) was obtained.

[0217] IIn:(S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butane Trill hydrochloride [ka] Step 1: (R,E)-2-methyl-N-(3-(trifluoro-methoxy)benzylidene Preparation of propane-2-sulfinamide [ka] 3-(trifluoromethoxy)benzaldehyde (30g) in DCE (600mL) And in a solution of (R)-2-methylpropane-2-sulfinamide (23.0 g), Cu SO4 (37.8g) was added. The mixture was stirred at 55°C for 24 hours and then filtered. The filtrate was washed with DCM (300 mL). The filtrate was combined, concentrated, and chromatographed (S The residue is purified by (R ,E)-2-methyl-N-(3-(trifluoro-methoxy)benzylidene)propane- 2-sulfinamide (41.8g) was obtained.

[0218] Step 2: Ethyl(S)-3-(((R)-tert-butylsulfinyl)amino)-3 Preparation of (3-(trifluoromethoxy)phenyl)propanoate [ka] (R,E)-2-methyl-N-(3-(trifluoromethyl) in THF (60 mL) A solution of (c) benzylidene)propan-2-sulfinamide (5g) is heated at 0°C in THF ( Activated Zn (11.15 g), CuCl (2.5 g), and ethyl 2-bromide in 60 mL It was added to a suspension of moacetate (7.1 g). The reaction mixture was stirred at 50°C for 2 hours and filtered. The filtration cake was washed with DCM (400 mL), and the combined organic filtrate was concentrated. Residue detected by chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) The substance is purified to obtain ethyl(S)-3-(((R)-tert-butylsulfinyl)amino )-3-(3-(trifluoromethoxy)phenyl)propanoate (7g, crude product) I got it. 1 H NMR(CDCl3400MHz):δ7.36(t,2H),7.20(s, 1H),7.14(d,1H),5.78(d,1H),5.14-5.10(m,1H ),4.14-4.10(m,2H),3.05-2.89(m,2H),1.31(s ,9H),1.18(t,3H).

[0219] Step 3: (R)-N-((S)-3-hydroxy-1-(3-(trifluoromethoxy) Preparation of phenyl)propyl)-2-methylpropane-2-sulfinamide [ka] Ethyl(S)-3-(((R)-tert-butylsulfini in THF (70 mL) (Lu)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7g) LiAlH4 (696 mg) was added to the solution at 0°C. The resulting mixture was incubated at 0°C for 1 hour. Stirring intermittently, then at 0°C, add H2O (0.7 mL), 10% NaOH (0.7 mL) solution and The mixture was quenched by sequentially adding H2O (2.1 mL). The mixture was filtered. The distillate is concentrated to obtain the crude product (R)-N-((S)-3-hydroxy-1-(3-(triflu Olomethoxyphenylpropyl-2-methylpropane-2-sulfinamide (4 0.2g was obtained.

[0220] Step 4: (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propane Preparation of -1-ol hydrochloride [ka] Crude product from the previous reaction step (R)-N-((S)-3-hydroxy-1-(3-(tri Fluoromethoxy(phenyl)propyl)-2-methylpropane-2-sulfinamide Dissolve (4g) in MeOH (40mL), and add HCl / MeOH (4M, 23.6mL) It was added. The reaction mixture was stirred at 20°C for 16 hours, concentrated, and (S)-3-amino-3- (3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride (3.2g, crude) (The product was obtained.)

[0221] Step 5: tert-butyl(S)-(3-hydroxy-1-(3-(trifluoromethyl Preparation of phenylpropyl carbamate [ka] Crude product from the previous reaction step: ethyl(S)-3-(((R)-tert-butyl sulfide Nyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate(3. Dissolve 2g) in THF (35mL), and add Boc2O (10.28g) and NaHCO3 ( 2g) was added. The reaction mixture was stirred at 20°C for 16 hours. The mixture was concentrated, and the residue was removed. Dilute with water (70 mL), extract with DCM (100 mL x 3), and combine with organic extract. The material was dried with Na2SO4, filtered, and concentrated. Chromatography (SiO2, petroleum ions) The residue is purified using tert-butyl ((ethyl acetate = 1 / 0~2 / 1)). S)-(3-Hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl) Rubamate (3.2g) was obtained.

[0222] Step 6: (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(tri Preparation of fluoromethoxy(phenyl)propylmethanesulfonate [ka] DCM (30 mL) contains tert-butyl(S)-(3-hydroxy-1-(3-( Et3N( 905 mg of (the substance) and methanesulfonyl chloride (683 mg) were added at 0°C. The reaction mixture was then prepared. Stir at 20°C for 16 hours, wash with ice water (15 mL), dry with anhydrous sodium 2 SO4, and filter. After passing through and concentrating, ((S)-3-((tert-butoxycarbonyl)amino)-3-( Obtain 3-(trifluoromethoxy)phenyl)propylmethanesulfonate (1.2g). Ta.

[0223] Step 7: tert-butyl(S)-(3-cyano-1-(3-(trifluoromethoxy) Preparation of phenyl(propyl)carbamates [ka] ((S)-3-((tert-butoxycarbonyl)amino)-3 obtained in the previous step -(3-(trifluoromethoxy)phenyl)propylmethanesulfonate is DMSO( Dissolve in 35 mL and add KCN (661 mg) at 20°C. The reaction mixture was then heated at 50°C. Stir for 16 hours, then dilute with 10% Na2CO3 solution (40 mL) and siRNA(7 Extraction was performed using 0 mL x 3. The combined organic extract was then diluted with water (50 mL) and brine (50 mL). Washed with (S), then dried with Na2SO4, filtered, and concentrated. Chromatography (S The residue is purified using 0O2, petroleum ether / ethyl acetate (1 / 0~3 / 1), and te rt-butyl(S)-(3-cyano-1-(3-(trifluoromethoxy)phenyl) I obtained Ropil carbamate (990 mg).

[0224] Step 8: (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butane Preparation of Toll Hydrochloride [ka] tert-butyl(S)-(3-cyano-1-(3-(tri in MeOH (14 mL)) In a solution of fluoromethoxyphenylpropyl carbamate (900 mg), HCl 1 / MeOH (4M, 6.53 mL) was added. The mixture was stirred at 20°C for 16 hours and concentrated. It is abbreviated as (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butane I obtained Trill hydrochloride (850 mg).

[0225] IIo:(S)-3,3-difluoro-1-(3-(trifluoromethoxy)phenyl) Propan-1-amine hydrochloride [ka] Using 3-(trifluoromethoxy)benzaldehyde as a starting material, to IIi It was prepared as described below.

[0226] IIp:(R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethane -1-amine hydrochloride [ka] Step 1: Ethyl(R)-2-((tert-butoxycarbonyl)amino)-2-(3- Preparation of (trifluoromethoxy)phenyl)acetate [ka] This intermediate was prepared as described in IIk, steps 1-4.

[0227] Step 2: tert-butyl(R)-(2-hydroxy-1-(3-(trifluoromethyl Preparation of phenylethyl carbamate [ka] Ethyl(R)-2-((tert-butoxycarbonyl) in EtOH (90mL) In a solution of mino-2-(3-(trifluoromethoxy)phenyl)acetate (10g) NaBH4 (4.17g) was added at 0°C. The mixture was removed from the cold bath and stirred for 2 hours. The reaction was quenched with water (20 mL) and concentrated. Column chromatography (Si The residue is purified using O2, petroleum ether / ethyl acetate (1 / 0~3 / 1), and the product ( 13.6g was obtained. 1 H NMR(CDCl3400MHz):δ7.39(t,1H),7.26(d, 1H),7.17-7.15(m,2H),5.34(s,1H),4.80(s,1H ),3.93-3.84(m,2H),2.06(s,1H),1.45(s,9H).

[0228] Step 3: tert-butyl(R)-(2-methoxy-1-(3-(trifluoromethoxy Preparation of phenyl(ethyl)carbamates [ka] tert-butyl(R)-(2-hydroxy-1-(3-(T) in THF (70mL) Dissolved in difluoromethoxyphenyl ethyl carbamate (1g) and MeI (4g). NaH (149 mg, 60% of the mineral oil) was added to the liquid at 0°C. The mixture was stirred at 0°C for 1 hour. Mix and stir at 25°C for 16 hours. Add water (1 mL) to stop the reaction. THF The residue was removed, and ethyl acetate (200 mL) was added to the remaining material. The solution was washed with water (50 mL x 3). Purified and concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate = 0 The residue is purified by (1~5 / 1), and tert-butyl(R)-(2-methoxy-1 -(3-(trifluoromethoxy)phenyl)ethyl)carbamate (3.2g) was obtained. . 1 H NMR(CDCl3400MHz):δ7.36(t,1H),7.25(m, 1H),7.19(s,1H),7.12(d,1H),5.34(s,1H),4.8 3(s,1H),3.63-3.56(m,2H),3.35(s,3H),1.43( s,9H).

[0229] Step 4: (R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethane Preparation of -1-amine hydrochloride [ka] tert-butyl(R)-(2-methoxy-1-(3-(T) in MeOH (40 mL) In a solution of difluoromethoxyphenyl ethyl carbamate (2.7g), at 25°C... HCl / MeOH (4M, 40 mL) was added. The mixture was stirred at 25°C for 16 hours. The mixture was concentrated to obtain the desired product (1.9 g, crude).

[0230] IIIa:(S)-3-hydroxy-4,4-dimethylpentanoic acid [ka] Wang Z.et al:Tetrahedron:Asymmetry 10(1 It is manufactured according to the literature described in 999)225-228.

[0231] IIIb: 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid [ka] Step 1: Ethyl 2-(3,3-difluoro-1-hydroxycyclobutyl)acetate Preparation [ka] Under N2 conditions, 3,3-difluorocyclobutanone (0.2g) in THF (13mL) and A solution of Zn (198 mg) and I2 (10 mg) is prepared by adding ethyl 2-bromoacetic acid (378 mg). ) was added dropwise. The mixture was stirred at 55°C for 6 hours. H2SO4 (10%, 10 mL) was added. The reaction mixture was carefully added at °C, and the mixture was extracted with ethyl acetate (20 mL x 3). Organic The extract was washed with NaHCO3 (saturated aqueous solution, 10 mL), dried with Na2SO4, and concentrated. It shrunk. The crude product (0.26 g) was used directly without further purification.

[0232] Step 2: Preparation of 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid [ka] Ethyl 2-(3,3-difluoro-1) in MeOH (10 mL) and H2O (2 mL) A solution of -hydroxycyclobutyl)acetate (0.26g) is dissolved in NaOH (1) at 0°C. (0.7 mg) was added. The mixture was stirred at 20°C for 8 hours. The reaction solution was cooled to 0°C and p 1N HCl was added to the solution until the H level reached 1-2. The residue was diluted with saline solution (10 mL). The mixture was then extracted with methyl-tert-butyl ether (30 mL x 5). The organic extract was dried with Na2SO4, filtered, and concentrated. The crude product (0.24g) was used. It was used without further purification.

[0233] IIIc:3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid [ka] Step 1: Ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate preparation [ka] Add 1-(1-fluorocyclopropyl) in THF (30 mL) until the solution becomes colorless. A solution of ethanol (0.5g), zinc (512mg), and nitrate (62mg) is stirred at 20°C. The mixture was mixed, and ethyl 2-bromoacetate (981 mg) was added drop by drop. The resulting mixture The mixture was stirred at 20°C for 0.5 hours and then at 65°C for 4.5 hours. The reaction was carried out in a 10% H2SO4 aqueous solution. Washed with 20 mL and extracted with ethyl acetate (50 mL x 2). Organic extract was brined ( Wash with 100 mL, dry with Na2SO4, concentrate, and ethyl 3-(1-fluorocarbon). Cyclopropyl)-3-hydroxy-butanoate (0.83 g, crude product) was obtained.

[0234] Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid [ka] Ethyl 3-(1-fluorocyclopropyl)-3-hydroxypropyl ethyl A solution of ci-butanoate (0.83g) is mixed with NaOH (350mg) in H2O (3mL). A solution of ) was added. The reaction mixture was stirred at 20°C for 2 hours, and then EtOAC (50 mL) was added. Extraction was performed using ×2). The aqueous layer was acidified to pH=3 with 10% HCl, and EtOAC(50 Extraction was performed using (mL x 2). The combined organic extracts were washed with brine (100 mL) and Na2 Dry with SO4 and concentrate to 3-(1-fluorocyclopropyl)-3-hydroxy- Butanoic acid (0.57 g, crude product) was obtained.

[0235] IIId:3-Cyclopropyl-3-Hydroxybutanoic Acid [ka] Step 1: Preparation of methyl 3-cyclopropyl-3-hydroxybutanoate [ka] TMSCl (1.3g) was added to Zn (12.4g) in THF (150mL), and The mixture was stirred at 20°C for 15 minutes, then heated to 70°C. Heating was stopped, and the solution was removed. Methyl 2-bromoacetic acid (21.8 g) was added dropwise at a rate that caused a gentle boil. The mixture was stirred at 70°C for 1 hour, followed by 20°C for 1 hour, and then THF (50 mL) was added. A solution of 1-cyclopropyl ethanoone (10 g) was added. This reaction was carried out at 20°C for 16 minutes. Stirred for 2 hours. Pour the mixture into NH3·H2O (100 mL, 28%) on ice and add acetate. Extraction was performed using chill (150 mL x 2). The organic extract was then diluted with water (150 mL) and saline solution (150 mL). Washed with L), dried over Na2SO4, and concentrated to obtain the desired product (8.9g, (Crude product).

[0236] Step 2: Preparation of 3-cyclopropyl-3-hydroxybutanoic acid [ka] Crude methyl 3-cyclopropyl in THF (100 mL) and H2O (50 mL) A mixture of -3-hydroxybutanoate (8.9g) and LiOH·H2O (11.8g). The mixture was stirred at 20°C for 16 hours. H2O (50 mL) was added, and ethyl acetate (100 mL) was added. Extraction was performed using L×2. The organic extract was discarded. The pH of the aqueous layer was adjusted to approximately 5 with 2N HCl. Extract with ethyl acetate (100 mL x 3), and the combined organic fraction is treated with saline solution (100 mL x 3). 10) Wash, dry with Na2SO4, filter, concentrate to obtain desired total yield of 30% The product was obtained (5.1 g). 1 H NMR(400MHz,CDCl3)2.67-2.51(m,2H),1.25 (s,3H),0.90-1.00(m,1H),0.33-0.50(m,4H).

[0237] IIIe:5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid [ka] Step 1: Ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate Preparation [ka] A mixture of Zn (6.9g) and I2 (89mg) in THF (80mL) contains 4,4,4 -Trifluorobutan-2-one (4.4g) and ethyl 2-bromoacetate (6.4g) g) was added at 15°C. The mixture was stirred at 60°C for 6 hours. The reaction mixture was cooled to 0°C. The mixture was quenched with H2SO4 (100 mL, 10% aqueous solution). Extraction was performed using 3 mL of solution. The combined organic extracts were washed with brine (15 mL) and then Na2S solution was used. The solution was dried over O4, filtered, and concentrated. The product (11.00 g, crude) was obtained and further purified. I used it directly without doing anything else.

[0238] Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid [ka] Ethyl 5,5,5-trifluoro-3-hydroxy-3-methyl A mixture of thiol-pentanoate (11 g, crude) and NaOH (4.1 g) was prepared at 15°C. The mixture was stirred for 16 hours. The pH was adjusted to approximately 2 with saturated KHSO4 at 0°C, and the mixture was dissolved in ethyl acetate. Extraction was performed using 200 mL x 3. The combined organic extract was washed with brine (300 mL). The product (10 g, crude) was dried with Na2SO4, filtered, and concentrated to obtain the product.

[0239] Using the relevant starting materials, prepare the following using the same methodology as described in IIIe: did:

[0240] IIIf:3-hydroxy-3,4-dimethylpentanoic acid [ka] 1 H NMR(CDCl3400MHz):δ2.65-2.46(m,2H),2. 09(s,1H),1.85-1.76(m,1H),1.20(s,3H),0.93 (dd,6H).

[0241] IIIg: 3-hydroxy-3,5-dimethylhexanoic acid [ka] 1H NMR(CDCl3400MHz):δ2.64-2.50(m,2H),1. 85-1.79(m,1H),1.49(d,2H),1.32(s,3H),1.03 -0.97 (m, 6H).

[0242] IIIh:3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoic acid [ka] Step 1: Ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate Preparation [ka] Ethyl 3-(3,3-dimethylcyclobutyl)-3-oxo- in MeOH (8 mL) NaBH4 (95 mg) was added to a solution of propanoate (IVd) (1 g). Stir the mixture at 0°C for 10 minutes, add H2O (1 mL) to quench, concentrate, and then Diluted with toluene (30 mL), dried with Na2SO4, filtered, and evaporated. Residue obtained by matrixing (SiO2, petroleum ether / ethyl acetate = 5 / 1~4 / 1) Purified, ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propano I obtained ethide (907 mg). 1 H NMR(DMSO-d6 400MHz):δ4.70(d,1H),4.06- 4.00(m,2H),3.71-3.68(m,1H),2.26-2.23(m,1 H),2.15-2.12(m,2H),1.63-1.59(m,3H),1.52- 1.49(m,1H),1.17(t,3H),1.09(s,3H),0.99(s, 3H).

[0243] Step 2: Preparation of 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoic acid [ka] Ethyl 3-(3,3-dimethylcyclobutyl)-3-hydro in MeOH (10 mL) A solution of xy-propanoate (900 mg) is mixed with NaOH (377) in H2O (5 mL). A solution of (mg) was added. The mixture was stirred at 25°C for 4 hours. 10% HCl was added to the reaction mixture. Add the solution to adjust the pH to 3-4, dilute with H2O (30 mL), and add HCl (3 Extract with 0 mL x 2, dry the combined organic layer with Na2SO4, filter, and concentrate. 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoic acid (760 mg) I got it. 1 H NMR(DMSO-d6 400MHz):δ11.96-11.95(m,1H ),4.65-4.61(m,1H),3.71-3.66(m,1H),2.19-2 .05(m,3H),1.63-1.51(m,4H),1.09(s,3H),1.0 0(s,3H).

[0244] Using the relevant starting materials, prepare the following using the same methodology as described in IIIh. did: IIIi: 3-Cyclopentyl-3-hydroxypropanoic acid [ka] 1 H NMR(DMSO-d6 400MHz):δ11.96(s,1H),4.63 (s,1H),3.66(s,1H),2.36-2.32(m,2H),1.83-1 0.75 (m, 1H), 1.62-1.35 (m, 8H).

[0245] IVa: Ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxopropane Noeto [ka] Step 1: Ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxopropane Preparation of Noate [ka] Et3N (2.34 g) and MgCl2 (1.8 g) in MeCN (30 mL) Suspension of 3-ethoxy-3-oxo-propanoyl)oxypotassium salt (2.6g) The mixture was added and stirred at 20°C for 2 hours. Carbonyl diimidazole in MeCN (20 mL) (CDI) (1.4g) and 1-(difluoromethyl)cyclopropanecarboxylic acid (1g) The pre-mixed mixture was added at 0°C and stirred at 20°C for 14 hours. The solution was diluted with H2O (30 mL) and extracted with ethyl acetate (80 mL x 2). The extract was washed with saline solution (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was analyzed by flash chromatography (SiO2, 0-10% ethyl acetate / petroleum ether). The product was purified using a gradient eluent. The product was obtained (0.98 g).

[0246] Using the relevant starting materials, prepare the following using the same methodology as described in IVa: Ta: IVb: Ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propane Noeto [ka] IVc: 3-(3,3-difluorocyclobutyl)-3-oxopropanoate [ka] IVd: Ethyl 3-(3,3-dimethylcyclobutyl)-3-oxopropanoate [ka] 1 H NMR(CDCl3400MHz):δ4.22-4.16(m,1H),3. 39(s,2H),3.34-3.25(m,1H),2.08-1.90(m,4H) ,1.29(t,3H),1.27(s,3H),1.06(s,3H).

[0247] IVe: Ethyl 3-cyclopentyl-3-oxo-propanoate [ka] 1 H NMR(CDCl3400MHz):δ4.24-4.18(m,2H),3. 49(s,2H),3.03-2.95(m,1H),1.84-1.60(m,8H) ,1.28(t,3H).

[0248] IVf: Ethyl 3-(1-ethylcyclopropyl)-3-oxo-propanoate [ka] 1 H NMR(CDCl3400MHz):δ4.22-4.16(m,2H),3. 33(s,2H),1.64-1.60(m,2H),1.26-1.20(m,6H) ,0.94(t,3H).

[0249] Va:(R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl(ethyl)-4,4-dimethyl-3-oxopentanamide [ka] Step 1: (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy) Preparation of phenyl(ethyl)-4,4-dimethyl-3-oxopentanamide [ka] (R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) in toluene (10 mL) Olomethoxyphenyl ethane-1-amine hydrochloride (IIa) (0.6g), methyl 4 ,4-dimethyl-3-oxopentanoate (750 mg), TEA (2.40 g) and A solution of DMAP (58 mg) was stirred at 90°C for 16 hours. The mixture was then prepared. Dilute with 50 mL, wash with water (30 mL) and brine (50 mL), and Na2SO4 It was dried and concentrated. Chromatography (SiO2, 30% EA in petroleum ether) Then the crude product is purified, (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy) (Oromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide 0.28g was obtained.

[0250] Using related intermediates, the following intermediates were prepared using a methodology similar to that of Va: Vb:(R)-N-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl) (Tyl)-4,4-dimethyl-3-oxopentanamide [ka] It was prepared from IIk and 4,4-dimethyl-3-oxopentanoic acid.

[0251] Vc:(R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl)ethyl)-3-oxo-3-(1-(trifluoromethyl)cyclopropyl ) Propanamide [ka] Prepared from IIa and IVb.

[0252] Vd:(R)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy) )phenyl)ethyl)-3-oxo-3-(1-trifluoromethyl)cyclopropyl) Propanamide [ka] Prepared from IVb and IIb.

[0253] Ve:(R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluorometh Xy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropane Mido [ka] Prepared from IVc and IIa.

[0254] Vf:(R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluorometh Xy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropane Amido [ka] Prepared from IVc and IIb.

[0255] Vg:(S)-3-(3,3-difluorocyclobutyl)-N-(1-(3-(difluoro (Methoxy)phenyl)butyl)-3-oxopropanamide [ka] Prepared from IVc and IIg.

[0256] Vh:(R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy) Phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-oxopropanamide [ka] Prepared from IVf and IIa. [Examples]

[0257] Example 1a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy(phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] And Example 1b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Preparation of phenyl(ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] (R)-N-(2-(difluoromethoxy)-1-(3-( Difluoromethoxy(phenyl)ethyl)-4,4-dimethyl-3-oxopentaneamide NaBH4 (56 mg) was added to a solution of (Va) (0.28 g) at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was concentrated, and the residue was taken out of 50 mL. Dissolve in (), wash with water (50 mL) and brine (50 mL), and dry with Na2SO4. It's concentrated.

[0258] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Separation of phenyl(ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Chromatography of ethyl(nyl)ethyl-3-hydroxy-4,4-dimethylpentanamide It was separated by [something].

[0259] Example 1a: 1 H NMR(CDCl3400MHz):δ7.34(t,1H),7.16(d, 1H),7.09(s,1H),7.04(d,1H),6.59(d,1H),6.5 0(t,1H),6.20(t,1H),5.30-5.26(m,1H),4.15- 4.08(m,2H),3.69-3.66(m,1H),2.90(d,1H),2. 43(dd,1H),2.28(dd,1H),0.91(s,9H). LC-MS:t R =2.49 minutes (LC-MS method 1), m / z=382.2[M+H] + . SFC:t R = 1.94 minutes (SFC method 1), ee% = 95.26%.

[0260] Example 1b: 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.16(d, 1H),7.06-7.04(m,2H),6.60(d,1H),6.50(t,1H ),6.20(t,1H),5.28(m,1H),4.10(m,2H),3.67( m,1H),3.04(d,1H),2.45(dd,1H),2.28(dd,1H) ,0.91(s,9H). LC-MS:t R =2.50 minutes (LC-MS method 1), m / z=382.2[M+H] + . SFC:t R = 2.03 minutes (SFC method 1), ee% = 95.26%.

[0261] Using related intermediates, by a similar methodology described for 1a and 1b, The following example was prepared: Example 2a: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)pheny (Ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] And Example 2b: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy) Ethyl(enyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl) Preparation of ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from Vb.

[0262] Step 2: (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2, 2,2-Trifluoroethoxy)phenyl)ethyl)pentanamide and (R)-3-H Droxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethylene Separation of Toxy(phenyl)ethyl)pentanamide [ka] N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl )-3-hydroxy-4,4-dimethylpentanamide is separated by chromatography. did.

[0263] Example 2a: 1 H NMR(DMSO-d6 300MHz):δ8.34(d,1H),7.48- 7.35(m,3H),7.23(d,1H),5.07(d,1H),4.61(d, 1H),3.34-3.54(m,5H),2.31-2.20(m,1H),2.17 -2.08(m,1H),1.08(t,2H),0.83(s,9H). LC-MS:t R =1.87 min (LC-MS method 4), m / z=378.2[M+H] + . SFC:t R = 1.71 minutes (SFC method 18), ee% = 96.0%.

[0264] Example 2b: 1 H NMR (DMSO-d6 300MHz): δ8.39(d,1H),7.46( t,J=7.8Hz,5H),7.35(t,2H),7.23(d,3H),5.06 (d,1H),4.63(d,1H),3.56-3.52(m,3H),3.49-3 .43(m,2H),2.29-2.25(m,1H),2.19-2.08(m,1H ), 1.07(t, 2H), 0.82(s, 9H). LC-MS:t R =1.87 min (LC-MS method 4), m / z=378.2[M+H] + . SFC:t R = 1.82 minutes (SFC method 18), ee% = 99.1%.

[0265] Example 3a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclo Propylpropanamide [ka] and Example 3b: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclo Propylpropanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclop Preparation of Ropil (propanamide) [ka] Prepared from Vc.

[0266] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl) Cyclopropyl)propanamide and (S)-N-((R)-2-(difluoromethoxy) )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1 - Separation of (trifluoromethyl)cyclopropyl)propanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Nyl(ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl) Propanamide was isolated by chiral SFC.

[0267] Example 3a: 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.16(d, 1H),7.07-7.05(m,2H),6.45(t,1H),6.33(s,1H ),6.22(t,1H),5.28-5.24(m,1H),4.17-4.04(m ,3H),3.68(s,1H),2.67(dd,1H),2.55(dd,1H), 0.92-0.88(m,3H),0.85-0.82(m,1H). LC-MS:t R =2.51 min (LCMS method 1), m / z=434.1[M+H] + . SFC:t R = 1.95 minutes (SFC method 3), ee% = 100%.

[0268] Example 3b: 1 H NMR(CDCl3400MHz):δ7.36(t,1H),7.16(d, 1H),7.06(m,2H),6.50(t,1H),6.38(d,1H),6.2 1(t,1H),5.27-5.23(m,1H),4.13-4.04(m,3H), 3.76(d,1H),2.67-2.56(m,2H),0.98-0.87(m,4 H). LC-MS:t R =2.51 min (LCMS method 1), m / z=434.1[M+H] + . SFC:t R = 1.58 minutes (SFC method 3), ee%=90, 0%.

[0269] Example 4a: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Toxy(phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)ethyl (L-propyl)propanamide [ka] and Example 4b: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Toxy(phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)ethyl (L-propyl)propanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (Phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclo Preparation of propyl propanamide [ka] Prepared from Vd.

[0270] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro (Methoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl) Cyclopropyl)propanamide and (S)-N-((R)-2-(difluoromethoxy) )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-( Separation of 1-(trifluoromethyl)cyclopropyl)propanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (Ethyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl Propanamide was separated by chiral SFC.

[0271] Example 4a: 1 H NMR(CDCl3400MHz):δ7.41(t,1H),7.27(s, 1H),7.18(m,2H),6.41(s,1H),6.23(t,1H),5.3 0(s,1H),4.16-4.06(m,3H),3.74(s,1H),2.69- 2.56 (m, 2H), 1.00-0.90 (m, 4H). LC-MS:t R =2.53 min (LCMS method 2), m / z=452.1[M+H] + . SFC:t R = 1.21 minutes (SFC method 7), ee% = 100%.

[0272] Example 4b: 1 H NMR(CDCl3400MHz):δ7.40(t,1H),7.27(s, 1H),7.18(m,2H),6.42(s,1H),6.24(t,1H),5.3 0(s,1H),4.19-4.05(m,3H),3.69(s,1H),2.71- 2.55 (m, 2H), 0.93-0.83 (m, 4H). LC-MS:t R =2.63 min (LCMS method 1), m / z=452.1[M+H] + . SFC:t R = 1.57 minutes (SFC method 7), ee% = 99.8%.

[0273] Example 5a: 3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro (Difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy Propanamide [ka] and Example 5b: 3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro (Difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy Propanamide [ka] Step 1: (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoro Toxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropane Preparation of amides [ka] Prepared from Ve

[0274] Step 2: (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(diph (Difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydro Xypropanamide and (S)-3-(3,3-difluorocyclobutyl)-N-((R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl Separation of )-3-hydroxypropanamide [ka] (R)-3-(3,3-difluorocyclobutyl)-N-(2-(trifluoromethoxy) (C)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropaneamide The dots were separated using chiral SFC.

[0275] Example 5a: 1 H NMR(CDCl3400MHz):δ7.37(t,1H),7.17(d, 1H),7.09-7.07(m,2H),6.51(t,1H),6.32(m,1H ),6.13(t,1H),5.30-5.25(m,1H),4.18-4.14(m ,1H),4.10-4.06(m,1H),4.00-3.96(m,1H),3.6 4(d, 1H), 2.59 - 2.55(m, 3H), 2.45 - 2.35(m, 2H), 2.34 - 2.26(m, 1H), 2.21 - 2.08(m, 1H). LC - MS: t R = 2.74 min (LCMS method 1), m / z = 416.1 [M + H] + . SFC: t R = 2.49 min (SFC method 4), ee% = 97.7%.

[0276] Example 5b: 1 1H NMR (CDCl3 400 MHz): δ 7.37(t, 1H), 7.17(d, 1H), 7.08 - 7.07(m, 2H), 6.51(t, 1H), 6.32(m, 1H ), 6.23(t, 1H), 5.30 - 5.26(m, 1H), 4.18 - 4.15(m , 1H), 4.11 - 4.07(m, 1H), 4.02 - 3.98(m, 1H), 2.6 4 - 2.51(m, 3H), 2.45 - 2.36(m, 2H), 2.33 - 2.25(m , 1H), 2.21 - 2.16(m, 1H). LC - MS: t R = 2.73 min (LCMS method 1), m / z = 416.1 [M + H] + . SFC: t R = 2.59 min (SFC method 4), ee% = 96.1%.

[0277] Example 6a: 3-(3,3 - difluorocyclobutyl)-N-((R)-2-(difluoro methoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3 - hydroxy propanamide[[ID=I48]]

Chemical formula

[0278] Step 2: (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(diph (Oromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-Hydromethyl Roxypropanamide and (S)-3-(3,3-difluorocyclobutyl)-N-(( R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl) Separation of tyl-3-hydroxypropanamide [ka] (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy) )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropaneamide The dots were separated using chiral SFC.

[0279] Example 6a: 1 H NMR(CDCl3400MHz):δ7.41(t,1H),7.26(d, 1H),7.19(d,2H),6.38(d,1H),6.24(t,1H),5.3 3 - 5.28 (m, 1H), 4.20 - 4.16 (m, 1H), 4.13 - 4.10 (m , 1H), 4.01 - 4.00 (s, 1H), 3.56 (d, 2H), 2.61 - 2.5 4 (m, 3H), 2.44 - 2.39 (m, 2H), 2.39 - 2.32 (m, 1H), 2.18 (m, 1H). LC - MS: t R = 2.53 min (LCMS method 1), m / z = 434.0 [M + H] + . SFC: t R = 1.62 min (SFC method 5), ee% = 92.9%.

[0280] Example 6b: 1 1H NMR (CDCl3 400 MHz): δ 7.42 (t, 1H), 7.26 (d, 1H), 7.20 - 7.18 (m, 2H), 6.34 (d, 1H), 6.24 (t, 1H ), 5.33 - 5.28 (m, 1H), 4.20 - 4.16 (m, 1H), 4.13 - 4 .00 (m, 1H), 4.00 (m, 1H), 3.61 (s, 1H), 2.61 - 2.5 7 (m, 3H), 2.43 - 2.39 (m, 2H), 2.39 - 2.32 (m, 1H), 2.20 (m, 1H). LC - MS: t R = 2.54 min (LCMS method 1), m / z = 434.0 [M + H] + . SFC: t R = 1.71 min (SFC method 5), ee% = 97.9%.

[0281] Example 7a: 3 - (3,3 - difluorocyclobutyl) - N - ((S) - 1 - (3 - (di fluoromethoxy)phenyl)butyl) - 3 - hydroxypropanamide

Chemical formula

[0282] Step 2: (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3- (Difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide and (R) -3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoro Separation of Toxy(phenyl)butyl)-3-hydroxypropanamide [ka] 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoro Toxy(phenyl)butyl)-3-hydroxypropanamide is separated by chiral SFC. I let go.

[0283] Example 7a: 1 H NMR(CDCl3400MHz):δ7.32(t,1H),7.11(d, 1H),7.01-7.00(m,2H),6.49(t,1H),5.85(d,1H ),4.93(q,1H),3.94-3.91(m,1H),3.81(d,1H), 2.56-2.21(m,7H),1.74-1.69(m,2H),1.33-1.2 8(m,2H), 0.91(t,3H). LC-MS:t R =2.41 min (LC-MS method 1), m / z=378.0[M+H] + . SFC:t R =2.37 minutes (SFC method 6), ee%=92.4%

[0284] Example 7b: 1 H NMR(CDCl3400MHz):δ7.31(t,1H),7.10(d, 1H),7.01-7.00(m,2H),6.49(t,1H),5.86(d,1H ),4.93(q,1H),3.96-3.92(m,1H),3.77(d,1H), 2.54-2.14(m,7H),1.74-1.70(m,2H),1.33-1.2 8(m,2H), 0.91(t,3H). LC-MS:t R =2.45 minutes (LC-MS method 1), m / z=378.0[M+H] + . SFC:t R = 2.49 minutes (SFC method 6), ee% = 99.5%

[0285] Example 8a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Namido [ka] and Example 8b: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Namido [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Preparation of Mido [ka] Prepared from Vh

[0286] Step 2: (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropyl Ropanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3(di Fluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-Hyd Separation of roxypropanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen (Nyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide It was separated using chiral SFC.

[0287] Example 8a: 1 H NMR(CDCl3400MHz):δ7.28(t,1H),7.11(d, 1H),7.03(s,1H),6.98(d,1H),6.66(d,1H),6.4 4(t,1H),6.14(t,1H),5.24-5.19(m,1H),4.10- 4.02(m,2H),3.47-3.44(m,1H),2.57(d,1H),2. 50-2.41(m,2H),1.53-1.48(m,2H),1.34-1.31( m,1H),0.83-0.80(m,3H),0.38-0.29(m,4H). LC-MS:t R =2.38 min (LCMS method 1), m / z=394.0[M+H] + . SFC:t R = 2.38 minutes (SFC method 1), ee% = 99.4%

[0288] Example 8b: 1 H NMR(CDCl3400MHz):δ7.29(t,1H),7.11(d, 1H),7.01-6.99(m,2H),6.67(d,1H),6.44(t,1H ),6.15(t,1H),5.24-5.19(m,1H),4.10-4.00(m ,2H),3.49-3.47(d,1H),2.64(d,1H),2.49-2.4 1(m,2H),1.53-1.48(m,2H),1.34-1.31(m,1H), 0.83-0.80(m,3H),0.39-0.29(m,4H). LC-MS:t R =2.38 min (LCMS method 1), m / z=394.0[M+H] + . SFC: t=2.60 min (SFC method 1), ee%=98.7%

[0289] Example 9a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybuta Namido [ka] and Example 9b: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh Xy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybuta Namido [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane Preparation of Mido [ka] (R)-2-(difluoromethoxy)-1-(3-(difluoro) in DCM (20 mL) Romethoxyphenyl)ethane-1-amine hydrochloride (IIa) (400 mg) and 3-( 1-Fluorocyclopropyl)-3-hydroxybutanoic acid (IIIc) (307 mg) In the solution, add N-hydroxybenzotriazole (HOBt) (213 mg) and 1-ethyl -3-(3-dimethylaminopropyl)carbodiimide (EDCI) (363 mg) and Et3N (320 mg) was added. The mixture was stirred at 25°C for 16 hours, and then water (10 mL) was added. Diluted and extracted with ethyl acetate (20 mL x 3). The combined organic extract was then treated with Na2SO4. The mixture was dried, filtered, and concentrated. The residue was purified by basic preparative HPLC. Prepared as N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane I obtained Mid (250 mg).

[0290] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Butanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(di Fluoromethoxy(phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-H Separation of droxybutanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Nyl(ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide It was separated using chiral SFC.

[0291] Example 9a: 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.20(d, 1H),7.10(m,2H),6.52(t,1H),6.39(d,1H),6.2 5(t,1H),5.31(m,1H),4.80(s,1H),4.15(m,2H) ,2.71(dd,1H),2.54(dd,1H),1.36(s,3H),0.85 -0.55 (m, 4H). LC-MS:t R =2.48 min (LCMS method 1), m / z=398.2[M+H] + . SFC:t R = 2.46 minutes (SFC method 12), ee% = 100%.

[0292] Example 9b: 1 H NMR(CDCl3400MHz):δ7.39(t,1H),7.19(d, 1H),7.10-7.08(m,2H),6.52(t,1H),6.42(m,1H ),6.24(t,1H),5.33-5.28(m,1H),4.71(s,1H), 4.19-4.10(m,2H),2.72(d,1H),2.52(d,1H),1. 36 (s, 3H), 0.99-0.85 (m, 4H). LC-MS:t R =2.47 min (LCMS method 1), m / z=398.1[M+H] + . SFC:t R = 2.65 minutes (SFC method 12), ee% = 98.8%.

[0293] Using the relevant intermediates, a similar methodology to that described in Examples 9a and 9b can be applied. Therefore, the following embodiments were prepared: Example 10a: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro Methoxy(phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Butanamide [ka] and Example 10b: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro Methoxy(phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Butanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) Phenylethyl-3-(1-fluorocyclopropyl)-3-hydroxybutane Preparation of amides [ka] Prepared from IIb and IIIc.

[0294] Step 2: (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro (Methoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxyl Sibutanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3-( Trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3 - Separation of hydroxybutanamides [ka] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (Ethyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide These were separated using chiral SFCs.

[0295] Example 10a: 1 H NMR(CDCl3400MHz):δ7.48(t,1H),7.35(d, 1H),7.27-7.25(m,2H),6.64(d,1H),6.31(t,1H ),5.40-5.38(m,1H),4.86(s,1H),4.26-4.18(m ,2H),2.78(d,1H),2.60(d,1H),1.42(s,3H),0. 86-0.57 (m, 4H). LC-MS:t R =2.64 min (LCMS method 1), m / z=416.2[M+H] + . SFC:t R = 2.38 minutes (SFC method 2), ee% = 100%.

[0296] Example 10b: 1 H NMR(CDCl3400MHz):δ7.42(t,1H),7.29(m, 1H),7.20-7.19(m,2H),6.44-6.06(m,2H),5.35 -5.31(m,1H),4.67(s,1H),4.20-4.12(m,2H),2 .73(dd,1H),2.53(dd,1H),1.36(s,3H),0.99-0 0.86 (m, 4H). LC-MS:t R =2.659 min (LCMS method 1), m / z=416.2[M+H] + . SFC:t R = 2.561 minutes (SFC method 6), ee% = 95.9%.

[0297] Example 11a: 3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1- (3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] and Example 11b: 3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1- (3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] Step 1: 3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3- Preparation of (trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] Prepared from IIb and IIId.

[0298] Step 2: (R)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1 -(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide and (S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3 Separation of (trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] 3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(tri Fluoromethoxy(phenyl)ethyl)-3-hydroxybutanamide to chiral SFC Therefore, they were separated.

[0299] Example 11a: 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.26(d, 1H),7.17-7.15(m,2H),6.72(d,1H),6.21(t,1H ),5.35-5.31(m,1H),4.17-4.09(m,2H),3.36(s ,1H),2.52-2.42(m,2H),1.18(s,3H),0.90-0.8 8 (m, 1H), 0.43-0.34 (m, 4H). LC-MS:t R =2.42 min (LCMS method 1), m / z=420.1[M+Na] + . SFC:t R = 2.17 minutes (SFC method 13), ee%=100%.

[0300] Example 11b: 1 H NMR (CDCl3400MHz): δ7.39(t,1H),7.29-7. 20(m,1H),7.21-7.16(m,2H),6.74(d,1H),6.23 (t,1H),5.36-5.32(m,1H),4.19-4.10(m,2H),3 .40(s,1H),2.49(s,2H),1.18(s,3H),0.90-0.8 7 (m, 1H), 0.41-0.27 (m, 4H). LC-MS:t R =2.95 min (LCMS method 1), m / z=420.1[M+Na] + . SFC:t R = 2.48 minutes (SFC method 13), ee% = 100%.

[0301] Example 12a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy(phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methyl Pentaneamide [ka] and Example 12b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy(phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methyl Pentaneamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpenta Preparation of naamide [ka] Prepared from IIa and IIIe.

[0302] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methyl Lupentanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3- (Difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy Separation of C-3-methylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Nyl(ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentaneamide The dots were separated using chiral SFC.

[0303] Example 12a: 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.17(d, 1H),7.10-7.08(m,2H),6.51(t,1H),6.37(d,1H ),6.25(t,1H),5.32-5.27(m,1H),4.68(s,1H), 4.18(dd,1H),2.52(dd,1H),2.61-2.52(m,2H), 2.47-2.41 (m, 2H), 1.40 (s, 3H). LC-MS:t R =2.52 min (LCMS method 1), m / z=422.1[M+H] + . SFC:t R = 1.10 minutes (SFC method 14), ee% = 100%.

[0304] Example 12b: 1 H NMR(CDCl3400MHz):δ7.39(t,1H),7.18(d, 1H),7.10-7.08(m,2H),6.52(t,1H),6.36(d,1H ),6.24(t,1H),5.33-5.29(m,1H),4.68(s,1H), 4.18(dd,1H),2.52(dd,1H),2.61-2.42(m,4H), 1.39 (s, 3H). LC-MS:t R =2.52 min (LCMS method 1), m / z=422.1[M+H] + . SFC:t R = 1.24 minutes (SFC method 14), ee% = 95.8%.

[0305] Example 13a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy(phenyl)ethyl)-3-hydroxy-3,5-dimethylhexaneamide [ka] and Example 13b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy(phenyl)ethyl)-3-hydroxy-3,5-dimethylhexaneamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Preparation of phenyl(ethyl)-3-hydroxy-3,5-dimethylhexaneamide [ka] Prepared from IIa and IIIg.

[0306] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-hydroxy-3,5-dimethylhexaneamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Separation of phenyl(ethyl)-3-hydroxy-3,5-dimethylhexaneamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Nyl(ethyl)-3-hydroxy-3,5-dimethylhexaneamide is converted to chiral SFC And then it separated.

[0307] Example 13a: 1 H NMR(CDCl3400MHz):δ7.37(t,1H),7.19(d, 1H),7.10-7.07(m,2H),6.76(d,1H),6.51(t,1H ),6.23(t,1H),5.35-5.30(m,1H),4.19-4.08(m ,2H),3.39(s,1H),2.51-2.34(m,2H),1.84-1.7 6(m,1H),1.43(d,2H),1.27(s,3H),0.98-0.95( m,6H). LC-MS:t R =2.54 min (LCMS method 1), m / z=396.1[M+H] + . SFC:t R = 2.40 minutes (SFC method 15), ee% = 99.3%.

[0308] Example 13b: 1 H NMR(CDCl3400MHz):δ7.37(t,1H),7.19(d, 1H),7.10(s,1H),7.07(d,1H),6.73(d,1H),6.5 1(t,1H),6.23(t,1H),5.35-5.31(m,1H),4.19- 4.09(m,2H),3.37(s,1H),2.50-2.34(m,2H),1. 85-1.76(m,1H),1.45(d,2H),1.26(s,3H),1.00 -0.94 (m, 6H). LC-MS:t R =2.54 min (LC-MS method 1), m / z=396.1[M+H] + . SFC:t R = 2.66 minutes (SFC method 15), ee% = 98.8%.

[0309] Example 14a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy(phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] and Example 14b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy(phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Preparation of phenyl(ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] Prepared from IIa and IIIf.

[0310] Step 2: (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Separation of phenyl(ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Nyl(ethyl)-3-hydroxy-3,4-dimethylpentanamide is used with chiral SFCs. It was separated using [a specific method / tool].

[0311] Example 14a: 1 H NMR(CDCl3400MHz):δ7.34(t,1H),7.16(d, 1H),7.07(s,1H),7.04(d,1H),6.76(d,1H),6.4 8(t,1H),6.20(t,1H),5.32-5.27(m,1H),4.16- 4.12(m,1H),4.09-4.04(m,1H),3.39(s,1H),2. 49-2.28(m,2H),1.77-1.70(m,1H),1.15(s,3H) ,0.93-0.89(m,6H). LC-MS:t R =2.41 min (LCMS method 1), m / z=382.0[M+H] + . SFC:t R = 2.44 minutes (SFC method 15), ee% = 100%.

[0312] Example 14b: 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.16(d, 1H),7.08(s,1H),7.04(d,1H),6.79(d,1H),6.4 8(t,1H),6.19(t,1H),5.31-5.26(m,1H),4.14- 4.10(m,1H),4.08-4.04(m,1H),3.43(s,1H),2. 48-2.28(m,2H),1.75-1.69(m,1H),1.12(s,3H) ,0.92-0.88(m,6H). LC-MS:t R =2.41 min (LCMS method 1), m / z=382.0[M+H] + . SFC:t R = 2.68 minutes (SFC method 15), ee% = 97.4%.

[0313] Example 15a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxy Propanamide [ka] and Example 15b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Toxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxy Propanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropane Preparation of naamide [ka] Prepared from IIa and IIIh.

[0314] Step 2: (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro Methoxy(phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxy Cypropanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3- (difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)- Separation of 3-hydroxypropanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phen Nyl(ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropaneamide The dots were separated using chiral SFC.

[0315] Example 15a: 1 H NMR (DMSO-d6 400MHz): δ8.41(d,1H),7.40( t,1H),7.26(d,1H),7.21(t,1H),7.20(s,1H),7 .09(d,1H),6.67(t,1H),5.17-5.12(m,1H),4.6 1(d,1H),3.98-3.97(m,2H),3.70-3.67(m,1H), 2.16-2.11(m,3H),1.64-1.52(m,4H),1.09(s,3 H), 0.99(s,3H). LC-MS:t R =2.35 minutes (LC-MS method 3), m / z=408.1[M+H] + . SFC:t R = 2.32 minutes (SFC method 16), ee% = 99.7

[0316] Example 15b: 1H NMR (DMSO-d6 400MHz): δ8.43(d,1H),7.40( t,1H),7.24(d,1H),7.22(t,1H),7.18(s,1H),7 .08(d,1H),6.67(t,1H),5.14-5.10(m,1H),4.6 3(d,1H),3.99-3.96(m,2H),3.70-3.67(m,1H), 2.13-2.08(m,3H),1.64-1.49(m,4H),1.06(s,3 H), 0.97(s,3H). LC-MS:t R =2.34 min (LCMS method 3), m / z=408.1[M+H] + . SFC:t R = 2.64 minutes (SFC method 16), ee% = 98.7%.

[0317] Example 16a: 3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1- (3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] and Example 16b: 3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1- (3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] Step 1: 3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3- Preparation of (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] Prepared from IIa and IIIi.

[0318] Step 2: (S)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1 -(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and bi(R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3 Separation of (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] 3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(diph (Oromethoxy)phenyl)ethyl)-3-hydroxypropanamide to chiral SFC Therefore, they were separated.

[0319] Example 16a: 1 H NMR(DMSO-d6 400MHz)δ8.43(d,1H),7.39(t ,1H),7.27-7.25(m,1H),7.20(s,1H),7.20(t,1 H),7.08(d,1H),6.66(t,1H),5.16-5.14(m,1H) ,4.61(d,1H),3.99-3.97(m,2H),3.69-3.65(m, 1H),2.26-2.25(m,2H),1.80-1.76(m,1H),1.64 -1.22 (m, 8H). LC-MS:t R =2.48 min (LC-MS method 1), m / z=394.1[M+H] + . SFC:t R = 2.64 minutes (SFC method 17), ee% = 98.8%.

[0320] Example 16b: 1H NMR (DMSO-d6 400MHz): δ8.41(d,1H),7.36( d,1H),7.20(d,1H),7.18(t,1H),7.15(s,1H),7 .04(m,1H),6.63(t,1H),5.13-5.07(m,1H),4.5 9(d,1H),3.98-3.91(m,2H),3.66-3.62(m,1H), 2.23-2.19(m,2H),1.73-1.69(m,1H),1.60-1.3 3 (m, 8H). LC-MS:t R =2.27 minutes (LC-MS method 2), m / z=394.2[M+H] + . SFC:t R = 3.08 minutes (SFC method 17), ee% = 100%

[0321] Example 36a: 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)- 2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide [ka] and Example 36b: 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)- 2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide [ka] Step 1: 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methyl Preparation of Toxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide [ka] Prepared from IIp and IIIc.

[0322] Step 2: (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R) -2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2 -Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide away [ka] Using chiral SFCs, 3-(1-fluorocyclopropyl)-3-hydroxy-N- ((R)-2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl) Pig Namide was isolated.

[0323] Example 36a: 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.29(d, 1H),7.22(s,1H),7.16(d,1H),6.58(d,1H),5.1 8-5.13(m,1H),5.04(s,1H),3.70-3.62(m,2H), 3.38(s,3H),2.72-2.68(m,1H),2.54-2.50(m,1 H),1.36(s,3H),0.81-0.53(m,4H). LC-MS:t R =2.43 minutes (LCMS method 1), m / z=380.0[M+H] + . SFC:t R = 1.29 minutes (SFC method 21), ee% = 99.6%.

[0324] Example 36b: 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.28-7. 27(m,1H),7.20(s,1H),7.15(d,1H),6.58(d,1H ),5.18-5.14(m,1H),4.93(s,1H),3.70-3.62(m ,2H),3.38(s,3H),2.71(dd,1H),2.52(dd,1H), 1.35 (s, 3H), 1.00-0.86 (m, 4H). LC-MS:t R =2.53 minutes (LCMS method 1), m / z=380.0[M+H] + . SFC:t R = 1.76 minutes (SFC method 22), ee% = 81.4%.

[0325] Example 17: (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethyl Toxy(phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy Preparation of phenylethyl-3-hydroxy-4,4-dimethylpentanamide [ka] (R)-2-cyclopropoxy-1-(3-(difluorometh) in DCM (10 mL) Xy(phenyl)ethane-1-amine hydrochloride (IIc) (0.2g), (3S)-3-H Droxy-4,4-dimethylpentanoic acid (IIIa) (144 mg) and HATU (3 DIEA (319 mg) was added to a 75 mg solution. The mixture was stirred at 20°C for 16 hours. Mixed and concentrated. The crude product was purified to obtain (S)-N-((R)-2-cyclopropoxy-1 -(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimeth Lupentanamide was obtained. 1 H NMR(CDCl3400MHz):δ7.33(t,1H),7.17(d, 1H),7.08(s,1H),7.03(d,1H),6.49(m,1H),6.5 1(t,1H),5.18-5.14(m,1H),3.80-3.78(m,1H), 3.72-3.66(m,2H),3.42(d,1H),3.35-3.25(m,1 H),2.44-2.26(m,2H),0.93(s,9H),0.57-0.45( m,4H). LC-MS:t R =2.40 min (LCMS method 1), m / z=372.1[M+H] + . SFC:t R = 1.988 minutes (SFC method 7), ee% = 97.5%.

[0326] Using the relevant intermediates, the following can be achieved by a similar methodology described for Example 17: Examples were prepared.

[0327] Example 18: (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2 -(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentaneamide Do [ka] Prepared from IIe and IIIa. 1 H NMR(CDCl3400MHz):δ7.41-7.36(m,1H),7. 18(d,1H),7.10-7.08(m,2H),6.67(d,1H),6.52 (t,1H),5.37-5.32(m,1H),4.28-4.20(m,1H),3 .69(d,1H),2.93(s,1H),2.47-2.43(m,1H),2.3 6-2.29 (m, 1H), 0.93 (s, 9H). LC-MS:t R =2.38 min (LCMS method 3), m / z=400.0[M+H] + . SFC:t R = 2.11 minutes (SFC method 4), ee% = 96.4%.

[0328] Example 19: (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)- 2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentane Mido [ka] 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.21-7. 19(m,1H),7.13-7.11(m,2H),6.65(d,1H),5.32 -5.27(m,1H),4.21-4.13(m,1H),3.64-3.61(m, 1H),2.83(d,1H),2.41-2.36(m,1H),2.29-2.25 (m,1H),0.86(s,9H). LC-MS:t R =2.56 min (LCMS method 3), m / z=418.0[M+H] + . HPLC:t R = 13.54 minutes (HPLC method 2), ee% = 65.9%

[0329] Example 20: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)buty (L)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from IIg and IIIa. 1 H NMR(CDCl3400MHz):δ7.33(t,1H),7.14(d, 1H),7.03-7.00(m,2H),6.52(t,1H),6.22-6.20 (m,1H),4.97(q,1H),3.68-3.64(m,1H),3.31(d ,1H),2.39-2.24(m,2H),1.75-1.72(m,2H),1.3 6-1.29(m,2H),0.95-0.91(m,12H). LC-MS:t R =2.30 minutes (LCMS method 3), m / z=344.1[M+H] + . SFC:t R = 2.13 minutes (SFC method 1), ee% = 98.7%.

[0330] Example 21: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4 ,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from IIh and IIIa. 1 H NMR(CDCl3400MHz):δ7.36(t,1H),7.14(d, 1H),7.05(m,2H),6.52(t,1H),6.25(d,1H),5.8 4(tt,1H),5.03(q,1H),3.68(m,1H),2.97(d,1H ),2.40-2.21(2H),1.98-1.77(4H),0.91(s,9H) . LC-MS:t R=2.43 minutes (LCMS method 1), m / z=380.0[M+H] + . HPLC:t R = 14.01 minutes (HPLC method 3), ee% = 95.7%.

[0331] Example 22: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3 ,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from IIi and IIIa. 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.14(d, 1H),7.05-7.03(m,2H),6.50(t,1H),6.53-6.50 (m,1H),5.80(tt,1H),5.30-5.24(m,1H),3.66( dd,1H),2.89(s,1H),2.40-2.22(m,4H),0.89(s ,9H). LC-MS:t R =2.63 min (LCMS method 1), m / z=366.2[M+H] + . HPLC:t R = 13.43 minutes (HPLC method 1), ee% = 96.7%.

[0332] Example 23: (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)eth (L)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from IIj and IIIa. 1 H NMR(CDCl3400MHz):δ7.34-7.30(m,1H),7. 16-7.12(m,1H),7.04-6.97(m,2H),6.31(t,1H) ,6.14(brs,1H),5.12-5.06(m,1H),3.67-3.62( m,1H),3.29(s,1H),2.37-2.31(m,1H),2.26-2. 19(m,1H),1.47-1.43(m,3H),0.98(s,9H). LC-MS:t R =2.155 minutes (LCMS method 2), m / z=316.1[M+H] + . SFC:t R = 2.416 minutes (SFC method 8), ee% = 100%.

[0333] Example 24: (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy) Phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from IIm and IIIa. 1 H NMR(400MHz,DMSO-d6):δ8.66(d,1H),7.51( t,1H),7.45-7.43(m,2H),7.30(d,1H),5.25-5. 23(m,1H),4.62(d,1H),3.57-3.51(m,1H),3.00 (dd,2H),2.31-2.11(m,2H),0.81(s,9H). LC-MS:t R =2.42 minutes (LSMS method 1), m / z=359.2[M+H] + . HPLC:t R = 12.56 minutes (HPLC method 4), ee% = 100%.

[0334] Example 25: (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy) Phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from IIn and IIIa. 1 H NMR(CDCl3400MHz):δ7.42(t,1H),7.24(m, 1H),7.18(d,1H),7.13(s,1H),6.49(d,1H),5.1 9-5.13(m,1H),3.75-3.71(m,1H),2.82(d,1H), 2.45-2.40(m,3H),2.30-2.27(m,1H),2.23-2.1 6 (m, 2H), 0.92 (s, 9H). LC-MS:t R =2.44 min (LCMS method 1), m / z=373.2[M+H] + . SFC:t R = 1.47 minutes (SFC method 9), ee% = 95.8%.

[0335] Example 26: (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N- (2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl) Acetamide [ka] Prepared from IIa and IIIb. 1 H NMR(CDCl3400MHz):δ7.37(t,1H),7.15(d, 1H),7.09-7.06(m,2H),6.50(t,1H),6.32(t,1H ),6.23(m,1H),5.29-5.24(m,1H),4.74(s,1H), 4.17(dd,1H),4.08(dd,1H),2.75-2.72(m,2H), 2.68 (s, 2 hours), 2.62-2.56 (m, 2 hours). LC-MS:t R =2.39 min (LCMS method 1), m / z=402.1[M+H] + . SFC:t R = 1.87 minutes (SFC method 1), ee% = 100%

[0336] Example 27: (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N- (2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl ) Acetamide [ka] Prepared from IIb and IIIb. 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.14-7. 09(m,3H),6.18(t,1H),6.21(d,1H),5.23(m,1H ),4.66(brs,1H),4.13(dd,1H),4.04(dd,1H),2 .72-2.66(m,2H),2.64(s,2H),2.56-2.50(m,2H) ). LC-MS:t R =2.53 minutes (LC-MS method 1), m / z=420.2[M+H] + . HPLC:t R = 12.77 minutes (HPLC method 2), ee% = 86.7%.

[0337] Example 28: (R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy) )phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetate Toamido [ka] Prepared from IId and IIIb. 1 H NMR(CDCl3400MHz):δ7.37(t,1H),7.22(d, 1H),7.15(m,2H),6.40(d,1H),5.13(m,1H),4.9 2(s,1H),3.81(m,1H),3.69(m,1H),3.29(m,1H) 2.78-2.52 (6H), 0.57-0.44 (4H). LC-MS:t R =2.53 minutes (LC-MS method 1), m / z=410.0[M+H] + . SFC:t R = 1.50 minutes (SFC method 7), ee% = 99.7%

[0338] Example 29: (R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy) Phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)aceto Amido [ka] Prepared from IIe and IIIb. 1 H NMR(CDCl3400MHz):δ7.35(d,1H),7.15(d, 1H),7.06(s,1H),7.05(d,1H),6.51(t,1H),6.3 9(d,1H),5.15-5.10(m,1H),4.98(m,1H),3.83- 3.67(m,2H),3.31-3.30(m,1H),2.79-2.75(m,2 H),2.68(d,2H),2.64-2.52(m,2H),0.60-0.46( m,4H). LC-MS:t R =2.40 minutes (LC-MS method 1), m / z=392.1[M+H] + . SFC:t R = 2.32 minutes (SFC method 6), ee% = 100.00%

[0339] Example 30: (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N- (1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl ) Acetamide [ka] Prepared from IIe and IIIb. 1 H NMR(CDCl3400MHz):δ7.39(t,1H),7.15(d, 1H),7.08(m,2H),6.51(t,1H),6.30(m,1H),5.3 2(m,1H),4.63(s,1H),4.23(m,2H),2.76-2.57( 6H). LC-MS:t R =2.48 minutes (LC-MS method 1), m / z=420.0[M+H] + . SFC:t R = 12.96 minutes (HPLC method 2), ee% = 75.5%

[0340] Example 31: (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N- (1-(3-(difluoromethoxy)phenyl)butyl)acetamide [ka] Prepared from IIg and IIIb. 1 H NMR(CDCl3400MHz):δ7.35(t,1H),7.13(d, 1H),7.04(m,2H),6.52(t,1H),5.91(m,1H),5.0 4(s,1H),4.96(q,1H),2.78-2.56(6H),1.76(m, 2H), 1.34(m,2H), 0.95(t,3H). LC-MS:t R =2.44 min (LC-MS method 1), m / z=364.0[M+H] + . SFC:t R = 1.71 minutes (SFC method 10), ee% = 94.8%.

[0341] Example 32: (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N- (1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetate Mido [ka] Prepared from IIh and IIIb. 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.13(d, 1H),7.08(d,1H),7.04(s,1H),6.52(t,1H),5.9 0(d,1H),5.85(tt,1H),5.00(q,1H),4.82(s,1H ),2.78-2.54(6H),2.00(m,2H),1.86(m,2H). LC-MS:t R =2.50 min (LCMS method 1), m / z=400.1[M+H] + . HPLC:t R = 12.48 minutes (HPLC method 2), ee% = 98.3%.

[0342] Example 33: (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N- (1-(3-(trifluoromethoxy)phenyl)propyl)acetamide [ka] Prepared from IIl and IIIb. 1 H NMR(CDCl3400MHz):δ7.38(t,1H),7.20(d, 1H),7.14(d,1H),7.10(s,1H),5.89(d,1H),4.9 9(brs,1H),4.89(q,1H),2.77-2.70(m,2H),2.6 3(d,2H),2.60-2.50(m,2H),1.87-1.80(m,2H), 0.92(t,3H). LC-MS:t R =2.57 min (LCMS method 1), m / z=368.1[M+H] + . SFC:t R = 13.09 minutes (SFC method 1), ee% = 100%

[0343] Example 34: (S)-N-(2-cyano-1-(3-(trifluoromethoxy)phenyl )ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide [ka] Prepared from IIm and IIIb. 1 H NMR(CDCl3400MHz):δ7.46(t,1H),7.30(d, 1H),7.24(m,1H),7.19(s,1H),6.51(s,1H),5.3 4-5.29(m,1H),4.44(s,1H),3.09-3.03(m,1H), 2.91-2.89(m,1H),2.77-2.73(m,2H),2.70-2.5 3(m,4H). LC-MS:t R =2.257 minutes (LC-MS method 1), m / z=379.0[M+H] + . SFC:tR = 2.60 minutes (SFC method 11), ee% = 100%.

[0344] Example 35: (S)-N-(3,3-difluoro-1-(3-(trifluoromethoxy) Phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetate Toamido [ka] Prepared from IIo and IIIb. 1 H NMR(CDCl3400MHz):δ7.44(t,1H),7.23(m, 2H),7.15(s,1H),6.15(brd,1H),5.83(tt,1H), 5.32(m,1H),4.69(s,1H),2.73(m,2H),2.66(s, 2H), 2.62-2.34 (4H). LC-MS:t R =2.53 minutes (LC-MS method 1), m / z=404.1[M+H] + . SFC:t R = 1.66 minutes (SFC method 19), ee% = 98.5%

Claims

1. Compound (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, or a pharmaceutically acceptable salt of this compound.

2. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

3. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of patients suffering from epilepsy, bipolar disorder, migraine, or schizophrenia.

4. A pharmaceutical composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of patients suffering from psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity disorder, personality disorders, schizotypal disorders, aggression, chronic pain, neurological disorders, autism spectrum disorder, Huntington's disease, sclerosis, multiple sclerosis, or Alzheimer's disease.

5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine, or schizophrenia.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity disorder, personality disorders, schizotypal disorders, aggression, chronic pain, neurological disorders, autism spectrum disorder, Huntington's disease, sclerosis, multiple sclerosis, or Alzheimer's disease.

7. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, for the treatment of epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures.

8. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof for the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), and benign familial neonatal convulsions, and other epilepsy syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with persistent spike-and-wave seizures during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or metabolic disorders (such as hyponatremia).

9. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof for the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, and frontotemporal lobar degeneration.

10. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures.

11. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE), benign familial neonatal seizures, and other epilepsy syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with persistent spike-and-wave seizures during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or for the manufacture of a medicament for treating epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body dementia, juvenile Huntington's disease, and frontotemporal lobar degeneration.

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