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] The present invention relates to novel compounds that activate Kv7 potassium channels. Aspects also include pharmaceutical compositions containing the compounds, and compounds that respond to activation of Kv7 potassium channels. The present invention relates to the use of compounds for treating diseases associated with rheumatoid arthritis. [Background technology]

[0002] Voltage-gated potassium (Kv) channels transport potassium across the cell membrane in response to changes in membrane potential. Muion (K + ) and thereby modulate (increase or decrease) the electrical activity of the cell. Functional Kv channels are composed of four α It exists as a multimeric structure formed by the association of a subunit and four β subunits The α subunit contains six transmembrane domains, a pore-forming loop, and a voltage sensor. The β or auxiliary subunits are arranged symmetrically around the central pore. The electrophysiological or biophysical properties, expression level, and or altering the properties of the channel complex, including but not limited to altering the expression pattern. You can ask questions.

[0003] Nine families of Kv channel α subunits have been identified, Kv1-Kv9 Therefore, the function of Kv channels is determined by the existence of many subfamilies and subgroups. The formation of both homologous and heterologous subunits within the β subunits There is a huge diversity that arises as a result of the additive effects of association with chromosomes (Christi e,25 Clinical and Experimental Pharmacol ogy and physiology,1995,22,944-951).

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

[0005] As mentioned above, Kv7 potassium channels in neurons play a role in regulating neuronal excitation. Kv7 channels, especially the Kv7.2 / Kv7.3 heterodimer, play a key role in It forms the basis of electric current (Wang et al. Science. 1998 Dec 4;282(5395):1890-3). M currents are produced by membrane potentials in response to multiple excitatory stimuli. It has a characteristic time and voltage dependence that results in stabilization of the potential.

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

[0007] Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl)caprylate carbamic acid ethyl ester) is a compound that binds to Kv7 potassium channels (Wu ttke,et al.,Molecular Pharmacology,2005, 67,1009-1017). Retigabine inhibits K + Activate the current and The pharmacology of electrogenic current is Kv7.2 / 3 K + M-channels correlate with heteromultimers This is consistent with the published pharmacology of Kv7.2 / 3 channels, which may explain the activity of Kv7.2 / 3 channels. This suggests that this may be responsible for at least part of the drug's anticonvulsant effects (Wicken den,et al.,Molecular Pharmacology 2000,5 8,591-600). Retigabine reduces the incidence of epileptic seizures in patients with epilepsy. (Bialer, et al., Epilepsy Research 2002, 51, 31-71). Retigabine has broad spectrum and potent anticonvulsant activity. It has been successfully administered orally and intraperitoneally to rats and mice in various anticonvulsant studies. (Rostock, et al., Epilepsy Research h 1996,23,211-223).

[0008] The five members of this family of ion channels differ in their expression patterns. Expression of Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle, whereas expression of Kv7.2 and Kv7.3 Expression of Kv7.1, Kv7.2, and Kv7.5 is increased in the hippocampus, cerebral cortex, ventral tegmental area, and dorsal root ganglia. It appears to be predominant in the nervous system, including ganglionic neurons (Greene & Hoshi ,Cellular and Molecular Life Sciences,20 17,74(3),495-508 for a review).

[0009] The KCNQ2 and KCNQ3 genes are involved in the development of a type of epilepsy known as benign familial neonatal convulsions. It appears to be mutated in genotypes (Rogawski, Trends in Ne urosciences 2000,23,393-398). KCNQ2 and KCNQ The proteins encoded by the three genes are involved in the initiation and propagation of epileptic seizures. It is localized in pyramidal neurons of the human cerebral cortex and hippocampus, the regions of the brain where al., Proceedings National Academy of Sci. ence USA 2000,97,4914-4919).

[0010] Furthermore, in addition to Kv7.2 mRNA, Kv7.3 and 5 mRNAs were expressed in astrocytes. Kv7.2, Kv7.3, and Kv7.5 are expressed in cytoplasmic and glial cells. Channels help regulate synaptic activity in the CNS and may mediate the neuroprotection of KCNQ channel openers. It can contribute to the protective effect (Noda, et al., Society for N Euroscience Abstracts 2003, 53.9), which is These include, but are not limited to, Heimer's disease, Parkinson's disease, and Huntington's chorea. This makes it suitable for the treatment of neurodegenerative diseases.

[0011] The mRNAs of Kv7.2 and Kv7.3 subunits are expressed in disorders such as depression and bipolar disorder. It has been found in brain regions associated with calming and emotional behaviors, such as the hippocampus, ventral tegmental area, and amygdala. Saganich, et al., Journal of Neuroscience ce 2001,21,4609-4624;Friedman et al.,Nat Commun. 2016;7:11671.) Retigabine has been shown to be effective in animal models of anxiety-like behavior. It has been reported to be effective in rmacol Exp Ther.2005 Jul;314(1):282-92.E Published 2005 Apr 6.) Therefore, Kv7 channels are thought to be involved in the treatment of bipolar depression, ataxia, and other conditions. Emotional disorders including but not limited to depression, anxiety, suicide, anxiety attacks, and social phobia Suitable for the treatment of related diseases.

[0012] Kv7.2 / 3 channels have also been reported to be upregulated in models of neuropathic pain. (Wickenden, et al., Society for Neuros Science Abstracts 2002,454.7), potassium channel regulator It has been hypothesized that it may be effective for both neuropathic pain and epilepsy (Sch roder,et al.,Neuropharmacology 2001,40,8 88-898). In addition to its role in neuropathic pain, it is also involved in the trigeminal and dorsal root ganglia, as well as The expression of Kv7.2-5 mRNA in the trigeminal nucleus caudalis indicates that openers of these channels This means that sensory processing in migraines may also be affected (Goldstein, et al. l.Society for Neuroscience Abstracts 200 3,53.8) Taken together, this evidence supports the potential for the treatment of chronic pain and neuropathic disorders. This demonstrates the validity of KCNQ channel openers.

[0013] WO 07 / 90409 reports Kv7 channel inhibitors for the treatment of schizophrenia. Kv7 channel openers regulate the function of the dopaminergic system. (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 2 006 Jun 14), psychosis, mania, stress-related disorders, acute stress reactions, attention deficit Hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive disorder, personality disorder, schizophrenia These include schizotypical disorder, aggression, and autism spectrum disorder. It is suitable for the treatment of psychiatric disorders, including but not limited to the following. The target is a regulator of the M current formed by the expression of KCNQ2 and KCNQ3 genes. The use of the compound for insomnia is disclosed in WO 01 / 092526. It is disclosed that a modulator of Kv7.5 can be used to treat sleep disorders. Brochure No. 09 / 015667 discusses the use of Kv7 openers in the treatment of sexual dysfunction. It is disclosed.

[0014] Patients suffering from the above diseases may have available treatment options, but these options Many of the options lack the desired efficacy and are associated with unwanted side effects. There is an unmet need for new therapeutic approaches to treat the aforementioned diseases.

[0015] In an effort to identify new therapeutic approaches, the present inventors have identified a series of novel compounds represented by Formula I: Thus, the present invention provides compounds that inhibit the activity of KCNQ potassium channels. The present invention provides novel compounds as pharmaceuticals for treating diseases. Summary of the Invention

[0016] The present invention relates to a compound of formula I [ka] With respect to the compound In the formula, R1 is C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3- C8 cycloalkyl, wherein the C3-C8 cycloalkyl is selected from the group consisting of or may be substituted with two or more C1-C3 alkyls, F, CHF2 or CF3, and Beauty R2 is H, C1-C6 alkyl, or CF3; or R1 and R2 may be bonded (together with the carbon atom to which they are attached) to form one or two F, CHF 2、 or forms a C3-C5 cycloalkyl optionally substituted with CF3; and to R3 is C1-C3 alkyl or CHO-C 1~3 alkyl, and the C1 to C3 Alkyl or CHO-C 1~3 Alkyl is C≡N, 3F or C3-C5 cycloalkyl. is replaced by ; R4 is selected from the group consisting of OCF3, or OCHF2.

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

[0018] The present invention further provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient. It relates to pharmaceutical compositions.

[0019] Furthermore, the present invention provides a method for treating a patient as described in the claims and embodiments. The present invention relates to a method for treating a rheumatoid arthritis, which comprises administering to a subject a therapeutically effective amount of a compound of the present invention. This includes treating patients with epilepsy, bipolar disorder, migraine, and schizophrenia. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention According to one embodiment, the compound of formula I may have an R group that is OCF or OCHF. do.

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

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

[0023] In yet other embodiments, any compound according to Formula I has an R1 group and an R2 group. and the R1 and R2 groups are joined to form a cyclobutene optionally substituted with one or two F groups. R4 is OCF3 or OCHF2

[0024] According to a particular embodiment of the invention, the compounds according to the invention are (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)-2-methyl- (nyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethyl ...2-(trifluoromethyl)phenyl)-2-(trifluoromethyl)phenyl)-2-(trifluoromethyl)phenyl)-2-(trifluoromethyl)phenyl)-2-(trifluoromethyl)phenyl)- (Oromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethyl ...methyl)phenyl)-2-(trifluoromethyl)phenyl)-1-(3-(trifluoromethyl)phenyl)-2-(trifluoromethyl)phenyl)-1-(3 (fluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethoxy) ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propanol) 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)ethoxy) (ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (Difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetami or (S)—N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)- 2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide, or The compound is selected from the group consisting of pharmaceutically acceptable salts of any of these compounds.

[0025] Another aspect of the present invention is (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-trimethyl-N- ... (trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropane propyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropane propyl)propanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (1-(trifluoromethyl)cyclopropyl)-3-hydroxy-3-(phenyl)ethyl)- propyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (1-(trifluoromethyl)cyclopropyl)-3-hydroxy-3-(phenyl)ethyl)- propyl)propanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl) (3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Panamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl)- (3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Panamide (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl) (3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropyl lopanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl)- (3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropyl lopanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoro) ... (Oromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoro)cyclobutyl)- (Oromethoxy)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-hydroxybenzoate hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluoro (Orobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoro (Oropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-phenyl hydroxy-4,4-dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoro) (3-(difluoromethoxy)phenyl)ethyl)acetamide ; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoro) (3-(trifluoromethoxy)phenyl)ethyl)acetamido 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)propanol) 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-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) (phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane amide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane amide; (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 amide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpenta amide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (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 amide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropane amide; (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) thoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2 -Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide or a pharmaceutically acceptable salt of any of these compounds. Regarding.

[0026] Reference to compounds encompassed by the present invention includes racemic mixtures of the compounds as well as the compounds to which they relate. This invention also includes optical isomers of the compounds, as well as tautomeric forms of the compounds to which it is related. The disclosed compounds may be present in polymorphic and amorphous forms, or in pharmaceutical compositions such as water, ethanol, etc. They may exist in unsolvated as well as solvated forms with commercially acceptable solvents.

[0027] The present invention also includes isotopically labeled forms of the compounds of the present invention, such as deuterium. Positrons for medical imaging and positron emission tomography (PET) to determine the distribution of radiation in the body Suitable positron emitting isotopes can be incorporated in the compounds of the present invention. The isotopes are C, N, O, and F. The isotope-labeled compounds of the present invention are Generally, the labeling of the nucleotides is carried out by conventional techniques known to those skilled in the art, or by using suitable isotopic labeling reagents in place of non-isotopic labeling reagents. Manufactured by a process similar to that described in the accompanying embodiment using a stereolabeling reagent. It is possible.

[0028] The compounds of the present invention can be used in pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable excipient or carrier. It can exist in things.

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

[0030] In another embodiment, the present invention provides a method for treating a patient suffering from epilepsy, bipolar disorder, migraine, or schizophrenia. A method of treating a patient in need thereof, comprising administering a therapeutically effective amount of a compound of the present invention. The present invention relates to a method comprising administering an agent to a subject.

[0031] In yet another embodiment, the present invention provides a method for treating a rheumatoid arthritis by administering a therapeutically effective amount of a compound of the present invention to a subject. including psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, and major depression Illness disorders, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsivity Sexual disorders, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum People with dementia, Huntington's disease, sclerosis, multiple sclerosis, and Alzheimer's disease are being treated. The present invention relates to a method of treating a patient in need thereof.

[0032] According to one embodiment, the compounds of the invention are used in therapy.

[0033] The use of the compounds of the present invention may be used to treat epilepsy, bipolar disorder, migraine, or schizophrenia. or in another embodiment, for the treatment of psychosis, mania, stress-related disorders, acute Stress response, bipolar depression, major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders , ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizophrenic disorder, aggression, chronic Pain, Neuropathy, Autism Spectrum Disorder, Huntington's Chorea, Sclerosis, Multiple Sclerosis The drug is intended to treat Alzheimer's disease.

[0034] In other embodiments, the compounds of the present invention are useful in treating epilepsy, fragile X syndrome, Angelmaniasis, for the manufacture of a medicament for the treatment of schizophrenia, bipolar disorder, migraine, or schizophrenia; In another embodiment, the treatment is for psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, Major depressive disorder, anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD , impulsive disorder, personality disorder, schizophrenia-type disorder, aggression, chronic pain, neurological disorders, autism spectrum disorder Treating encephalopathy, Huntington's chorea, sclerosis, multiple sclerosis, and Alzheimer's disease The purpose of the present invention is to manufacture a medicine for the treatment of

[0035] In the context of this invention, "optionally substituted" means that the indicated moiety is substituted. It means that the group may be substituted or unsubstituted, and if substituted, it may be mono- or di-substituted. If no substituents are present that are designated as "optionally substituted" moieties, then It will be understood that the position is held by a hydrogen atom.

[0036] Ranges are indicated by using "~" (dash) or "from to" interchangeably. For example, the term "C 1~3 "Alkyl" is synonymous with C1 to C3 alkyl is.

[0037] The terms "C1-C3 alkyl" and "C1-C6 alkyl" refer to alkyls having 1 to 6 alkyl groups (1 and 6 being the same or different). Examples of such groups are: Examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and These include, but are not limited to, t-butyl.

[0038] The term "C1-C3 alkoxy" refers to a moiety of formula -OR, where R is as defined above. As can be seen, it refers to C1 to C3 alkyl.

[0039] The terms "C3-C4 cycloalkyl", "C3-C5 cycloalkyl", "C3-C8 cycloalkyl" and "C3-C8 cycloalkyl" are used interchangeably. "Cycloalkyl," or "cyclopropyl" refers to a saturated monocyclic ring. Examples of such groups are For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl Examples include cyclohexyl and cyclooctyl.

[0040] Route of administration: Pharmaceutical compositions containing the compounds of the present invention as defined above can be administered orally, rectally, nasally, bucally, sublingually, or intravenously. by any suitable route, including intravenous, transdermal, and parenteral (e.g., subcutaneous, intramuscular, and intravenous) routes. Thus, it may be particularly formulated for administration, preferably by the oral route.

[0041] The route depends on the general condition and age of the subject, the nature of the disease being treated, and the active ingredient. It will be understood that this will change.

[0042] Pharmaceutical Formulations and Excipients: Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" refers to a filler, an anti-adhesive agent, or a pharmaceutical composition. antiadherents, binders, coatings, dyes, disintegrants, flavorings, Glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles, and adjuvants. "Pharmaceutical excipients" refers to pharmaceutical excipients including, but not limited to:

[0043] The present invention also relates to a compound of the invention, such as one of the compounds disclosed in the experimental section herein. The present invention also provides a pharmaceutical composition comprising the compound of the present invention. The pharmaceutical compositions of the present invention are described in Remington's "Th eScience and Practice of Pharmacy”22th Disclosed in the 2012 edition (ed. Allen, Loyd V., Jr.) The compositions can be formulated using pharmaceutically acceptable excipients according to conventional techniques such as:

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

[0045] Each solid oral dosage form contains a predetermined amount of the active ingredient and preferably one or more suitable excipients. The compound may be provided as a discrete unit (e.g., a tablet or a hard or soft capsule) containing: Where appropriate, solid dosage forms may be enteric coated according to methods well known in the art. or may be prepared with a coating such as delayed release or sustained release. Where appropriate, the solid dosage form may be formulated to provide modified release of the active ingredient. The form may be a dosage form that disintegrates in saliva, such as an orodispersible tablet.

[0046] Examples of suitable excipients for solid oral formulations include microcrystalline cellulose, corn starch, and lactic acid bacteria. Inositol, mannitol, povidone, croscarmellose sodium, sucrose, cyclohexyl methylcellulose Rhodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid Examples of suitable cellulose acetate copolymers include, but are not limited to, cellulose acetate, cellulose acetate diol ... Similarly, solid formulations may be prepared using conventional glycerol monostearate or hypromellose. The solid material may also contain excipients for delayed or sustained release formulations known in the art. When used for oral administration, the formulation may, for example, be prepared by mixing the active ingredient with a solid excipient. The mixture may then be compressed in a conventional tablet machine, or For example, the formulation may be placed in a hard capsule, e.g., in the form of a powder, pellets, or mini-tablets. The amount of solid excipient may vary widely but is typically present in a dosage unit. The range is about 25 mg to about 1 g per unit.

[0047] Liquid oral dosage forms include, for example, elixirs, syrups, oral drops ), or liquid-filled capsules. Liquid oral dosage forms may also be provided as aqueous or non-aqueous liquids. It may also be provided as a powder for solution or suspension in liquid. Examples include ethanol, propylene glycol, glycerol, and polyethylene glycol. ethanol, poloxamer, sorbitol, polysorbates, mono- and diglycerides, cyclodextrins Examples of suitable oils include, but are not limited to, coconut oil, palm oil, and water. Oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid. Alternatively, the active ingredient may be incorporated into an oil-in-water or water-in-oil liquid emulsion. This can be done.

[0048] Additional excipients such as colorants, flavoring agents, and preservatives may be used in solid and liquid oral formulations. It is possible.

[0049] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, injections or infusions. ready-to-use suspensions or emulsions, concentrates for injection or infusion, and concentrates for injection or infusion before use Suitable excipients for parenteral formulations include sterile powders to be reconstituted into sterile solutions or dispersions. Examples of such agents include solutions of water, coconut oil, palm oil, and cyclodextrin. Aqueous formulations should be suitably buffered if necessary. , should be made isotonic with sufficient saline or glucose.

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

[0051] The excipients used in any pharmaceutical formulation will depend on the intended route of administration and on the composition of the active ingredient. Compatibility is essential.

[0052] dose: In one embodiment, the compounds of the present invention are administered in a dose of from about 0.001 mg / kg to about 10 mg / kg of body weight per day. The dose is 0.01 mg / kg body weight. The exact dosage may vary depending on the frequency of administration. and method, sex, age, weight, general condition of the subject to be treated, nature and severity of the disease to be treated, The amount of administration will depend on any comorbidities being treated, the desired therapeutic effect, and other factors known to those skilled in the art. It exists.

[0053] Typical oral dosages for adults range from 0.1 to 1000 mg / day of a compound of the invention. For example, it is 1 to 500 mg / day, for example, 1 to 100 mg / day or 1 to 50 mg / day. Conveniently, the compounds of the present invention are administered in a unit dosage form containing said compound in an amount of about 0.1 to 500 ml. g, e.g., 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg is administered in an amount of a compound of the present invention.

[0054] Isomers and tautomeric forms: When a compound of the invention contains one or more chiral atoms, a reference to the compound will not necessarily be construed as limiting the scope of the invention. Unless otherwise specified, enantiomerically or diastereoisomerically pure compounds, as well as compounds in any ratio This encompasses mixtures of enantiomers or diastereomers in the form

[0055] MDL Extended Stereo Representation (MDL En) is used to represent the unknown stereochemistry of the compounds of the present invention. Converged Stereo representation is used. Therefore, the label "or1" on the chiral carbon atom indicates that the absolute configuration at this atom is unknown. For example, the configuration at this carbon atom is either (S) or (R )

[0056] Additionally, carbon atoms labeled "or1" with an upward or downward wedge The chiral bonds from are equivalent representations, e.g., the two figures have the same meaning, and their meanings and The absolute configuration at the carbon atom labeled "or1" is unknown, and (S) Or it could be (R).

[0057] Therefore, the upward wedge bond and the downward wedge bond from the atom labeled "or1" The use of the Ru bond represents the different stereoisomers, with the carbon atoms labeled "or1" in the diagram. It is merely intended to provide a visual cue that the conformation in the child is unknown.

[0058] Furthermore, some of the compounds of the present invention may exist in different tautomeric forms; Any tautomeric forms that the compounds are able to form are intended to be included within the scope of the present invention. can be.

[0059] Therapeutically effective amount: The term "therapeutically effective amount" of a compound in the context of the present invention refers to a treatment comprising the administration of said compound. In therapeutic interventions, the clinical manifestations of a given disease and its complications are reduced, prevented or partially prevented; An amount sufficient to accomplish this is called a "therapeutic" amount. The effective amount for each purpose will depend on the severity of the disease or injury, and The dosage depends on the weight and general condition of the subject. The appropriate dosage can be determined using routine experimentation. This is achieved by building a matrix of points and testing various points in the matrix. It will be appreciated that this is all within the ordinary skill of a skilled physician. .

[0060] Treatment and cure: In the context of the present invention, the term "treatment" or "treating" is used interchangeably with "treatment" or "treating" and is used interchangeably with "treating" and "treating" and is used interchangeably with "treatment." "reducing" means reducing, preventing, partially preventing, eliminating, or slowing the progression of clinical signs of a disease. The term "patient management and care" is intended to refer to the management and care of a patient with the objective of ensuring that the patient is , preferably mammals, particularly humans.

[0061] All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference. and the like, all of which are incorporated herein by reference in their entireties, as if each reference were expressly incorporated by reference. When incorporated, all such terms and conditions are individually and specifically indicated to the same extent as if set forth in their entirety (including, without limitation, the terms and conditions of the Act). (to the fullest extent permitted by law) are incorporated herein by reference.

[0062] Use in epilepsy, epileptic syndromes, epileptic symptoms or epileptic seizures In other embodiments, the present invention provides a method for treating epilepsy, epilepsy syndromes, epilepsy symptoms, treatment resistance, Patients who are suffering from or in need of treatment for resistant or intractable epilepsy or epileptic seizures A method of treating a subject, comprising administering a therapeutically effective amount of a compound according to the present invention. Regarding the method.

[0063] In yet another embodiment, the present invention provides a method for treating focal (partial) epilepsy with simple partial seizures, complex epilepsy, Focal (partial) epilepsy with miscellaneous partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, epilepsy Status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial newborn Convulsions and other epilepsy syndromes (severe myoclonic epilepsy in infancy, slow wave sleep persistent spike-and-wave epilepsy, West syndrome, Lennox-Gastaut syndrome, Doraemon syndrome, syndrome and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or stress, hormonal changes, drugs (such as amphetamines or cocaine), alcohol, infections, or metabolic disorders Patients who suffer from or need to treat epileptic seizures related to or a method for treating Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontal lobectomy, Used in the treatment of epileptic symptoms as part of neurodegenerative diseases such as temporal lobar degeneration A method comprising administering to a subject a therapeutically effective amount of a compound of the present invention. .

[0064] The use of the compounds according to the invention can be used to treat focal (partial) epilepsy with simple partial seizures, complex partial seizures, Focal (partial) epilepsy with seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus , neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsy syndromes (severe myoclonic epilepsy in infancy, persistent seizures during slow wave sleep) Epilepsy with spike-and-wave seizures, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome group and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or stress, hormonal changes, Drugs, alcohol, infectious diseases, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or for use in the treatment of epileptic seizures associated with metabolic disorders (e.g., hyponatremia). Includes Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, and frontotemporal lobar degeneration For the treatment of epilepsy, used in epileptic conditions as part of neurodegenerative diseases such as It is used for this purpose.

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

[0066] The classification of epilepsy is based on ICD-10 (2016, published by WHO), and is divided into sections. These compounds are described in Sections G40 and G41 and are encompassed in the treatment of epilepsy according to the present invention. G40.0 Localization-related (focal) (partial) idiopathic epileptic seizures with localized onset Epilepsy and epilepsy syndromes G40.1 Localization-related (focal) (partial) symptomatic epilepsy and epilepsy with simple partial seizures syndrome G40.2 Localization-related (focal) (partial) symptomatic epilepsy and epilepsy with complex partial seizures syndrome G40.3 Idiopathic generalized epilepsies and epilepsy syndromes G40.4 Other generalized epilepsies and epilepsy syndromes G40.5 Special epilepsy syndromes G40.6 Grand mal epilepsy, unspecified (with or without petit mal seizures) G40.7 Petit mal, unspecified, without grand mal seizures G40.8 Other epilepsies G40.9 Epilepsy, unspecified G41 Status epilepticus

[0067] Treatment of epileptic seizures An epileptic seizure is a sudden, uncontrolled electrical disturbance in the brain. It can affect behavior, movements, or may cause altered emotions and levels of consciousness. If a patient has a tendency to have recurrent epileptic seizures, this should be diagnosed as epilepsy. .

[0068] There are many types of epileptic seizures, classified by severity. Types of epileptic seizures The types of seizures vary depending on where and how they occur in the brain. Most epileptic seizures occur within 3 It lasts from 0 seconds to 2 minutes.

[0069] focal seizures Focal seizures result from abnormal electrical activity in one area of ​​the brain. Focal seizures are not accompanied by consciousness. This can occur with or without loss of consciousness. Focal seizures with impaired consciousness. These epileptic seizures cause altered or lost consciousness or awareness. The person may stare into space and not respond normally to their environment, or may rub their hands, chew, or They may make repetitive movements such as swallowing or walking in circles. Focal seizures without loss of consciousness. These epileptic seizures may alter emotions or It may change the way things look, smell, feel, taste, or hear, but the person loses consciousness. These epileptic seizures are characterized by involuntary spasms of body parts such as the arms or legs, and tingling, 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. Generalized seizures include the following: Absence seizures. Traditionally known as petit mal seizures, absence seizures often occur in children. gazing into space, or blinking or smacking one's lips, These epileptic seizures may occur in clusters and cause a brief loss of consciousness. I can get used to it. Tonic seizures. Tonic seizures cause muscle stiffness. These epileptic seizures usually occur in the back, It affects the muscles of the arms and legs. Cataplexy. Also known as drop attacks, cataplexy causes loss of muscle control. , which may cause it to suddenly collapse or tip over. Clonic seizures. Clonic seizures involve repetitive or rhythmic muscle jerking movements. These epileptic episodes The condition usually affects the neck, face, and arms. Myoclonic seizures. Myoclonic seizures usually involve sudden, brief jerks or jerks of the arms and legs. appears as a twitch. Tonic-clonic epilepsy, formerly known as grand mal epilepsy, A seizure is the most dramatic type of epileptic seizure and is characterized by sudden loss of consciousness, stiffening and shaking, Occasionally, loss of bladder control or tongue biting may occur.

[0071] Seizures often occur: High fever associated with infections such as meningitis lack of sleep Low blood sodium (hyponatremia) can occur with diuretic therapy medications such as certain painkillers, antidepressants or smoking cessation treatments that lower the seizure threshold Head trauma that causes areas of bleeding in the brain stroke Brain tumor Drugs such as amphetamines or cocaine alcohol It may be related to or result from

[0072] Headings and subheadings are used herein for convenience only and in no way constitute a guide to the present invention. should not be construed as limiting the

[0073] Any examples or use of exemplary language herein (for example, nce), "for example," "eg," and " "As such" (including "as such"), unless otherwise specified, is merely an attempt to improve the invention. They are intended to be illustrative and not limiting of the scope of the invention.

[0074] Citation and incorporation of patent documents herein is done solely for convenience. and does not assume any responsibility for any view as to the validity, patentability, and / or enforceability of such patent documents. It does not reflect the solution.

[0075] The present invention is limited to the scope of the claims appended hereto as permitted by applicable law. This includes all modifications and equivalents of the subject matter used.

[0076] Experimental section Biological evaluation: Cell culture A gene encoding human Kv7.3 and human Kv7.2 separated by a P2A sequence The synthesized cDNA fragment was ligated into pcDNA5 / FRT / T using the BamHI and XhoI restriction sites. The construct was then inserted into a vector. Transfected into HEK Flp-In 293 cells. Cells were cultured in DMEM containing 10% (v / v) FBS and 1% PenStrep. Growth was allowed to continue for 48 hours, followed by incubation at 37°C in a humidified atmosphere of 5% CO2 with 10% (v / v) F BS, 1% PenStrep, and 200 μg / mL Hygromycin B The cells were maintained under selection in DMEM containing HCl. The resulting stable hKv7.2 / hKv7 cells were then cultured in HCl. Three cell lines (HEK-hKv7.2 / hKv7.3) were measured using automated whole-cell patch clamp. When tested functionally, the patient was sensitive to XE991 and showed a typical response to retigabine. They showed typical Kv7 currents.

[0077] Thallium influx assay FLIPR Potassium Assay Kit (Molecular Devices) ces) according to published procedures (C.D. Weaver, et al., J. Biol. mol Screen 2004,9,671-677) and potassium channels Thallium influx assay of activation was performed. HEK-hKv7.2 / hKv7.3 cells , 96-well black-walled, clear-bottom culture dishes (Corning, Acton, MA, US A) If cells are to be assayed the next day, add 80,000 cells / well (100 μl / well), or 40,000 cells / well if cells are assayed 2 days after plating. The cells were plated at a density of 100 μl / well.

[0078] On the day of the assay, remove the medium and then resuspend the cells in HBSS containing 20 mM HEPES. Add 50 μL / well of test compound diluted to 2x final concentration in 2x dye loading buffer. 50 μL / well of PBS was added. The cells were then incubated at room temperature in the dark for 60 minutes. Five times the final concentration of Tl + and K. + (5x concentration: 5mM in both cases) Chloride-free stimulation buffer, as well as test compounds at 1x final concentration, were added during the incubation. The cells were then cultured in a FDSS7000EX Functional Drug Store. The assay was carried out in a screening system (Hamamatsu). Following baseline fluorescence signal readings at 400 rpm for 60 seconds and at 1 Hz for 10 seconds, 25 μL L / well of stimulation buffer was added and fluorescence was monitored at 1 Hz for 50 seconds followed by 0.1 Hz for 4 minutes. The effect of the compounds was quantified using AUC as the readout and Normalization was performed against a reference compound included on the plate.

[0079] Compound effects In the assays described above, the compounds of the present invention had the following biological activities:

[0080] [Table 1]

[0081] [Table 2]

[0082] Synthesis of compounds of the present invention: General law: The general procedure for the synthesis of intermediates and compounds of general formula I is illustrated in Reaction Scheme 1, and These procedures are specifically exemplified in the Preparations section and Examples. Variations of the procedures described, known to those skilled in the art, are also within the scope of the present invention. It is included in the range of light.

[0083] The compounds of the present invention are prepared as illustrated in Scheme 1. Among the compounds of general formula I Some contain two chiral carbon atoms and are formed as mixtures of diastereomers In this case, the diastereomers can be separated to give the single stereoisomers Ia and Ib. can.

[0084] Scheme 1 [ka] Scheme I illustrates the preparation of compounds of general formula I by two general routes. The first route is , generally via methods well known in the art for converting acids and amines to amides. The preparation of compounds of formula I by reaction of enantiomerically pure amines of formula II with acids of general formula III This method involves the synthesis of activated esters and reactive mixed anhydrides. Formation of a reactive derivative of an acid of non-limiting formula III, followed by condensation with an amine of general formula II One such method involves reacting the hydroxyl group of the hydroxyl group with HCl in 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 diethylamine (DIPEA).

[0085] Or, R 2 When is H, compounds of general formula I can be prepared via a second general route wherein the intermediate of general formula V can be reacted with NaB The intermediate of formula V is treated with a suitable reducing agent such as H4 to produce an enantiomeric intermediate of general formula II This conversion can be obtained from a pure amine and a carboxylic acid of general formula IV (R=H). under the same reaction conditions as described above for condensing II and III to form I. This can be achieved using the following conditions:

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

[0087] Optically active amines of general formula II can be prepared as outlined in Scheme 2a. Cut. Scheme 2a [ka] The aldehyde of general formula VI can be desiccated with a drying agent such as titanium(IV) isopropoxide or copper sulfate. in a suitable solvent such as dichloroethane in the presence of (R)-2-methylpropane-2-sulfonyl The resulting sulfinyl imine XV can be condensed with TH In a suitable inert solvent such as F, 3 Treatment with MgBr afforded the corresponding substituted (R)- 2-Methyl-N-((S)-1-aryl-alkyl)propane-2-sulfinamide (VII) is obtained, which is treated with a suitable acid in a suitable solvent, such as HCl in MeOH. This is converted to a compound of general formula II.

[0088] In a variation of this procedure, R having a functional group 3 The substituents may also be selected by a chemist skilled in the art. These methods for producing chiral amines can be modified by standard functional group transformation methodologies known to those skilled in the art. An example of the procedure is shown in Scheme 2b. 3 = allylic) intermediate is formed from XV and allyl-MgBr and reacted with Pd / C or the like in a suitable solvent such as ethyl acetate. using H2(g) in the presence of a suitable catalyst of R 3 = Catalytic reduction to n-propyl Alternatively, the reaction can be carried out in the presence of a suitable base such as 2,6-lutidine. and suitable cations such as K2OsO4 and NaIO4 in a suitable solvent such as dioxane / H2O. By treating with a suitable catalyst, a compound of general formula VII (wherein R 3 = allylic) intermediate is subjected to dihydroxylation followed by oxidative cleavage to give R 3 = acetaldehyde The intermediate VII is obtained. The resulting aldehyde can be further transformed; for example, by condensation with an appropriate solvent such as DCM. By treatment with a suitable reagent such as diethylaminosulfur trifluoride (DAST) in a solvent, In the final step, the chiral amine is subjected to an exchange of oxygen for two fluorine atoms. It can be obtained by the above-mentioned hydrolysis.

[0089] In another embodiment, the compound of formula XVI (wherein R 3 The intermediates in the reaction (where acetic acid is present) are CuCl and Ethyl 2-bromoacetate in the presence of activated Zn in a suitable solvent such as THF can be formed from XV by reaction with The ester group can be further derivatized by, for example, The ester can be converted to a primary alkane by treatment with a suitable reducing agent such as LiAlH4. The resulting alcohol can also be reduced to ethanol by transformations known to those skilled in the art. For example, the alcohol can be further derivatized by trichloroisopropyl ether in a suitable solvent such as DCM. Activation with a reagent such as mesyl chloride in the presence of a suitable base such as ethylamine (TEA) The resulting mesylate can be converted to a leaving group by diluting it in a suitable solvent such as DMSO. The compound can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent.

[0090] Scheme 2b: [ka]

[0091] Aldehydes of general formula VI can also be converted to general formula I by an alternative strategy, as shown in Scheme 2c. can be converted to the chiral amine of formula I. Scheme 2c: [ka] Following this procedure, Wittig methodology known to chemists of ordinary skill in the art may be used to appropriately The substituted benzaldehyde VI can be converted to the corresponding appropriately substituted styrene. These intermediates can be subjected to alkylation-oxidation reactions to give the keto intermediates XVI Intermediates of general formula XVII can be prepared by reacting the intermediates of general formula XVII with the corresponding aryl groups in a suitable solvent such as dichloroethane. (R)-2-methylpropane in the presence of a suitable drying agent such as titanium(IV) ethoxide. The sulfinyl imine formed can be condensed with benzo-2-sulfinamide. A suitable inert solvent such as L-Selectride is prepared by the following procedure: with an appropriate reducing agent to give the corresponding appropriately substituted (R)-2-methyl-N-((S) (1-aryl-alkyl)propane-2-sulfinamide is formed, By treatment with a suitable acid in a suitable solvent such as HCl, chiral amines of general formula II can be obtained. It can be converted into

[0092] Those skilled in the art will recognize that other transformations are possible from each of the intermediates; the present invention does not limit such alternative transformations. It will be appreciated that the present invention is intended to encompass

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

[0094] In another procedure, reagents such as L-selectride were used, as shown in Scheme 3a. The intermediate sulfur obtained from the reaction with (R)-2-methylpropane-2-sulfinamide Chiral amines of formula II can be obtained from aryl ketones by hydride reduction of the phenyl imines. It is possible.

[0095] Scheme 3a [ka] A variation of this procedure is shown in Scheme 3b. In this procedure, a further ether is R 3 The substituents are the common α-brominated groups obtained by bromination of the correspondingly substituted acetophenones. Examples include, but are not limited to, R 3 year Therefore, this methodology under Finkelstein conditions using dimethylacetone The correspondingly substituted bromoacetophenone is trichloroethylene in a suitable solvent such as dichloromethane (DMA). Fluoroalkoxy donors such as fluoromethyl trifluoromethanesulfonate and KF Reaction of the amine with methyl methyl amine affords intermediate XII, which can be further converted to the chiral amine as described above. Other examples include, but are not limited to, R 3 Alkylmethylene as The introduction of ethers is one example. Thus, the correspondingly substituted bromoacetophenones are A suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the presence of 4-methyl-N'-(p-trisulfo) by reacting with methyl)benzenesulfonohydrazide to give the acyl diazo intermediate XI Intermediate XIII can be converted to II by the reaction of methyl ... By treating with an appropriate solvent, such as indium triflate, the compound can be subjected to a carbene formation reaction. The formed carbene can be trapped in situ by a suitable alcohol. From intermediate XIV, the chiral amine of formula II can be prepared. The resulting product is obtained by standard procedures as described above.

[0096] Scheme 3b: [ka] The correspondingly substituted ketones or acetophenones used in the preparation of the compounds of the present invention are commercially available. They are commercially available or can be prepared by methods known to those skilled in the art.

[0097] Those skilled in the art will recognize that other transformations are possible from intermediates of general formula XI and that the present invention does not limit the scope of such alternative transformations. It will be appreciated that the term "combination" is intended to encompass substitutions.

[0098] General formula II (wherein, R 3 Other suitable procedures for obtaining chiral amines of the formula (wherein This is outlined in Scheme 4. Scheme 4: [ka] In this procedure, as described in JP 2017-095366 A, During the condensation reaction of xylates with (R)-2-methylpropane-2-sulfinamide The glyoxylic acid sulfinyl imine formed in Bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoro This can be reacted with a suitably substituted boronic acid using a suitable catalyst such as a borate. The resulting intermediate VIII is hydrolyzed and converted to a suitable protecting group such as Boc under standard conditions. Reprotection and ester reduction under appropriate conditions such as LiAlH4 in THF generally The alcohol intermediate of formula IX can be obtained. The intermediate of formula IX can be further derivatized to obtain the desired Target R 3 For example, the alcohol group in intermediate IX can be substituted with an acetonitrile. 2,2-difluoro- can be difluoromethylated using a suitable reagent such as 2-(fluorosulfonyl)acetic acid or the alcohol group in IX can be converted to a methyl group such as THF in the presence of a suitable base such as NaH. In any suitable solvent, a simple alkyl halide such as methyl iodide can be used to convert alkyl Alternatively, the hydroxyl group can be converted to hydroxyl group by cleavage with a suitable base such as DCM in the presence of a suitable base such as TEA. Activation using a reagent such as mesyl chloride in a suitable solvent affords intermediate IX The resulting mesylate can be dissolved in a suitable solvent 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 recognize that other transformations are possible from intermediates of general formula IX. The present 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 can be prepared, for example, by the reaction of bromoacetic acid with Zn and iodine. reacting with a alkyl ester to produce the corresponding aldol adduct. The bromoacetate is activated using Zn and TMSCl (trimethylsilyl chloride). In the final step, the hydrolysis of the alkyl ester can be carried out in a suitable solvent such as water. with a suitable base such as NaOH or LiOH or an alcohol in water, This is accomplished by subsequent acidification with a suitable acid to give the compound of formula III.

[0101] Carboxylic acid esters of general formula IV (R=Me, Et) are commercially available or can be synthesized by the method described in Scheme It can be prepared as outlined in 6. Scheme 6 [ka] The correspondingly substituted carboxylic acid is activated using a suitable reagent such as CDI and then treated with MgCl 2, condensation with potassium 3-ethoxy-3-oxo-propanoate to give the compound An intermediate of formula IV can be obtained.

[0102] Bruker Avance III400 equipment at 400.13MHz, or Br On 300.13MHz with a UKER Avance300 device, 1 H NMR spectrum Deuterated dimethyl sulfoxide or deuterated chloroform was used as the solvent. Tetramethylsilane was used as an internal reference standard. Chemical shift values ​​were calculated from the tetramethylsilane The following abbreviations are used for 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 = triplet triplet, m = multiplet, and brs = broad singlet.

[0103] To assess chemical purity (LCMS method) and chiral purity (SFC and HPLC methods) Chromatographic systems and methods are described below.

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

[0105] [Table 3]

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

[0107] [Table 4]

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

[0109] [Table 5]

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

[0111] [Table 6]

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

[0113]

Table 7

[0114] SFC method 2: Apparatus: Agilent 1260

[0115]

Table 8

[0116] SFC method 3: Apparatus: Agilent 1260

[0117]

Table 9

[0118] SFC method 4: Apparatus: Agilent 1260

[0119]

Table 10

[0120] SFC method 5: Apparatus: Agilent 1260

[0121]

Table 11

[0122] SFC method 6: Apparatus: Agilent 1260

[0123]

Table 12

[0124] SFC method 7: Apparatus: Waters UPC2

[0125]

Table 13

[0126] SFC method 8: Apparatus: Waters UPC2

[0127]

Table 14

[0128] SFC method 9: Apparatus: Waters UPC2

[0129]

Table 15

[0130] SFC method 10: Apparatus: Agilent 1260

[0131] Table 16

[0132] SFC method 11: Apparatus: Agilent 1260

[0133] Table 17

[0134] SFC method 12: Apparatus: Waters UPC2

[0135] Table 18

[0136] SFC method 13: Apparatus: Waters UPC2

[0137] Table 19

[0138] SFC method 14: Apparatus: Waters UPC2

[0139] Table 20

[0140] SFC method 15: Apparatus: Waters UPC2

[0141] Table 21

[0142] SFC method 16: Apparatus: Waters UPC2

[0143] Table 22

[0144] SFC method 17: Apparatus: Waters UPC2

[0145] Table 23

[0146] SFC method 18: Apparatus: Agilent

[0147] Table 24

[0148] SFC Method 19: Apparatus: Agilent

[0149] Table 25

[0150] SFC method 20: Apparatus: Waters UPC2

[0151] Table 26

[0152] SFC method 21: Apparatus: 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] Korra HPLC method 2: Apparatus: SHIMADZU LC-20AB

[0159]

Table 30

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

[0161] Table 31

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

[0163] Table 32

[0164] Preparation of intermediates: IIb: ((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (phenyl)ethan-1-amine [ka] Step 1: Preparation of ethyl 2-[(R)-tert-butylsulfinyl]iminoacetate [ka] Ethyl 2-oxoacetate (7.5 g, 36.7 mmol) in DCM (150 mL) ) and (R)-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol ), CuSO4 (12.9 g, 80.8 mmol) was added, and the reaction mixture was stirred for 2 The mixture was stirred at 5° C. for 24 hours. The solid matter was filtered off and washed with ethyl acetate (50 mL). The resulting residue was purified by column chromatography (silica gel, petroleum ether). The desired product was obtained (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]acetate in dioxane (100 mL) ]iminoacetate (7 g, 34.1 mmol) and [3-(trifluoromethoxy)phenanthroline To a solution of [Rh(COD)(MeC N)2]BF4 (1.3 g, 3.4 mmol) was added, and the mixture was heated at 80 °C for 16 h. The product was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1). Purification by HCl gave 9.8 g (78%).

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

[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]propanol in THF (150 mL) To a mixture of [(trimethoxy)phenyl]acetate hydrochloride (6 g) and BocO (8.7 g), NaHCO3 (1.7 g) was added and stirred at 25 °C for 16 h. The mixture was concentrated and The product was purified by chromatography on a 10:1 mixture of petroleum ether and ethyl acetate. The product was obtained (7.2g).

[0168] Step 5: tert-butyl (R)-(1-(3-(difluoromethoxy)phenyl)-2 Preparation of (hydroxyethyl) carbamate [ka] To a suspension of LiAlH4 (1.7 g) in THF (200 mL) was added TH (R)-2-((tert-butoxycarbonyl)amino)-2-( 3-(Difluoromethoxy)phenyl)acetate (4 g) was added and the reaction was allowed to warm to 25°C. The mixture was heated to rt and stirred for 2 hours. Anhydrous magnesium sulfate was added, followed by one drop of water and ethyl acetate. The insoluble material was filtered off through a celite pad. The filtrate was concentrated and The product was purified by chromatography on a silica gel column (petroleum ether:ethyl acetate=5:1). .1g).

[0169] Step 6: tert-Butyl (R)-(2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... Preparation of (fluoromethoxy)phenyl)ethyl)carbamate [ka] tert-Butyl (R)-(1-(3-difluoromethacrylate)) in MeCN (20 mL) A solution of 1.5g of phenyl-2-hydroxyethyl carbamate was added to the solution of CuI( 360 mg) was added and stirred at 25°C under N2 atmosphere for 30 minutes. A solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.7 g) in (5 mL) was added over 30 min at 45° C. and the reaction was stirred for 1 h at 45° C. The mixture was concentrated This was followed by dilution with ethyl acetate (100 mL), filtration and concentration to give the desired product. (1.5g, crude).

[0170] Step 7: (R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)- Preparation of (phenyl)ethan-1-amine [ka] tert-Butyl (R)-(2-(difluoromethoxy)-) in MeOH (15 mL) Dissolve 1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1.5 g) To the solution was added HCl / MeOH (4 M in MeOH, 30 mL) at 25°C, and the reaction was stirred at 25°C. The solution was stirred at rt for 30 min. Ammonium hydroxide (30%) was added to adjust the pH to 9. was concentrated and purified by chromatography on silica (petroleum ether:ethyl acetate=2:1). Purify and obtain (R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)- As a result, 700 mg of (phenyl)ethan-1-amine was obtained.

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

[0172] IIc: (R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl) Ethan-1-amine hydrochloride [ka] Step 1: Preparation of 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydrazide [ka] 4-Methylbenzenesulfonohydrazide (70g) and 4-methylbenzenesulfonyl To a mixture of 93 g of chloroform was added 400 mL of DCM. The mixture was cooled to 0°C. Then, pyridine (38.65 g) was added dropwise and the reaction mixture was stirred at 0°C for 1 hour and at 20°C for 1 hour. The mixture was stirred at rt for 7 hours. Water (200 mL) and methyl tert-butyl ether ( METB (200 mL) was added and filtered. The filter cake was washed with METB (200 mL). Wash, dry and prepare 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydride Razide (125 g) was obtained. 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)ethan-1-one preparation [ka] 1-[3-(difluoromethoxy)phenyl]ethanone in dioxane (100 mL) To a solution of (10 g) was added a solution of Br2 (8.58 g) in dioxane (100 mL). The resulting mixture was stirred at 20°C for 2 hours. Saturated aqueous NaHCO3 (50 mL) and H2O (100 mL) were added, and the aqueous phase was extracted with EtOAc (200 mL x 2). The organic phase was washed with brine (200 mL), dried over Na2SO4, and concentrated to give 2-bromine. Bromo-1-[3-(difluoromethoxy)phenyl]ethanone (17 g) 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-iminoethan-1-one preparation [ka] 2-Bromo-1-[3-(difluoromethoxy)phenyl] in THF (100 mL) Ethanone (5.6 g) and 4-methyl-N'-(p-trisulfonyl)benzenesulfonate To a solution of hydrazide (11.51 g), DBU (12.87 g) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 1 hour and at 20°C for 4 hours. The mixture was quenched with 200 mL of water, diluted with 200 mL of EtOAc, and The organic layer was washed with brine (100 mL) and dried over Na2SO4. The crude product was purified by column chromatography on silica gel (20% in petroleum ether). % EtOAc) and purified to give 1-(3-(difluoromethoxy)phenyl)-2-isopropyl Minoethan-1-one (6.4 g) 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- Preparation of 1-one [ka] Cyclopropanol (1.75 g) and 2-diazo-1-[ In a solution of 3-(difluoromethoxy)phenyl]ethanone (3.2 g), indium (I II) Triflate (1.7 g) was added under N2. The resulting mixture was heated at 20 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3 (100 mL) and H2O ( 50 mL) and then extracted with EtOAc (100×2). The organic layer was washed with brine ( The crude product was washed with 200 mL of HCl, dried over Na2SO4, and concentrated. The compound was purified by column chromatography (5% EtOAc in petroleum ether) to give 2-cyclohexyl Propoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one (6.1 g ) 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-(difluoromethacrylate)] in THF (100 mL) (R)-2-methylpropane-2-sulfine To a solution of amide (4.6 g) was added Ti(OEt)4 (11.5 g). The mixture was stirred at 60° C. for 8 h and then used directly in the next step.

[0177] Step 6: (R)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethacrylate) Preparation of (phenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] (R,Z)-N-(2-cyclopropoxy-)-2-(2-methyl-2-propoxy-)-2-methylpropional from the previous step in THF (150 mL) 1-(3-(difluoromethoxy)phenyl)ethylidene)-2-methylpropane-2- To the solution of sulfinamide, add a solution of L-selectride (1 M in THF, 50.36 mL) ) was added dropwise at −45° C. The mixture was stirred at −45° C. for 1 h and then MeOH (10 The mixture was quenched with HCl (100 mL) and HO (100 mL) and filtered over Celite. The filtrate was diluted with EtO Extract with Ac (200 mL x 2), wash the organic layer with brine (200 mL x 2), and The crude product was purified by column chromatography on silica gel (petroleum ethanol). Purification by 30-50% EtOAc in ether was performed to obtain (R)-N-((R)-2-cyclohexanediol). Propoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropoxy As a result, 2.4 g of benzo-2-sulfinamide was obtained.

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

[0179] IId: (R)-2-Cyclopropoxy-1-(3-(trifluoromethoxy)phenyl) ) Ethan-1-amine hydrochloride [ka] Using 1-[3-(trifluoromethoxy)phenyl]ethanone as the starting material, Prepared as described for IIc.

[0180] IIe: (R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethyl) (thoxy)ethan-1-amine hydrochloride [ka] Step 1: Preparation of 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone [ka] 1-[3-(difluoromethoxy)phenyl]ethanone ( To a solution of Br2 (4.29 g) in dioxane (50 mL) was added a solution of Br2 (4.29 g) at 20 °C. The mixture was stirred at 20° C. for 1 h, diluted with EtOAc (200 mL), and (100 mL x 3). The organic phase was dried over anhydrous Na2SO4 and concentrated. The material was purified by chromatography on a silica gel column (petroleum ether: EtOAc = 10:1). 2-Bromo-1-[3-(difluoromethoxy)phenyl]ethanone ( 5g) was obtained.

[0181] Step 2: 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy) Preparation of ethan-1-one [ka] To a solution of KF (712 mg) in DMA (20 mL) was added trifluoromethyltrifluoromethyl. Fluoromethanesulfonate (4.11 g) was added at 0° C. The reaction mixture was stirred in a sealed tube. Stir for 1 hour, then add 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanoic acid. To this solution at 0°C, 2.5 g (9.43 mmol) of ketone (2.5 g, 9.43 mmol) and KI (157 mg) were added, The mixture was allowed to warm to 20°C and stirred for 16 hours. The mixture was diluted with EtOAc (100 mL) and water (5 The organic phase was concentrated to give the product, which was purified by 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-(trifluoromethyl ... Preparation of (2-methyl-2-methoxyethylidene)-2-methylpropane-2-sulfinamide [ka] 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethyl ... (R)-2-methylpropane-2-one (900 mg), (R)-2-methylpropane-2- A mixture of sulfinamide (606 mg) and Ti(OEt)4 (2.28 g) was heated at 60°C. The product (1.2 g, crude) in THF (70 mL) was stirred at rt under N for 16 h. was obtained and used 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-sulfina To a solution of 1.2 g of amide, L-selectride (1 M in THF, 3.86 mL) was added -6 The mixture was stirred at -60°C for 0.5 h, and then EtOAc (100 mL The organic phase was dried, filtered and concentrated. The product was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5:1). and purified as (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 (trihydroxy)ethan-1-amine hydrochloride [ka] (R)-N-((R)-1-(3-(difluoromethoxy)methyl ... (phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfonyl To a solution of phenamide (600 mg) was added HCl / MeOH (4 M in MeOH, 8.0 mL). The mixture was stirred at 15° C. for 1 hour and then concentrated to give ((R)-1-(3 -(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethane-1-amine As a result, 500 mg of benzophenone hydrochloride (crude) was obtained. 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)ethan-1-amine hydrochloride [ka] Using 1-[3-(trifluoromethoxy)phenyl]ethanone as the starting material, 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)butan-1-amine hydrochloride salt [ka] Step 1: (R)—N-(3-(difluoromethoxy)benzylidene)-2-methylpropane Preparation of benzo-2-sulfinamide [ka] 3-(Difluoromethoxy)benzaldehyde (3 g) in DCE (120 mL) and To a solution of (R)-2-methylpropane-2-sulfinamide (2.54 g), CuSO 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) The residue was purified by HCl (=100 / 1 to 10:1) to give the product (3 g).

[0187] Step 2: (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3 Preparation of (-en-1-yl)-2-methylpropane-2-sulfinamide [ka] (R)-N-(3-(difluoromethoxy)benzylidene)- in DCM (40 mL) A solution of 2-methylpropane-2-sulfinamide (1 g) in THF at 0° C. was added to the solution of allyl (Bromo)magnesium (1 M solution in THF, 10.9 mL) was added slowly. The resulting mixture was stirred at 0°C for 1 hour and at 25°C for 2 hours. The reaction mixture was quenched by the addition of HCl (4 mL), diluted with HO (50 mL), and diluted with DCM (4 mL). The combined organic phase was washed with H2O (40 mL) and extracted with Na2SO4 The mixture was dried over 100°C, filtered and concentrated. Column chromatography (SiO2, petroleum ether / The residue was purified with ethyl acetate (100 / 1 to 1:2) and (R)-N-((S)-1 -(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropional Propane-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-(difluoromethoxyphenyl)-2-methyl-2-propanol)) in EtOAc (20 mL) )phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide To a solution of (580 mg) was added Pd / C (0.4 g, purity 10%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was heated under H2 (18 psi) for 2 The mixture was stirred at 5° C. for 0.5 h. The reaction mixture was filtered and concentrated to give (R)-N-((S)-1 -(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulfonyl The resulting product was divinamide (560 mg).

[0189] Step 4: (S)-1-(3-(difluoromethoxy)phenyl)butan-1-amine hydrochloride Salt preparation [ka] (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)-2,4-difluoropropanediol) in MeOH (8 mL) To a solution of (phenylbutyl)-2-methylpropane-2-sulfinamide (580 mg) HCl / MeOH (4M, 3.1 mL) was added. The mixture was stirred at 25° C. for 3 hours. It was then concentrated to give (1S)-1-[3-(difluoromethoxy)phenyl]butane-1- The amine hydrochloride (250 mg) was obtained.

[0190] IIh: (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutanol Tan-1-amine hydrochloride [ka] Step 1: Preparation of 1-(difluoromethoxy)-3-vinyl-benzene [ka] Dissolution of methyltriphenylphosphonium iodide (7.05 g) in DME (50 mL) To the solution was added K2CO3 (2.41 g). The resulting mixture was stirred at 20°C for 1 hour, and then 3-(difluoromethoxy)benzaldehyde (1.5 g) was added at 80°C for 1 Stirring was continued for 5 hours, the mixture was filtered, and the filter cake was washed with petroleum ether (100 mL). The filtrate was concentrated and purified by column chromatography (SiO2, petroleum ether / ethyl acetate). =1 / 0 to 10 / 1), and purified by 1-(difluoromethoxy)-3-vinyl-benzophenone. Zene (1.4 g) was obtained. 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 Preparation of -one [ka] 1,1-Difluoro-2-iodo-ethane (1 g), 1-(difluoro-2-iodoethane) in ACN (20 mL) fluoromethoxy)-3-vinyl-benzene (1.33 g), bis[(Z)-1-methyl -3-oxo-but-1-eneoxy] copper (273 mg) and Ag2SO4 (325 mg ), EtN (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 saturated aqueous Na2S2O3 and extracted with DCM (10 mL x 3). The organic phases were combined, washed with brine (5 mL × 2), dried over Na2SO4, and concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / The residue was purified by 1) and 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-difluorobenzoate in THF (10 mL) Fluorobutan-1-one (300 mg) and (R)-2-methylpropane-2-sulfonyl To a solution of benzophenone (218 mg) was added Ti(OEt) (547 mg). The mixture was stirred for 6 hours at 60° C. The reaction mixture was used directly in the next step.

[0193] Step 4: N-[(1S)-1-[3-(difluoromethoxy)phenyl]-4,4-difluoro Preparation of [fluoro-butyl]-2-methyl-propane-2-sulfinamide [ka] (S)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluoromethyl ... Fluorobutylidene)-2-methylpropane-2-sulfinamide (423 mg) To the solution at 48°C was added L-selectride (1 M in THF, 3.59 mL). The mixture was stirred for 0.5 h, then brought to 0 °C and H2O (ca. 10 mL) was added. The resulting mixture was extracted with EtOAc (35 mL × 2). The organic extract was washed with brine (10 mL). The mixture was extracted with HCl, dried over Na2SO4, and concentrated. The residue was purified by petroleum ether / ethyl acetate (1 / 0 to 1 / 1) to obtain N-[(1S) -1-[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2- Methyl-propane-2-sulfinamide (140 mg) was obtained.

[0194] Step 5: (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutanol Tan-1-amine hydrochloride [ka] N-[(1S)-1 -[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2-methyl The mixture was stirred at 20°C for 1 hour. was concentrated to give (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-difluoropropane Propan-1-amine hydrochloride [ka] Step 1: (S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane Preparation of propane-2-sulfinamide [ka] 3-(Difluoromethoxy)benzaldehyde (5 g) in DCE (150 mL) and To a solution of (R)-2-methylpropane-2-sulfinamide (4.22 g), CuSO 4 (23 g) was added. The reaction mixture was stirred at 55°C for 20 h, filtered, and concentrated. Chromatography on silica (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) The crude product was purified by (S,E)-N-(3-(difluoromethoxy)benzylidene)- As a result, 6.9 g of 2-methyl-2-propane-2-sulfinamide 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)but-3 Preparation of (-en-1-yl)-2-methylpropane-2-sulfinamide [ka] (S,E)-N-(3-(difluoromethoxy)benzylidene) in DCM (60 mL) A solution of 2-methylpropane-2-sulfinamide (2 g) was added to the solution of 2-methylpropane-2-sulfinamide (2 g) at 0°C. M) Magnesium (1 M solution in THF, 21.79 mL) was added slowly. The mixture was stirred at 0°C for 1 hour and at 25°C for 2 hours. The reaction was quenched by the addition of HO (50 mL) and then diluted with DCM (40 mL). The combined organic phase was washed with H2O (40 mL) and dried over Na2SO4. It was dried, filtered and concentrated. Chromatography (SiO2, petroleum ether / ethyl acetate = The residue was purified by 100 / 1 to 1 / 2 distillation and (S)-N-((S)-1-(3-(di- Fluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2- Sulfinamide (2.3 g) 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-ol Preparation of (xopropyl)-2-methylpropane-2-sulfinamide [ka] (S)-N-((S)-1-( 3-(Difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane 2,6-lutidine (1.69 g) and periodine To a stirred solution of sodium osmium dioxide (5.05 g), The hydrous compound (276 mg) was added in one portion. The reaction mixture was stirred at 20°C for 1 hour, then The aqueous layer was diluted with DCM (100 mL) and water (20 mL). The combined organic extracts were dried over Na2SO4. The crude reaction mixture was subjected to the next step. It was used directly in the process.

[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)methyl ... (phenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (2g ) at -78°C, diethylaminosulfur trifluoride (DAST) (3.03 g) was added dropwise. The reaction mixture was allowed to warm to 20°C and stirred for 2 hours. The solution was then cooled to 20°C and stirred for 2 hours. The solution was poured into saturated aqueous solution (50 mL) and the organic phase was separated. The mixture was dried and concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate = The residue was purified by 5 / 1 to 1 / 1 and (S)-N-((S)-1-(3-(difluoromethyl)-2-phenylpropanol) (3,3-difluoromethoxy)phenyl)-2-methylpropane-2- Sulfinamide (500 mg) was obtained.

[0199] Step 5: (1S)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoro Preparation of 1-propan-1-amine hydrochloride [ka] (S)-N-((S)-1-(3-(difluoromethoxy) (phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamine To a solution of 380 mg of HCl / MeOH (25 mL, 4 M) was added at 0°C, and the reaction The mixture was stirred for 0.5 h and allowed to reach 25° C. The reaction mixture was concentrated to give (1S)-1-[3 -(Difluoromethoxy)phenyl]-3,3-difluoro-propan-1-amine hydrochloride The salt (300 mg, crude, HCl salt) was obtained and used directly without further purification.

[0200] IIj: (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride salt [ka] Step 1: ((S,E)—N-(3-(difluoro-methoxy)benzylidene)-2-methyl Preparation of propane-2-sulfinamide [ka] 3-(Difluoromethoxy)benzaldehyde (2 g) in DCE (60 mL) and To a mixture of R)-2-methylpropane-2-sulfinamide (1.7 g), CuSO4 (9.3 g) was added at 55° C. under N2. The reaction mixture was stirred at 55° C. for 12 hours. The mixture was chromatographed on a silica gel column. The crude product was purified by filtration (petroleum ether / ethyl acetate = 20:1 to 10:1). ((S,E)-N-(3-(difluoro-methoxy)benzylidene)-2-methylpropane As a result, 4.5 g of benzo-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)benzylidene)- To a solution of bromo(methyl)-2-methylpropane-2-sulfinamide (2 g), ) Magnesium (3 M in EtO, 4.8 mL) was added dropwise at 0 °C. The mixture was stirred at 0° C. for 1 hour and at 20° C. for 16 hours. Saturated aqueous NH4Cl (10 mL) The reaction was quenched by HCl and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic extract was washed with brine (40 mL x 2), dried over anhydrous Na2SO4, filtered, and Concentrated and purified by chromatography on a silica gel column (petroleum ether / ethyl acetate = 5:1 ~ The crude product was purified by (S)-N-((S)-1-(3-(difluoromethyl)-2-methyl-2-propanol)-1:1) (Methoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (960m g) was obtained.

[0202] Step 3: (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride Salt preparation [ka] (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-2,4-difluorobenzoate in MeOH (4 mL) To a solution of (phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8 g), HCl / MeOH (4M, 2 mL) was added, and the resulting mixture was stirred at 25°C for 3 h. , concentrated to give (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine The hydrochloride salt (1.6 g, crude) 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 of [ka] Ethyl 2-oxoacetate (7.5 g) and ( To a solution of R)-2-methylpropane-2-sulfinamide (4.90 g), CuSO4 (12.9 g) was added and the reaction mixture was stirred at 25° C. for 24 hours. The solid was filtered off and The organic layer was washed with ethyl acetate (50 mL) and concentrated. The residue was purified by ethanol / ethyl acetate (5 / 1) to give ethyl (R,E)-2-((t To obtain 5 g of ert-butylsulfinyl)imino)acetate.

[0204] Step 2: Ethyl (R)-2-(((S)-tert-butylsulfinyl)amino)-2 Preparation of -(3-(trifluoromethoxy)phenyl)acetate [ka] Ethyl (R,E)-2-((tert-butylsulfinyl)sulfonyl)sulfonyl in dioxane (80 mL) (trifluoromethoxy)phenyl)boron (5g) and [3-(trifluoromethoxy)phenyl]boron A solution of bis(acetonitrile)(1,5-cyclooctadiene)bromine (6.02 g) was added to the solution. Sodium(I) tetrafluoroborate (CAS: 32679-02-0) (1.85g) was added and the mixture was stirred at 80° C. for 16 hours. The solution was filtered and the organic phase was concentrated. The residue was purified by chromatography (SiO2, petroleum ether: EtOAc = 6:1). Purify and prepare 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)a Preparation of acetate [ka] Ethyl (R)-2-(((S)-tert-butylsulfide) in MeOH (30 mL) (3-(trifluoromethoxy)phenyl)-2-(3-(trifluoromethoxy)phenyl)acetate (4.6g To a solution of HCl / MeOH (4M, 25.04 mL) was added at 0° C. The reaction mixture The mixture was stirred at 25°C for 1 hour and concentrated to give ethyl (R)-2-amino-2-(3-(trifluoromethyl)-2-methyl-2-oxo ... (Oromethoxyphenyl)acetate was obtained as the hydrochloride salt (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-(trifluoromethacrylate)-2-yl)-2-(2-methyl-2-propanol) in THF (80 mL) A mixture of phenylacetate hydrochloride (3.3 g), Boc2O (4.81 g) and and NaHCO3 (925 mg) were added and the reaction was stirred at 25 °C for 16 h. was concentrated, diluted with EtOAc (20 mL), washed with water (20 mL), and then concentrated The residue was purified by chromatography (SiO2; petroleum ether: EtOAc = 10:1). was purified to obtain ethyl (R)-2-((tert-butoxycarbonyl)amino)-2-( 3-(trifluoromethoxy)phenyl)acetate (3.8 g) was obtained.

[0207] Step 5: tert-Butyl (R)-(2-hydroxy-1-(3-(trifluoromethyl)-2-methyl ... Preparation of phenylethyl carbamate [ka] To a suspension of LiAlH4 (2.1 g) in THF (200 mL), THF (20 mL) Ethyl (R)-2-((tert-butoxycarbonyl)amino)-2-(3- ... (trifluoromethoxy)phenyl)acetate (5 g) was added under ice cooling, and the mixture was cooled to 0 The mixture was stirred for 2 hours at 25° C. Anhydrous magnesium sulfate was added, followed by water (5 mL) and vinegar. Ethyl acetate (100 mL) was gradually added, and the insoluble material was filtered off using Celite. The mixture was concentrated and purified by chromatography (SiO2, petroleum ether: EtOAc = 5:1). The crude product was purified to give tert-butyl (R)-(2-hydroxy-1-(3-(trifluoromethyl)phenyl)-2-methyl-2-propanol). To obtain 3.37 g of 4-(4-(2-fluoromethoxyphenyl)ethyl)carbamate.

[0208] Step 6: tert-Butyl (R)-(2-ethoxy-1-(3-(trifluoromethoxy) Preparation of phenylethyl carbamates [ka] tert-Butyl (R)-(2-hydroxy-1-(3-( A solution of (trifluoromethoxy)phenyl)ethyl)carbamate (1 g) was added to diethyl sulfate. ammonium chloride (TBAC) (87 mg), and Na A solution of OH (324 mg) and HO (1.5 mL) was added. The resulting mixture was heated at 25°C. The reaction mixture was stirred at rt for 20 h. The reaction mixture was diluted with EtOAc (200 mL) and water (100 mL ) and brine (100 mL), dried over Na2SO4 and concentrated. The crude material was purified by lithography (SiO2, 10% ethyl acetate in petroleum ether). tert-butyl (R)-(2-ethoxy-1-(3-(trifluoromethoxy)-2-methyl ... )phenyl)ethyl)carbamate (5.9 g) 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-( To a solution of (trifluoromethoxy)phenyl)ethyl)carbamate (5.9 g), HCl / MeOH (4M, 63.33 mL) was added at 25°C, and the mixture was stirred at 25°C for 16 h. The solution was concentrated to give (R)-2-ethoxy-1-(3-(trifluoromethyl)-2-methyl-2-propanol. To obtain 4.5 g of hydroxy)phenyl)ethan-1-amine hydrochloride.

[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 mL) in DCE (200 mL) g), (R)-2-methylpropane-2-sulfinamide (7.7 g) and CuSO4 A mixture of (12.6 g) was stirred at 55° C. for 16 hours. The mixture was filtered and the filter cake The residue was washed with DCM (200 mL). The filtrate was concentrated. Chromatography (SiO2, 0 Purify the residue by elution with a ~10% ethyl acetate / petroleum ether gradient (S,E). -2-methyl-N-(3-(trifluoromethoxy)benzylidene)propan-2-sulfonyl Finamide (12.6 g) was obtained.

[0211] Step 2: (S)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)- Preparation of (Nyl)propyl)propane-2-sulfinamide [ka] (S,E)-2-methyl-N-(3-(trifluoromethyl)-2-methyl-N-(2-methyl-N ... To a solution of (2.0 g) 2-(2-hydroxybenzylidene)propane-2-sulfinamide, EtM gBr (3 M in EtO, 9.1 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 1 The mixture was stirred for 3 hours at 20°C. The mixture was cooled to 0°C and added with saturated aqueous NH4Cl (100 The mixture was extracted with DCM (100 mL x 2), the phases were separated, and the organic layer was Washed with brine (200 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (SiO2, 0-50% ethyl acetate / petroleum ether gradient). The product (1.4 g) was obtained.

[0212] Step 3: (S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine Preparation of the hydrochloride salt [ka] (S)-2-Methyl-N-((S)-1-(3-(trifluoromethyl)phenyl)-2-methyl ... (1.4 g) of (2-(4-methoxyphenyl)propyl)propane-2-sulfinamide To the solution was added HCl / MeOH (4 M, 20 mL). The resulting mixture was heated at 30° C. for 12 h. The mixture was stirred for 1 hour and then concentrated to give crude (S)-1-(3-(trifluoromethoxy)phenyl)- (1g)nylpropan-1-amine hydrochloride was obtained, which was 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)methyl)methyl) Preparation of phenylethyl carbamate This intermediate was prepared as described for intermediate IIk, steps 1-5.

[0214] Step 2: (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trimethylsilyl)amino)-2-(3-methyl-2-propanol) Preparation of (fluoromethoxy)phenyl)ethyl methanesulfonate [ka] tert-Butyl (R)-(2-hydroxy-1-(3-(trimethylsilyl)methyl)-2-methyl-2-propanol) in DCM (20 mL) To a solution of (trifluoromethoxy)phenyl)ethyl)carbamate (2 g), Et3N(7 To the mixture was added methanesulfonyl chloride (1.75 g) at 0°C. The mixture was stirred for 16 hours at 20°C. The reaction mixture was washed with saturated aqueous NH4Cl (15 mL). Wash, dry over Na2SO4, filter, concentrate, and distill off (R)-2-((tert-butoxy) (carbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethylmethane The sulfonate (2.50 g, crude) was obtained and used in the next step without further purification. Ta.

[0215] Step 3: (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propane Preparation of nitrile hydrochlorides [ka] (R)-2-((tert-butoxycarbonyl)amino)- in DMSO (5 mL) 2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate (420mg To a solution of ), KCN (225 mg) was added 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 added to EtOAc (30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL). The mixture was washed with water, then dried over NaSO, filtered, and concentrated. 2, petroleum ether / ethyl acetate = 5 / 1 to 4 / 1) to purify the residue into tert -butyl(S)-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl ) carbamate (665 mg) was obtained. 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-(trifluoromethyl)phenyl)propanol) in MeOH (8 mL) To a solution of (fluoromethoxyphenyl)ethyl)carbamate (400 mg), HCl / M eOH (4 M, 4.00 mL) was added at 0° C. The mixture was stirred at 25° C. for 16 h. The reaction mixture was then concentrated to give (S)-3-amino-3-(3-(trifluoromethacrylamide)). (ii)phenyl)propanenitrile hydrochloride (280 mg, crude product) was obtained.

[0217] IIn: (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanediol Tolyl Hydrochloride [ka] Step 1: (R,E)-2-methyl-N-(3-(trifluoro-methoxy)benzylidene ) Preparation of propane-2-sulfinamide [ka] 3-(Trifluoromethoxy)benzaldehyde (30 g) in DCE (600 mL) and (R)-2-methylpropane-2-sulfinamide (23.0 g), SO4 (37.8 g) was added. The mixture was stirred at 55°C for 24 hours and filtered. The filtrate was combined, concentrated and purified by chromatography (S The residue was purified by HClO2, petroleum ether / ethyl acetate = 0 / 1 to 5:1 (R ,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane- 2-Sulfinamide (41.8 g) 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)-2-methyl-N-(3-methyl-N-methyl)-2-methyl-N-(3-(trifluoromethyl)-2 ... A solution of (c)benzylidene)propane-2-sulfinamide (5 g) was added to THF ( Activated Zn (11.15 g), CuCl (2.5 g) and ethyl 2-bromo The reaction mixture was stirred at 50°C for 2 hours and filtered. The filter cake was washed with DCM (400 mL) and the combined organic filtrate was concentrated. The residue was purified by chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1). The product was purified to give ethyl (S)-3-(((R)-tert-butylsulfinyl)amino )-3-(3-(trifluoromethoxy)phenyl)propanoate (7 g, crude) 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-butylsulfinyl)sulfonyl) (3-(trifluoromethoxy)phenyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7g) To the solution was added LiAlH4 (696 mg) at 0°C. The resulting mixture was stirred at 0°C for 1 hour. The mixture was stirred for 1 hour, and then at 0°C, HO (0.7 mL), 10% NaOH (0.7 mL) solution and The mixture was quenched by the addition of H2O (2.1 mL). The mixture was filtered. The distillate was concentrated to give crude (R)-N-((S)-3-hydroxy-1-(3-(trifluoromethyl)-2,4-difluoromethyl)-2,4-difluoromethyl-1,4-difluoromethyl ... (4-( ... 0.2g) was obtained.

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

[0221] Step 5: tert-Butyl (S)-(3-hydroxy-1-(3-(trifluoromethacrylate) Preparation of phenylpropyl carbamates [ka] The crude ethyl (S)-3-(((R)-tert-butylsulfide) from the previous reaction step nyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (3. 2 g) was dissolved in THF (35 mL) and BocO (10.28 g) and NaHCO ( 2 g) was added. The reaction mixture was stirred at 20°C for 16 hours. The mixture was concentrated and the residue was Dilute with water (70 mL), extract with DCM (100 mL x 3), and combine organic extracts The residue was dried over Na2SO4, filtered and concentrated. The residue was purified by tert-butyl ( S)-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)caprylamide The rubamate (3.2 g) was obtained.

[0222] Step 6: (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(trimethylsilyl)amino)- Preparation of fluoromethoxy)phenyl)propyl methanesulfonate [ka] tert-Butyl (S)-(3-hydroxy-1-(3-(trimethylsilyl)methyl)-2-methyl-2-methyl-1 ... To a solution of (trifluoromethoxy)phenyl)propyl)carbamate (1 g), Et3N( To the reaction mixture was added 100 mg of methyl 2-chloro-3-(2-methyl-2-propanol) (905 mg) and methanesulfonyl chloride (683 mg) at 0° C. The mixture was stirred at 20°C for 16 hours, washed with ice water (15 mL), dried over anhydrous Na2SO4, and filtered. The residue was filtered and concentrated to give ((S)-3-((tert-butoxycarbonyl)amino)-3-( 3-(trifluoromethoxy)phenyl)propyl methanesulfonate (1.2 g) was obtained. 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)propyl methanesulfonate in DMSO ( The reaction mixture was dissolved in 35 mL of HCl and KCN (661 mg) was added at 20° C. The reaction mixture was heated at 50° C. Stir for 16 h, then dilute with 10% Na2CO3 solution (40 mL) and add EtOAc (7 The combined organic extracts were extracted with water (50 mL) and brine (50 mL). ), then dried over Na2SO4, filtered and concentrated. The residue was purified by HClO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give te rt-Butyl (S)-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propionate propyl)carbamate (990 mg) was obtained.

[0224] Step 8: (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanediol Preparation of tolyl hydrochloride [ka] tert-Butyl (S)-(3-cyano-1-(3-(trimethylsilyl)methyl ... To a solution of fluoromethoxyphenylpropylcarbamate (900 mg), HCl l / MeOH (4M, 6.53 mL) was added. The mixture was stirred at 20°C for 16 hours and concentrated. Condensed to (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanediol Tolyl hydrochloride (850 mg) was obtained.

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

[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 for IIk, steps 1-4.

[0227] Step 2: tert-Butyl (R)-(2-hydroxy-1-(3-(trifluoromethyl)methyl)methyl) Preparation of phenylethyl carbamate [ka] Ethyl (R)-2-((tert-butoxycarbonyl)acetate) in EtOH (90 mL) to a solution of 2-(3-(trifluoromethoxy)phenyl)-2-(3-amino)-2-(trifluoromethoxy)phenyl)acetate (10 g) Then, NaBH4 (4.17 g) 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. The residue was purified by HCl, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to obtain 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 phenylethyl carbamates [ka] tert-Butyl (R)-(2-hydroxy-1-(3-(trimethylsilyl)methyl)-2-methyl-2-propanol) in THF (70 mL) A solution of (trifluoromethoxy)phenyl)ethyl)carbamate (1 g) and MeI (4 g) To the solution was added NaH (149 mg, 60% in mineral oil) at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was stirred at 25°C for 16 hours. Water (1 mL) was added to quench the reaction. The solution was removed and EtOAc (200 mL) was added to the residue. The solution was washed with water (50 mL × 3). The mixture was purified and concentrated. Column chromatography (SiO2, petroleum ether / ethyl acetate = 0 The residue was purified by tert-butyl (R)-(2-methoxy-1 -(3-(trifluoromethoxy)phenyl)ethyl)carbamate (3.2 g) 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-(trimethylsilyl)methyl)-2-methyl-2-propanol) in MeOH (40 mL) To a solution of (trifluoromethoxy)phenyl)ethyl)carbamate (2.7 g) at 25°C HCl / MeOH (4M, 40 mL) was added, and the mixture was stirred at 25° C. for 16 h. The mixture was concentrated to give the desired product (1.9 g, crude).

[0230] IIIa: (S)-3-hydroxy-4,4-dimethylpentanoic acid [ka] Wang Z.et al:Tetrahedron:Asymmetry 10(1 999) 225-228.

[0231] IIIb: 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid [ka] Step 1: Ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate Preparation of [ka] 3,3-Difluorocyclobutanone (0.2 g) in THF (13 mL) under N2 A solution of Zn (198 mg) and I2 (10 mg) was added to ethyl 2-bromoacetate (378 mg ) was added dropwise. The mixture was stirred at 55 °C for 6 h. H2SO4 (10%, 10 mL) was added dropwise. The mixture was extracted with ethyl acetate (20 mL x 3). The extract was washed with NaHCO3 (saturated aqueous solution, 10 mL), dried over Na2SO4, and concentrated. The crude product (0.26 g) was used directly without further purification.

[0232] Step 2: Preparation of 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetic acid [ka] Ethyl 2-(3,3-difluoro-1,4-difluoromethyl ... A solution of 1-hydroxy-cyclobutyl) acetate (0.26 g) was added to NaOH (1 07 mg) was added. The mixture was stirred at 20°C for 8 hours. The reaction solution was cooled to 0°C and 1N HCl was added to the solution until the H reached 1-2. The residue was diluted with brine (10 mL). The mixture was extracted with methyl tert-butyl ether (30 mL x 5). The organic extract was dried over Na2SO4, filtered and concentrated. The crude product (0.24 g) was obtained. and used without further purification.

[0233] IIIc: 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid [ka] Step 1: Ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate preparation [ka] in THF (30 mL) until the solution turns colorless ) A solution of ethanone (0.5 g), Zn (512 mg), and I2 (62 mg) was stirred at 20 °C. The mixture was stirred and ethyl 2-bromoacetate (981 mg) was added dropwise. The mixture was stirred at 20°C for 0.5 hours and at 65°C for 4.5 hours. The reaction was then diluted with 10% H2SO4 aqueous solution ( The organic extract was washed with brine ( 100 mL), dried over Na2SO4, concentrated and purified to give ethyl 3-(1-fluoro- To obtain cyclopropyl)-3-hydroxy-butanoate (0.83 g, crude).

[0234] Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-butanoic acid [ka] Ethyl 3-(1-fluorocyclopropyl)-3-hydroxybenzoate in EtOH (10 mL) A solution of s-butanoate (0.83 g) was added to a solution of NaOH (350 mg) in HO (3 mL). ) was added. The reaction mixture was stirred at 20° C. for 2 h, and then EtOAc (50 mL The aqueous layer was acidified to pH 3 with 10% HCl and extracted with 50% EtOAC (50 The combined organic extracts were washed with brine (100 mL) and Na Dry over SO4 and concentrate to give 3-(1-fluorocyclopropyl)-3-hydroxy- Butanoic acid (0.57 g, crude) was obtained.

[0235] IIId: 3-Cyclopropyl-3-hydroxybutanoic acid [ka] Step 1: Preparation of methyl 3-cyclopropyl-3-hydroxybutanoate [ka] To Zn (12.4 g) in THF (150 mL) was added TMSCl (1.3 g) to obtain The resulting mixture was stirred at 20°C for 15 minutes and then heated to 70°C. Heating was discontinued and the solution Methyl 2-bromoacetate (21.8 g) was added dropwise at such a rate that the mixture was gently boiling. The resulting mixture was stirred at 70°C for 1 hour, then at 20°C for 1 hour, followed by THF (50 mL). A solution of 1-cyclopropylethanone (10 g) in 10 ml of HCl was added. The reaction was stirred at 20° C. for 16 h. The mixture was poured into NH3·H2O (100 mL, 28%) on ice and ethyl acetate was added. The organic extract was extracted with water (150 mL) and brine (150 mL). L), dried over Na2SO4 and concentrated to give the desired product (8.9 g, crude).

[0236] Step 2: Preparation of 3-cyclopropyl-3-hydroxybutanoic acid [ka] Crude methyl 3-cyclopropyl in THF (100 mL) and HO (50 mL) -3-hydroxybutanoate (8.9 g) mixed with LiOH·H2O (11.8 g) The mixture was stirred at 20° C. for 16 h. H2O (50 mL) was added and ethyl acetate (100 mL) was added. The organic extract was discarded. The pH of the aqueous layer was adjusted to approximately 5 with 2N HCl. , extracted with ethyl acetate (100 mL × 3), and the combined organic fractions were washed with brine (100 mL × 10), dried over Na2SO4, filtered, and concentrated to give the desired product in 30% overall yield. 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 of [ka] A mixture of Zn (6.9 g) and I2 (89 mg) in THF (80 mL) was added to 4,4,4 -trifluorobutan-2-one (4.4 g) and ethyl 2-bromoacetate (6.4 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). The combined organic extracts were washed with brine (15 mL) and Na2S Dried over O4, filtered and concentrated to give the product (11.00 g, crude) which could be further purified It was used directly without any pretreatment.

[0238] Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid [ka] Ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpropional in H2O (150 mL) A mixture of ethyl pentanoate (11 g, crude) and NaOH (4.1 g) was heated at 15°C. The mixture was stirred for 16 hours. The pH was adjusted to about 2 with saturated KHSO4 at 0°C, and the mixture was diluted with ethyl acetate ( The combined organic extracts were washed with brine (300 mL) and Drying over Na2SO4, filtering and concentration gave the product (10 g, crude).

[0239] Prepare the following by the same methodology as described in IIIe using the relevant starting materials: 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-dimethyl-hexanoic acid [ka] 1 H 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-hydroxy-propanoic acid [ka] Step 1: Ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate Preparation of [ka] Ethyl 3-(3,3-dimethylcyclobutyl)-3-oxo- in MeOH (8 mL) To a solution of propanoate (IVd) (1 g), NaBH4 (95 mg) was added. The mixture was stirred at 0° C. for 10 min, quenched by the addition of H2O (1 mL), concentrated, and then It was diluted with EtOAc (30 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 4 / 1). Purify to obtain ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate The ester (907 mg) was obtained. 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-hydrochloride in MeOH (10 mL) A solution of hydroxy-propanoate (900 mg) was added to a solution of NaOH (377 mL) in HO (5 mL). A solution of 10 mg of HCl was added to the reaction mixture. The mixture was stirred at 25° C. for 4 hours. The reaction mixture was diluted with 10% HCl The solution was added to adjust the pH to 3-4, diluted with HO (30 mL), and 0 mL × 2), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoic acid (760 mg) 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] Prepare the following by the same methodology as described in IIIh using the relevant starting materials: did: IIIi: 3-Cyclopentyl-3-hydroxy-propanoic 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 .75(m,1H),1.62-1.35(m,8H).

[0245] IVa: Ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propane Noate [ka] Step 1: Ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propanediol Preparation of noate [ka] EtN (2.34 g) and MgCl (1.8 g) were dissolved in MeCN (30 mL) Add 3-ethoxy-3-oxo-propanoyl)oxypotassium salt (2.6 g) to a suspension The mixture was added and stirred for 2 hours at 20° C. Carbonyl-diimidazole in MeCN (20 mL) (CDI) (1.4 g) and 1-(difluoromethyl)cyclopropanecarboxylic acid (1 g) The reaction mixture was stirred at 20° C. for 14 hours. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (80 mL x 2). The organic extract was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (SiO2, 0–10% ethyl acetate / petroleum ether). The product was purified by elution with a gradient of 1000 kJ / ml to give the product (0.98 g).

[0246] Prepare the following by the same methodology as described in IVa using the relevant starting materials: Ta: IVb: Ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propionate Noate [ka] IVc: 3-(3,3-difluorocyclobutyl)-3-oxopropanoate [ka] IVd: Ethyl 3-(3,3-dimethylcyclobutyl)-3-oxo-propanoate [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-(difluoromethyl)-2-(2- ...1-(3-(difluoromethyl)-2-(2-fluoromethyl)-1-(3-(difluoromethyl)-1-(2-fluoro (Oromethoxy)phenyl)ethan-1-amine hydrochloride (IIa) (0.6 g), methyl 4 , 4-dimethyl-3-oxo-pentanoate (750 mg), TEA (2.40 g) and A solution of DMAP (58 mg) was stirred at 90°C for 16 hours. 50 mL), washed with water (30 mL) and brine (50 mL), and The mixture was dried over 1000 kJ / min and concentrated. Chromatography (SiO2, 30% EA in petroleum ether) The crude product was purified by (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethyl)-2-methyl-2-propanol). (fluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide ( 0.28g) was obtained.

[0250] The following intermediates were prepared by methodology similar to Va using related intermediates: Vb: (R)-N-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethoxy) (ethyl)-4,4-dimethyl-3-oxopentanamide [ka] It was prepared from IIk and 4,4-dimethyl-3-oxo-pentanoic 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-(difluoromethyl) (oxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanediol Mido [ka] Prepared from IVc and IIa.

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

[0255] Vg: (S)-3-(3,3-difluorocyclobutyl)-N-(1-(3-(difluorocyclobutyl) (trimethoxy)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. [Example]

[0257] Example 1a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh)yl)-2-methyl-2-propanol (Hydroxy)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-oxopentanamine To a solution of Va (0.28 g) was added NaBH (56 mg) at 0 °C. The mixture was stirred at 0° C. for 1 h. The mixture was concentrated, and the residue was dissolved in EtOAc (50 mL ), washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and 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) Isolation of )phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (Nyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was chromatographed. was separated by

[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: R =2.49 minutes (LC-MS method 1), m / z=382.2[M+H] + . SFC:t R = 1.94 min (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: R =2.50 minutes (LC-MS method 1), m / z=382.2[M+H] + . SFC:t R = 2.03 min (SFC method 1), ee% = 95.26%.

[0261] The following compounds can be prepared by similar methodology as described for 1a and 1b using related intermediates: The following examples were prepared: Example 2a: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)-2-methyl-2-propanol (ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] and Example 2b: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)-2-methyl-2-propanol (phenyl)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-hydroxybenzoate Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethylene) Separation of (trimethoxy)phenyl)ethyl)pentanamide [ka] N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl )-3-Hydroxy-4,4-dimethylpentanamide was 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: R =1.87 min (LC-MS method 4), m / z=378.2[M+H] + . SFC:t R = 1.71 min (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: R =1.87 min (LC-MS method 4), m / z=378.2[M+H] + . SFC:t R= 1.82 min (SFC method 18), ee% = 99.1%.

[0265] Example 3a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh)yl)-2-methyl-2-propanol 3-hydroxy-3-(1-(trifluoromethyl)cyclo[2-(2-hydroxyphenyl)ethyl]-2-methyl- ... Propyl)propanamide [ka] and Example 3b: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh)yl)-2-methyl-2-propanol 3-hydroxy-3-(1-(trifluoromethyl)cyclo[2-(2-hydroxyphenyl)ethyl]-2-methyl- ... Propyl)propanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)- )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropane Preparation of (propyl)propanamide [ka] Prepared from Vc.

[0266] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro) methoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl) (S)-N-((R)-2-(difluoromethoxy)-2-methyl-2-propanamide )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1 Isolation of (trifluoromethyl)cyclopropyl)propanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (1-(trifluoromethyl)cyclopropyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)- The propanamides were separated 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: R =2.51 min (LCMS method 1), m / z=434.1[M+H] + . SFC:t R = 1.95 min (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: R =2.51 min (LCMS method 1), m / z=434.1[M+H] + . SFC:tR = 1.58 min (SFC method 3), ee% = 90,0%.

[0269] Example 4a: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... (trifluoromethyl)-3-hydroxy-3-(1-(trifluoromethyl)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclohexane (propyl)propanamide [ka] and Example 4b: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... (trifluoromethyl)-3-hydroxy-3-(1-(trifluoromethyl)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclohexane (propyl)propanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)-2-methyl ... (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-(trifluoromethyl)-2-methyl ... (trifluoromethyl)-3-hydroxy-3-((trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-((trifluoromethyl) (S)-N-((R)-2-(difluoromethoxy)-2-methyl-2-propanamide )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-( Separation of 1-(trifluoromethyl)cyclopropyl)propanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)-2-(difluoromethoxy)phenyl) (phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl ) Propanamides were 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: R =2.53 min (LCMS method 2), m / z=452.1[M+H] + . SFC:t R = 1.21 min (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: R =2.63 min (LCMS method 1), m / z=452.1[M+H] + . SFC:t R = 1.57 min (SFC method 7), ee% = 99.8%.

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

[0274] Step 2: (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro) ... (fluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydro (S)-3-(3,3-difluorocyclobutyl)-N-((R )-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl )-3-Hydroxypropanamide [ka] (R)-3-(3,3-difluorocyclobutyl)-N-(2-(trifluoromethacrylate) 1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanamine The compounds were separated by 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: 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 H NMR(CDCl3400MHz):δ7.37(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: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-(difluorocyclobutyl)- (trifluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy Cypropanamide [ka] and Example 6b: 3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluorocyclobutyl)- (trifluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy Cypropanamide [ka] Step 1: (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethyl)methyl)- (trifluoromethoxy)phenyl)ethyl)-3-oxopropanol Preparation of benzonamide [ka] Prepared from Vf.

[0278] Step 2: (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoro) ... (fluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy hydroxypropanamide and (S)-3-(3,3-difluorocyclobutyl)-N-(( R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethoxy Separation of (ethyl)-3-hydroxypropanamide [ka] (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy) )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropanamine The compounds were separated by 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: R =2.53 minutes (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 H NMR(CDCl3400MHz):δ7.42(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: 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-(difluorocyclobutyl)-N-methyl ... Fluoromethoxyphenylbutyl-3-hydroxypropanamide [ka] and Example 7b: 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluorocyclobutyl)-N-methyl ... Fluoromethoxyphenylbutyl-3-hydroxypropanamide [ka] Step 1: 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluorocyclobutyl)-N-methyl)- Preparation of (2-(4-methoxyphenyl)butyl)-3-hydroxypropanamide [ka] Prepared from Vg.

[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-(difluoromethyl)- Separation of ((2-(2-(phenyl)butyl)-3-hydroxypropanamide) [ka] 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethyl) ((2- ... 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: R =2.41 min (LC-MS method 1), m / z=378.0[M+H] + . SFC:t R = 2.37 min (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: R =2.45 minutes (LC-MS method 1), m / z=378.0[M+H] + . SFC:t R = 2.49 min (SFC method 6), ee% = 99.5%

[0285] Example 8a: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh)yl)-2-methyl-2-propanol (1-hydroxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Namide [ka] and Example 8b: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh)yl)-2-methyl-2-propanol (1-hydroxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropane Namide [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 (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-propanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-propanamide) Fluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxy Separation of hydroxypropanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (1-ethylcyclopropyl)-3-hydroxypropanamide Separation was carried out by 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: R =2.38 min (LCMS method 1), m / z=394.0[M+H] + . SFC:t R = 2.38 min (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: 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)yl)-2-methyl-2-propanol (1-hydroxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanol Namide [ka] and Example 9b: N-((R)-2-(difluoromethoxy)-1-(3-(difluorometh)yl)-2-methyl-2-propanol (1-hydroxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanol Namide [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-(difluoromethyl)-2-methyl-2-methyl-3-methyl-2 ... (trimethoxy)phenyl)ethan-1-amine hydrochloride (IIa) (400 mg) and 3-( 1-Fluorocyclopropyl)-3-hydroxybutanoic acid (IIIc) (307 mg) To the solution, N-hydroxybenzotriazole (HOBt) (213 mg), 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 diluted with water (10 mL). The combined organic extracts were diluted with Na2SO4 The residue was purified by basic preparative HPLC. N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl-2-propanol) )phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane Mido (250 mg) was obtained.

[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-(difluoromethyl)-2-methyl ... (fluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybenzoate Isolation of hydroxybutanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (1-(1-methyl-4-methyl-1,4-diphenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide Separation was carried out by 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: R =2.48 min (LCMS method 1), m / z=398.2[M+H] + . SFC:t R = 2.46 min (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: R =2.47 min (LCMS method 1), m / z=398.1[M+H] + . SFC:t R = 2.65 min (SFC method 12), ee% = 98.8%.

[0293] Using related intermediates, similar methodology as described for Example 9a and Example 9b was used. Thus, the following examples were prepared: Example 10a: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... (Methoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Butanamide [ka] and Example 10b: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... (Methoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Butanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)-2-methyl ... (phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane Preparation of amides [ka] Prepared from IIb and IIIc.

[0294] Step 2: (S)—N—((R)-2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... (1-fluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxy Sibutanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3-( (trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3 Isolation of -hydroxybutanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)-2-(difluoromethoxy)phenyl) (phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide were separated using chiral SFC.

[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: R =2.64 min (LCMS method 1), m / z=416.2[M+H] + . SFC:t R = 2.38 min (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 .86(m,4H). LC-MS: R =2.659 min (LCMS method 1), m / z=416.2[M+H] + . SFC:t R = 2.561 min (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 and (S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3 Isolation of (trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] 3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethyl)-2-methyl ... Chiral SFC of (fluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide So it was 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: R =2.42 min (LCMS method 1), m / z=420.1[M+Na] + . SFC:t R = 2.17 min (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: R =2.95 min (LCMS method 1), m / z=420.1[M+Na] + . SFC:t R = 2.48 min (SFC method 13), ee% = 100%.

[0301] Example 12a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl ... (trifluoro)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methyl Pentanamide [ka] and Example 12b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl ... (trifluoro)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methyl Pentanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)- )phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpenta Preparation of benzonamide [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 rupentanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3- (Difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy Isolation of 3-methylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (Nyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamine The compounds were separated by 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: R =2.52 min (LCMS method 1), m / z=422.1[M+H] + . SFC:t R = 1.10 min (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: R =2.52 min (LCMS method 1), m / z=422.1[M+H] + . SFC:t R = 1.24 min (SFC method 14), ee% = 95.8%.

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

[0306] Step 2: (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro) (Methoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) Isolation of )phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (Nyl)ethyl-3-hydroxy-3,5-dimethylhexanamide was analyzed by chiral SFC. And they 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: R =2.54 min (LCMS method 1), m / z=396.1[M+H] + . SFC:t R = 2.40 min (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: R =2.54 min (LC-MS method 1), m / z=396.1[M+H] + . SFC:t R = 2.66 min (SFC method 15), ee% = 98.8%.

[0309] Example 14a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl ... (trimethyl)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] and Example 14b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl ... (trimethyl)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) Isolation of )phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl) (Nyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide, was used to separate it.

[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: R =2.41 min (LCMS method 1), m / z=382.0[M+H] + . SFC:t R = 2.44 min (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: R =2.41 min (LCMS method 1), m / z=382.0[M+H] + . SFC:t R = 2.68 min (SFC method 15), ee% = 97.4%.

[0313] Example 15a: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl ... (3,3-dimethylcyclobutyl)-3-hydroxyphenyl)ethyl Propanamide [ka] and Example 15b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)-2-methyl ... (3,3-dimethylcyclobutyl)-3-hydroxyphenyl)ethyl Propanamide [ka] Step 1: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)- )phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropane Preparation of benzonamide [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)phenyl) (3,3-dimethylcyclobutyl)-3-hydroxypropanamine The compounds were separated by 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: R =2.35 minutes (LC-MS method 3), m / z=408.1[M+H] + . SFC:t R = 2.32 min (SFC method 16), ee% = 99.7

[0316] Example 15b: 1 H 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: R =2.34 min (LCMS method 3), m / z=408.1[M+H] + . SFC:t R = 2.64 min (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 and (R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3 Isolation of (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] 3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoro) (Fluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide in chiral SFC So it was 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: R =2.48 min (LC-MS method 1), m / z=394.1[M+H] + . SFC:t R = 2.64 min (SFC method 17), ee% = 98.8%.

[0320] Example 16b: 1 H 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: R =2.27 minutes (LC-MS method 2), m / z=394.2[M+H] + . SFC:t R = 3.08 min (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 thoxy-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 SFC, 3-(1-fluorocyclopropyl)-3-hydroxy-N- ((R)-2-Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)buta The amide 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: R =2.43 minutes (LCMS method 1), m / z=380.0[M+H] + . SFC:t R = 1.29 min (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: R =2.53 minutes (LCMS method 1), m / z=380.0[M+H] + . SFC:t R = 1.76 min (SFC method 22), ee% = 81.4%.

[0325] Example 17: (S)—N—((R)-2-cyclopropoxy-1-(3-(difluoromethyl)methyl)methyl) (trimethyl)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethacrylate) Preparation of (phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] (R)-2-Cyclopropoxy-1-(3-(difluoromethyl)methyl)-2-(2-methyl-3-methyl-2-propanol) in DCM (10 mL) (3S)-3-hydroxyphenyl)ethan-1-amine hydrochloride (IIc) (0.2 g), Hydroxy-4,4-dimethyl-pentanoic acid (IIIa) (144 mg) and HATU (3 To a solution of 75 mg of DIEA (319 mg) was added. The mixture was stirred at 20°C for 16 hours. The crude product was purified to give (S)-N-((R)-2-cyclopropoxy-1H-methyl-2H-pyridin-1 ... -(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethyl Rubentanamide 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: R =2.40 min (LCMS method 1), m / z=372.1[M+H] + . SFC:t R = 1.988 min (SFC method 7), ee% = 97.5%.

[0326] The following was prepared by similar methodology as described for Example 17 using the relevant intermediates: Examples were prepared.

[0327] Example 18: (S)—N—((R)-1-(3-(difluoromethoxy)phenyl)-2 -(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamine 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: R =2.38 min (LCMS method 3), m / z=400.0[M+H] + . SFC:t R = 2.11 min (SFC method 4), ee% = 96.4%.

[0328] Example 19: (S)—N—((R)-1-(3-(trifluoromethoxy)phenyl)- 2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentaenoic acid 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: R =2.56 min (LCMS method 3), m / z=418.0[M+H] + . HPLC:t R = 13.54 min (HPLC method 2), ee% = 65.9%

[0329] Example 20: (S)—N—((S)-1-(3-(difluoromethoxy)phenyl)butyl) (I)-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: R =2.30 minutes (LCMS method 3), m / z=344.1[M+H] + . SFC:t R = 2.13 min (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: R =2.43 minutes (LCMS method 1), m / z=380.0[M+H] + . HPLC:t R = 14.01 min (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: R =2.63 min (LCMS method 1), m / z=366.2[M+H] + . HPLC:t R = 13.43 min (HPLC method 1), ee% = 96.7%.

[0332] Example 23: (S)—N—((S)-1-(3-(difluoromethoxy)phenyl)ethyl) (I)-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: R =2.155 minutes (LCMS method 2), m / z=316.1[M+H] + . SFC:t R = 2.416 min (SFC method 8), ee% = 100%.

[0333] Example 24: (S)—N—((S)-2-cyano-1-(3-(trifluoromethoxy) (phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] It was 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: R =2.42 minutes (LSMS method 1), m / z=359.2[M+H] + . HPLC:t R = 12.56 min (HPLC method 4), ee% = 100%.

[0334] Example 25: (S)—N—((S)-3-cyano-1-(3-(trifluoromethoxy) (phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide [ka] It was 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: R =2.44 min (LCMS method 1), m / z=373.2[M+H] + . SFC:t R= 1.47 min (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,2H),2.62-2.56(m,2H). LC-MS: R =2.39 min (LCMS method 1), m / z=402.1[M+H] + . SFC:t R = 1.87 min (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: R =2.53 minutes (LC-MS method 1), m / z=420.2[M+H] + . HPLC:t R = 12.77 min (HPLC method 2), ee% = 86.7%.

[0337] Example 28: (R)—N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)-2-methyl ... )phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetate Toamide [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: R =2.53 minutes (LC-MS method 1), m / z=410.0[M+H] + . SFC:t R = 1.50 min (SFC method 7), ee% = 99.7%

[0338] Example 29: (R)—N-(2-cyclopropoxy-1-(3-(difluoromethoxy) (phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetoacetate amide [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: 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: R =2.48 minutes (LC-MS method 1), m / z=420.0[M+H] + . SFC:t R = 12.96 min (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: R =2.44 min (LC-MS method 1), m / z=364.0[M+H] + . SFC:t R = 1.71 min (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: R =2.50 min (LCMS method 1), m / z=400.1[M+H] + . HPLC:t R = 12.48 min (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: R =2.57 min (LCMS method 1), m / z=368.1[M+H] + . SFC:t R = 13.09 min (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: R =2.257 minutes (LC-MS method 1), m / z=379.0[M+H] + . SFC:t R = 2.60 min (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 Toamide [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 min (LC-MS method 1), m / z=404.1[M+H] + . SFC:t R =1.66 points (SFC method 19),ee%=98.5%

Claims

1. Formula I 【Chemical 1】 (Wherein R1 is C １ ~C ６ Alkyl, CF ３ , C.H. ２ CF ３ , C.F. ２ CHF ２ , C ３ ~C ８ cycloalkyl, wherein said C ３ ~C ８ Cycloalkyl is C １ ~C ３ Alkyl, F, CHF ２ and CF ３ One or two selected from the group consisting of optionally substituted with a substituent; and R2 is H, C １ ~C ６ Alkyl or CF ３ or R1 and R2 bond together to form one or two F, CHF ２ or optionally substituted with CF3 C was ３ ~C ５ forming a cycloalkyl; and R3 is C １ ~C ３ Alkyl or CH ２ O-C １～３ alkyl, １ ~C ３ Alkyl or CH ２ O-C １ ~C ３ is C≡N, 3F or C ３ ~C ５ Cycloalkyl substituted alkyl; R4 is OCF ３ , or OCHF ２ or a compound of the formula (I) selected from the group consisting of A pharmaceutically acceptable salt of any of the compounds of formula (I).

2. R4 is OCF ３ or OCHF ２ 2. The compound of claim 1, wherein Acceptable salt.

3. R3 is CH ２ O-CF ３ , C.H. ２ O-cyclopropyl, CH ２ -C≡N A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from salt.

4. R1 is one or two C １ ~C ３ Alkyl, F, CHF ２ or CF ３ Place it arbitrarily with Replaced C ３ ~C ４ A compound according to any one of the preceding claims, which is cycloalkyl. or a pharmaceutically acceptable salt thereof.

5. R1 and R2 combine to form a cyclobutyl optionally substituted with one or two F. and R4 is OCF ３ or OCHF ２ 2. The method of claim 1, wherein The compound, or a pharmaceutically acceptable salt thereof.

6. (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)fluoro)phenyl) (phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethyl)phenyl) (Oromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N—((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethyl)phenyl) (fluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethoxy) (ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propane) 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)ethoxy) (ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3- (difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetami Do; or (S)—N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)- From the group consisting of 2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide A compound according to claim 1, or a pharmaceutically acceptable salt of any of these compounds. Useful salt.

7. (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) (i)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)cyclopropane (propyl)propanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropane (propyl)propanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (1-(trifluoromethyl)cyclopropyl)-3-hydroxy-3-(phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl) (propyl)propanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (1-(trifluoromethyl)cyclopropyl)-3-hydroxy-3-(phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl) (propyl)propanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl) (3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Panamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl) (3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropyl Panamide (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl) (trifluoromethoxy)phenyl)ethyl)-3-hydroxypropyl lopanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethyl) (trifluoromethoxy)phenyl)ethyl)-3-hydroxypropyl lopanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluorocyclobutyl) (Oromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluorocyclobutyl) (Oromethoxy)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-hydroxybenzoate hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluoro (Orobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoro (Oropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-phenyl hydroxy-4,4-dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoro) (3-(difluoromethoxy)phenyl)ethyl)acetamide ； (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoro) (3-(trifluoromethoxy)phenyl)ethyl)acetamido 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)propane) 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-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) (i)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane amides; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy) (i)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutane amides; (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 amide; (S)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpenta amide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (S)—N—((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide; (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 amide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy) )phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropane amide; (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) thoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2 -methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide 1. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of any of these compounds.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or a plurality of pharmaceutically acceptable excipients.

9. Treating patients in need who suffer from epilepsy, bipolar disorder, migraine, or schizophrenia A method for treating a rheumatoid arthritis, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 7, or administering to said subject a pharmaceutically acceptable salt.

10. Psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, major depressive disorder, Anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorders, people personality disorder, schizophrenia-type disorder, aggression, chronic pain, neurological disorders, autism spectrum disorder, People with Chinton's chorea, sclerosis, multiple sclerosis, or Alzheimer's disease who need A method for treating a patient suffering from a disease comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 7. A method comprising administering to said subject a compound comprising the steps of:

11. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof in therapy. The use of salt.

12. A compound according to claims 1 to 7 for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. Use of a compound or a pharmaceutically acceptable salt thereof.

13. Psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, major depressive disorder, Anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorders, people personality disorder, schizophrenia-type disorder, aggression, chronic pain, neurological disorders, autism spectrum disorder, Claims for treating Chinton's chorea, sclerosis, multiple sclerosis, and Alzheimer's disease Use of a compound according to any one of 1 to 7 or a pharmaceutically acceptable salt thereof.

14. Claims for the manufacture of a medicine for the treatment of epilepsy, bipolar disorder, migraine, or schizophrenia Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

15. Psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, major depressive disorder, Anxiety, anxiety attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorders, people personality disorder, schizophrenia-type disorder, aggression, chronic pain, neurological disorders, autism spectrum disorder, Manufactures medicines for the treatment of Chinton's chorea, sclerosis, multiple sclerosis, and Alzheimer's disease. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in treating atopic dermatitis.

16. Epilepsy, epilepsy syndromes, epilepsy symptoms, treatment-resistant or refractory epilepsy, or A compound according to claims 1 to 7 or a compound thereof for use in the treatment of epileptic seizures.

17. A pharmaceutical salt or pharmaceutical composition according to claim 16.

17. 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 seizures Cancerous encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsy syndromes (infant severe myoclonic epilepsy in the early stages, epilepsy with continuous spike-and-wave during slow wave sleep, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Otahara syndrome, or stress, hormonal changes, drugs, alcohol, infections, trauma Brain injury, stroke, brain tumor, autism spectrum disorder or metabolic disorder (hyponatremia) A compound according to claims 1 to 7 for use in the treatment of epileptic seizures associated with or a pharmaceutical salt thereof, or the pharmaceutical composition of claim 16.

18. Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, and other conditions A compound according to claims 1 to 7 for use in the treatment of epileptic symptoms as part of a degenerative disease. or a pharmaceutical salt thereof, or a pharmaceutical composition according to claim 16.

19. Epilepsy, epilepsy syndrome, epilepsy symptoms, treatment-resistant or intractable epilepsy or 1. A method of treating a patient in need thereof suffering from epileptic seizures, comprising administering a therapeutically effective amount of The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, is administered to the subject. The method of claim 1, further comprising administering to

20. Focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures , idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, neonatal seizures, K CNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsies syndrome (severe myoclonic epilepsy of infancy with persistent spike-and-wave during slow-wave sleep) Epilepsy, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myocardial infarction Knee encephalopathy, Otahara syndrome, etc., or stress, hormonal changes, drugs, alcohol, Infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder or metabolic disorder (low NA Treat patients who are suffering from and in need of treatment for epileptic seizures associated with thorium or Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobe Methods for use in treating epileptic conditions as part of neurodegenerative diseases such as encephalopathy and encephalopathy A therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof. administering to said subject an acceptable salt.

21. Epilepsy, epilepsy syndromes, epilepsy symptoms, treatment-resistant or refractory epilepsy, or A compound according to claims 1 to 7 or a pharmaceutically acceptable salt thereof for treating epileptic seizures. Use of salt.

22. 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 seizures Cancerous encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsy syndromes (infant severe myoclonic epilepsy in the early stages, epilepsy with continuous spike-and-wave during slow wave sleep, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Otahara syndrome, or stress, hormonal changes, drugs, alcohol, infections, or For use in the treatment of epileptic seizures associated with metabolic disorders (e.g., hyponatremia) or Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration Claims for use in treating epileptic symptoms as part of a neurodegenerative disease such as Use of a compound according to any one of 1 to 7 or a pharmaceutically acceptable salt thereof.

23. Epilepsy, epilepsy syndromes, epilepsy symptoms, treatment-resistant or refractory epilepsy, or A compound according to claims 1 to 7, or a compound thereof, for the manufacture of a medicament for the treatment of epileptic seizures. Pharmaceutically acceptable salts.

24. 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 seizures Cancerous encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsy syndromes (infant severe myoclonic epilepsy in the early stages, epilepsy with continuous spike-and-wave during slow wave sleep, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, for the manufacture of drugs for the treatment of diseases such as Alzheimer's disease, Lewy body disease, Epilepsy as part of neurodegenerative disorders such as juvenile Huntington's disease and frontotemporal lobar degeneration A compound according to claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment of Possible salt.

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