Alcohol derivatives as KV7 potassium channel openers

Abstract

The present invention provides novel compounds that activate Kv7 potassium channels. Other aspects of the invention are directed to pharmaceutical compositions containing the compounds and to methods of using the compounds to treat diseases responsive to activation of Kv7 potassium channels.

Description

[Technical Field]

[0001] The present invention relates to novel compounds that activate Kv7 potassium channels. Another aspect of the invention relates to pharmaceutical compositions containing said compounds and methods of using the compounds to treat diseases responsive to activation of Kv7 potassium channels. [Background technology]

[0002] Voltage-gated potassium (Kv) channels transport potassium ions (K) across the cell membrane in response to changes in membrane potential. + ) and thereby regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell. Functional Kv channels exist as multimeric structures formed by the association of four α subunits and four β subunits. The α subunits contain six transmembrane regions, a pore-forming loop, and a voltage sensor, and are symmetrically arranged around the central pore. The β or auxiliary subunits can interact with the α subunits to modify the properties of the channel complex, including, but not limited to, alterations in the electrophysiological or biophysical properties of the channel, expression level, or expression pattern.

[0003] Nine families of Kv channel α subunits have been identified, designated Kv1-Kv9, and there is therefore enormous diversity in Kv channel function resulting from the numerous subfamilies, the formation of both homologous and heterologous subunits within subfamilies, and the additive effects of association with β subunits (Christie, 25 Clinical and Experimental Pharmacology and Physiology, 1995, 22, 944-951).

[0004] The Kv7 channel family consists of at least five members, including one or more of the mammalian channels Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.5, and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof. Members of this family are alternatively referred to by the gene names KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5, respectively (Dalby-Brown, et al., Current Topics in Medicinal Chemistry, 2006, 6, 9991023).

[0005] As mentioned above, neuronal Kv7 potassium channels play a role in regulating neuronal excitability. Kv7 channels, particularly the Kv7.2 / Kv7.3 heterodimer, underlie the M-current (Wang et al. Science. 1998 Dec 4;282(5395):1890-3). The M-current has characteristic time- and voltage-dependent properties that result in stabilization of the membrane potential in response to multiple excitatory stimuli.

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

[0007] Retigabine (N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester) is a compound that binds to the Kv7 potassium channel (Wuttke, et al., Molecular Pharmacology, 2005, 67, 1009-1017). Retigabine binds to the Kv7 channel in neurons. + The pharmacology of this induced current is determined by the Kv7.2 / 3 K +This is consistent with the published pharmacology of M-channels, which correlates with channel heteromultimerization, suggesting that activation of Kv7.2 / 3 channels may mediate at least part of the drug's anticonvulsant activity (Wickenden, et al., Molecular Pharmacology 2000, 58, 591-600). Retigabine is effective in reducing the incidence of epileptic seizures in epileptic patients (Bialer, et al., Epilepsy Research 2002, 51, 31-71). Retigabine has broad-spectrum and potent anticonvulsant activity, which is effective after oral and intraperitoneal administration in rats and mice in various anticonvulsant studies (Rostock, et al., Epilepsy Research 1996, 23, 211-223).

[0008] The five members of this family of ion channels differ in their expression patterns: Kv7.1 expression is restricted to the heart, peripheral epithelium, and smooth muscle, whereas Kv7.2, Kv7.3, Kv7.4, and Kv7.5 expression appears to predominate in the nervous system, including the hippocampus, cerebral cortex, ventral tegmental area, and dorsal root ganglion neurons (see Greene & Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508 for a review).

[0009] The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal convulsions (Rogawski, Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localized in pyramidal neurons of the human cerebral cortex and hippocampus, brain regions associated with the generation and propagation of epileptic seizures (Cooper et al., Proceedings National Academy of Science USA 2000, 97, 4914-4919).

[0010] Furthermore, in addition to Kv7.2 mRNA, Kv7.3 and Kv7.5 mRNA are expressed in astrocytes and glial cells. Thus, Kv7.2, Kv7.3, and Kv7.5 channels may help regulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (Noda, et al., Society for Neuroscience Abstracts 2003, 53.9), making them suitable for the treatment of neurodegenerative diseases such as, but not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0011] Kv7.2 and Kv7.3 subunit mRNAs are found in brain regions associated with anxiety and emotional behaviors, such as the hippocampus, ventral tegmental area, and amygdala, which are involved in depression and bipolar disorder (Saganich et al. Journal of Neuroscience 2001, 21, 4609-4624; Friedman et al. Nat Commun. 2016; 7:11671). Retigabine has been reported to be effective in animal models of anxiety-like behavior (Korsgaard et al. J Pharmacol Exp Ther. 2005 Jul; 314(1):282-92. Epub 2005 Apr 6). Therefore, Kv7 channels are suitable for the treatment of emotion-related disorders, including, but not limited to, bipolar depression, major depressive disorder, anxiety, suicide, panic attacks, and social phobia.

[0012] Kv7.2 / 3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden, et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators have been hypothesized to be effective in both neuropathic pain and epilepsy (Schroder, et al., Neuropharmacology 2001, 40, 888-898). In addition to their role in neuropathic pain, Kv7.2-5 mRNA expression in the trigeminal ganglion and dorsal root ganglion, as well as the trigeminal nucleus caudalis, suggests that openers of these channels may also affect sensory processing in migraine headaches (Goldstein, et al., Society for Neuroscience Abstracts 2003, 53.8). Taken together, this evidence supports the applicability of KCNQ channel openers for the treatment of chronic pain and neuropathy-related disorders.

[0013] WO 07 / 90409 relates to the use of Kv7 channel openers for the treatment of schizophrenia. Kv7 channel openers are useful for modulating the function of the dopaminergic system (Friedman et al., Nat Commun. 2016; Scotty et al. J Pharmacol Exp Ther. 2009 Mar;328(3):951-62. doi:10.1124 / jpet.108.146944. Epub 2008 Dec 19; Koyama et al. J Neurophysiol. 2006 Aug;96(2):535-43. Epub 2006 Jan 4; Li et al. Br J Pharmacol. 2017 Dec;174(23):4277-4294. doi:10.1111 / bph.14026. Epub 2017 Oct 19; Hansen et al. J Pharmacol Exp Ther. 2006 Sep;318(3):1006-19. Epub These compounds are suitable for the treatment of psychiatric disorders, including, but not limited to, psychosis, mania, stress-related disorders, acute stress reaction, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive disorder, personality disorder, schizotypical disorder, aggression, and autism spectrum disorder. International Publication No. WO 01 / 96540 discloses the use of regulators of M-currents formed by the expression of KCNQ2 and KCNQ3 genes for insomnia, and International Publication No. WO 01 / 092526 discloses that regulators of Kv7.5 can be used to treat sleep disorders. International Publication No. WO 09 / 015667 discloses the use of Kv7 openers in the treatment of sexual dysfunction.

[0014] Although patients suffering from the above diseases may have available treatment options, many of these options lack the desired efficacy and are accompanied by undesirable side effects. Thus, there is an unmet need for new therapies for treating the above diseases.

[0015] In an effort to identify new therapeutics, the present inventors have identified a series of novel compounds represented by Formula I. Accordingly, the present invention provides novel compounds as pharmaceuticals for treating diseases modulated by KCNQ potassium channels. Summary of the Invention

[0016] The present invention relates to a compound of formula I [ka] With respect to the compound wherein R1 is selected from the group consisting of C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, and C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is optionally substituted with one or two C1-C3 alkyl, F, CHF2, or CF3; and R2 is H, C1-C6 alkyl, or CF3; or R1 and R2 are bonded together (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 R3 is C1-C3 alkyl or CHO-C 1~3 alkyl, and the C1-C3 alkyl or CHO-C 1~3 alkyl is substituted with C≡N, 3F or C3-C5 cycloalkyl; 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 relates to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient.

[0019] Additionally, the present invention relates to methods for treating a patient as described in the claims and embodiments, including treating a patient suffering from epilepsy, bipolar disorder, migraine, and schizophrenia, comprising administering to the subject a therapeutically effective amount of a compound of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention According to one embodiment, the compound of formula I may have an R4 group that is OCF3 or OCHF2.

[0021] According to other embodiments, compounds according to formula I may have an R3 group selected from the group including CH2-O-CF3, CH2O-cyclopropyl, CH2-C≡N.

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

[0023] In still other embodiments, any compound according to Formula I can have an R1 group and an R2 group that combine to form a cyclobutyl optionally substituted with one or two F, and 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)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide; or (S)—N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide, 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-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide; (S)—N-(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (S)-3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-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-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide; (S)-3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide, or a pharmaceutically acceptable salt of any of these compounds.

[0026] Reference to a compound encompassed by the present invention includes racemic mixtures of the compound, as well as optical isomers of the compound to which it is related, and tautomeric forms of the compound to which it is related. Furthermore, the compounds of the present invention may optionally exist in polymorphic and amorphous forms, or in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0027] The present invention also includes isotopically labeled forms of the compounds of the present invention, such as deuterium. The compounds may also incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) to determine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into the compounds of the present invention are C, N, O, and F. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying embodiments, using appropriate isotopically labeled reagents instead of non-isotopically labeled reagents.

[0028] The compounds of the present invention can be present in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier.

[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 relates to a method of treating a patient suffering from epilepsy, bipolar disorder, migraine, or schizophrenia in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0031] In yet another embodiment, the present invention relates to a method of treating a patient in need thereof suffering from psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorders, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, or Alzheimer's disease, comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

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

[0033] The compounds of the invention can be used to treat epilepsy, bipolar disorder, migraine, or schizophrenia, or in another embodiment, to treat 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, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease.

[0034] In another embodiment, the compounds of the invention are for the manufacture of a medicament for treating epilepsy, fragile X syndrome, Angelman syndrome, bipolar disorder, migraine, or schizophrenia, or in another embodiment, for the manufacture of a medicament for treating 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, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease.

[0035] In the context of the present invention, "optionally substituted" means that the indicated moiety may or may not be substituted, and if substituted, may be mono- or di-substituted. When no substituent is present as indicated in an "optionally substituted" moiety, it will be understood that that position is held by a hydrogen atom.

[0036] Ranges may be indicated interchangeably using "~" (a dash) or "to", e.g., the term "C 1~3 The term "alkyl" is synonymous with C1 to C3 alkyl.

[0037] The terms "C1-C3 alkyl" and "C1-C6 alkyl" refer to an unbranched or branched saturated hydrocarbon having from 1 up to 6, inclusive, carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and t-butyl.

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

[0039] The terms "C-C cycloalkyl," "C-C cycloalkyl," "C-C cycloalkyl," or "cyclopropyl" refer to a saturated monocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0040] Route of administration: Pharmaceutical compositions containing the compounds of the present invention as defined above may be particularly formulated to be administered by any suitable route, such as oral, rectal, nasal, buccal, sublingual, transdermal, and parenteral (e.g. subcutaneous, intramuscular, and intravenous) routes, with the oral route being preferred.

[0041] It will be appreciated that the route will vary depending on the general condition and age of the subject being treated, the nature of the condition being treated, and the active ingredient.

[0042] Pharmaceutical Formulations and Excipients: Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients, including but not limited to fillers, antiadherents, binders, coatings, dyes, disintegrants, flavors, glidants, lubricants, preservatives, adsorbents, sweeteners, solvents, vehicles, and adjuvants.

[0043] The present invention also provides pharmaceutical compositions comprising the compounds of the present invention, such as one of the compounds disclosed in the experimental section herein. The present invention also provides processes for producing pharmaceutical compositions comprising the compounds of the present invention. The pharmaceutical compositions of the present invention can be formulated using pharmaceutically acceptable excipients according to conventional techniques, such as those disclosed in Remington's "The Science and Practice of Pharmacy" 22nd edition (2012) (edited by Allen, Loyd V., Jr.).

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

[0045] Solid oral dosage forms may be provided as discrete units (e.g., tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient and, preferably, one or more suitable excipients. Where appropriate, solid dosage forms may be prepared with coatings, such as enteric coatings, or may be formulated to provide modified release of the active ingredient, such as delayed or sustained release, according to methods well known in the art. Where appropriate, solid dosage forms may be in the form of disintegrating in saliva, such as, for example, orodispersible tablets.

[0046] Examples of excipients suitable for solid oral formulations include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid formulations may contain excipients known in the art for delayed-release or sustained-release formulations, such as glyceryl monostearate or hypromellose. When solid materials are used for oral administration, the formulations may be prepared, for example, by mixing the active ingredient with a solid excipient and then compressing the mixture in a conventional tablet machine. Alternatively, the formulations may be placed in a hard capsule in the form of, for example, powder, pellets, or mini-tablets. The amount of solid excipient varies widely but typically ranges from about 25 mg to about 1 g per dosage unit.

[0047] Liquid oral dosage forms can be provided as, for example, elixirs, syrups, oral drops, or liquid-filled capsules. Liquid oral dosage forms can also be provided as powders for solution or suspension in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral formulations include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbates, mono- and diglycerides, cyclodextrin, coconut oil, palm oil, and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0048] Additional excipients such as colorants, flavors, and preservatives may be used in both solid and liquid oral formulations.

[0049] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, injectable or infusible suspensions or emulsions, injectable or infusible concentrates, and sterile powders to be reconstituted into sterile solutions or dispersions for injection or infusion before use. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. Aqueous formulations should be suitably buffered, if necessary, and rendered isotonic with sufficient saline or glucose.

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

[0051] It is essential that excipients used in any pharmaceutical formulation be compatible with the active ingredient and according to the intended route of administration.

[0052] dose: In one embodiment, the compound of the present invention is administered in an amount of about 0.001 mg / kg to about 100 mg / kg of body weight per day. Specifically, the daily dosage may be within the range of 0.01 mg / kg to about 50 mg / kg of body weight per day. The exact dosage will depend on the frequency and method of administration, the sex, age, body weight, and general condition of the subject, the nature and severity of the disease being treated, any complications being treated, the desired therapeutic effect, and other factors known to those skilled in the art.

[0053] A typical oral dosage for an adult is in the range of 0.1 to 1000 mg / day of a compound of the invention, for example 1 to 500 mg / day, for example 1 to 100 mg / day or 1 to 50 mg / day. Conveniently, the compound of the invention is administered in an amount of about 0.1 to 500 mg, for example 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of a compound of the invention in a unit dosage form containing said compound.

[0054] Isomers and tautomeric forms: Where the compounds of the invention contain one or more chiral atoms, reference to the compounds, unless otherwise specified, encompasses enantiomerically or diastereomerically pure compounds as well as mixtures of enantiomers or diastereomers in any ratio.

[0055] MDL Enhanced Stereo Representation is used to represent the unknown stereochemistry of compounds of the present invention. Thus, the label "or1" on a chiral carbon atom is used to indicate that the absolute configuration at this atom is unknown; for example, the configuration at this carbon atom is either (S) or (R).

[0056] Additionally, the chiral bond from the carbon atom labeled "or1" with an up or down wedge is an equivalent representation, e.g., the two figures have the same meaning, which is that the absolute configuration at the carbon atom labeled "or1" is unknown and can be (S) or (R).

[0057] Thus, the use of wedge up and wedge down bonds from the atom labeled "or1" is intended simply to provide a visual cue that the diagrams represent different stereoisomers and that the conformation at the carbon atom labeled "or1" is unknown.

[0058] Furthermore, some of the compounds of the present invention can exist in different tautomeric forms, and it is intended that any tautomeric form a compound is able to form is included within the scope of the present invention.

[0059] Therapeutically effective amount: The term "therapeutically effective amount" of a compound in the context of the present invention means an amount sufficient to alleviate, prevent, partially prevent, eliminate, or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention involving the administration of said compound. An amount sufficient to achieve this is defined as a "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that the determination of appropriate dosages can be achieved using routine experimentation, by constructing a matrix of values and testing various points in that matrix, all of which is within the ordinary skill of a skilled physician.

[0060] Treatment and cure: In the context of the present invention, "treatment" or "treating" is intended to refer to the management and care of a patient with the purpose of alleviating, arresting, partially arresting, eliminating or slowing the progression of clinical signs of disease. The patient to be treated is preferably a mammal, in particular a human being.

[0061] All references cited in this specification, including publications, patent applications, and patents, are hereby incorporated by reference in their entirety and to the same extent (to the maximum extent permitted by law) as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety.

[0062] Use in epilepsy, epileptic syndromes, epileptic symptoms or epileptic seizures In another embodiment, the present invention relates to a method of treating a patient in need thereof suffering from epilepsy, an epileptic syndrome, an epileptic condition, treatment-resistant or refractory epilepsy, or an epileptic seizure, comprising administering to the subject a therapeutically effective amount of a compound according to the present invention.

[0063] In yet another embodiment, the present invention provides a method for the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial newborn convulsions, as well as other epilepsy syndromes (severe myoclonic epilepsy of infancy, epilepsy with persistent spikes and waves during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtawara syndrome). The present invention relates to a method for treating a patient suffering from or in need thereof from epileptic seizures associated with stress, hormonal changes, drugs (such as amphetamines or cocaine), alcohol, infection, or metabolic disorders (such as hyponatremia), or for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, etc., which method comprises administering to a subject a therapeutically effective amount of a compound of the present invention.

[0064] Uses of the compounds according to the invention are for the treatment of epilepsy, including use in the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, as well as other epileptic syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with persistent spikes and waves during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain tumour, autism spectrum disorder or metabolic disorders (such as hyponatremia), or in epileptic conditions as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, etc.

[0065] In other embodiments, the compounds of the present invention are used to treat epilepsy, epilepsy syndromes, epileptic conditions, treatment-resistant or refractory epilepsy, or focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsy syndromes (severe myoclonic epilepsy of infancy, epilepsy with persistent spikes and waves during slow wave sleep, West syndrome, and compounds for the manufacture of a medicament for treating epileptic seizures associated with neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, and frontotemporal lobar degeneration (e.g., Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or metabolic disorders (e.g., hyponatremia), or for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, and frontotemporal lobar degeneration.

[0066] The classification of epilepsy is based on ICD-10 (2016, published by WHO) and is set out in sections G40 and G41, and is encompassed in the treatment of epilepsy according to the present invention. G40.0 Localization-related (focal) (partial) idiopathic epilepsies and epilepsy syndromes with localized onset epileptic seizures G40.1 Localization-related (focal) (partial) symptomatic epilepsy and epilepsy syndromes with simple partial seizures G40.2 Localization-related (focal) (partial) symptomatic epilepsy and epilepsy syndromes with complex partial seizures 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 cause changes in behavior, movements or emotions, and level of consciousness. A person is diagnosed with epilepsy when they have had two or more epileptic seizures or are prone to having recurrent epileptic seizures.

[0068] There are many types of epileptic seizures, classified by severity. The types of epileptic seizures vary depending on where and how they occur in the brain. Most epileptic seizures last between 30 seconds and 2 minutes.

[0069] focal seizures Focal seizures result from abnormal electrical activity in one area of the brain and can occur with or without loss of consciousness. Focal seizures with impaired consciousness. These epileptic seizures involve an alteration or loss of consciousness or awareness. The person may stare into space and not respond normally to their environment, or they may make repetitive movements such as rubbing their hands, chewing, swallowing, or walking in circles. Focal seizures without loss of consciousness. These epileptic seizures may change emotions or alter the way things look, smell, feel, taste, or hear, but the person does not lose consciousness. These epileptic seizures may also cause involuntary jerking of body parts such as the arms or legs, and spontaneous sensory symptoms such as tingling, dizziness, and flashing lights.

[0070] Generalized seizures Epileptic seizures that appear to involve all areas of the brain are called generalized seizures. Different types of generalized seizures include: Absence seizures. Previously known as petit mal seizures, absence seizures often occur in children and are characterized by staring into space or small body movements such as blinking or lip smacking. These epileptic seizures can occur in clusters and can result in a brief loss of consciousness. Tonic seizures. Tonic seizures cause muscle stiffness. These epileptic seizures usually affect the muscles of the back, arms, and legs. Cataplexy. Also known as drop attacks, cataplexy can result in loss of muscle control, causing a sudden collapse or fall. Clonic seizures. Clonic seizures involve repetitive or rhythmic jerking muscle movements. These epileptic seizures usually affect the neck, face, and arms. Myoclonic seizures. Myoclonic seizures usually manifest as sudden, brief jerks or twitching of the arms and legs. Tonic-clonic epilepsy. Tonic-clonic epilepsy, formerly known as grand mal epilepsy, is the most dramatic type of epileptic seizure and can cause sudden loss of consciousness, stiffening and shaking of the body, and sometimes loss of bladder control or tongue biting.

[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 injuries that cause 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 sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

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

[0074] The citation and incorporation of patent documents herein is done merely as a matter of convenience and does not reflect any view as to the validity, patentability, and / or enforceability of such patent documents.

[0075] This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. The present invention may include the following aspects. [1] Formula I [ka] (Wherein R1 is C 1 ~C 6 Alkyl, CF 3 , C.H. 2 CF 3 , CF 2 CHF 2 、C 3 ~C 8 cycloalkyl, wherein C 3 ~C 8 Cycloalkyl is C 1 ~C 3 Alkyl, F, CHF 2 and CF 3 and R2 is H, C 1 ~C 6 Alkyl or CF 3 is; or R1 and R2 combine to form one or two F, CHF 2 , or C optionally substituted with CF3 3 ~C 5 forming a cycloalkyl; and R3 is C 1 ~C 3 Alkyl or CH 2 OC 1~3 alkyl, 1 ~C 3 Alkyl or CH 2 OC 1 ~C 3 is C≡N, 3F or C 3 ~C 5 is alkyl substituted with cycloalkyl; R4 is OCF 3 , or OCHF 2 or a pharmaceutically acceptable salt of any of these compounds. [2] R4 is OCF 3 or OCHF 2 2. The compound of claim 1, wherein: [3] R3 is CH 2 O-CF 3 , C.H. 2 O-cyclopropyl, CH 2 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: -C≡N. [4] R1 is one or two C 1 ~C 3 Alkyl, F, CHF 2 or CF 3 C optionally substituted with 3 ~C 4 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is cycloalkyl. [5] R1 and R2 join to form a cyclobutyl optionally substituted with one or two F, and R4 is OCF 3 or OCHF 2 10. A compound according to any one of the preceding claims, wherein: [6] (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide; or 10. The compound of claim 1 selected from the group consisting of: (S)—N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide, or a pharmaceutically acceptable salt of any of these compounds. [7] (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide; (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)butyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)propyl)acetamide; (S)—N-(3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide; (R)-3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (S)-3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-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-hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide; (S)-3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide; (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide; and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide, or a pharmaceutically acceptable salt of any of these compounds. [8] 8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [9] 10. A method of treating a patient in need thereof suffering from epilepsy, bipolar disorder, migraine, or schizophrenia, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

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

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

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

[13] Use of a compound according to claims 1 to 7 or a pharmaceutically acceptable salt thereof for treating 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, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, and Alzheimer's disease.

[14] 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof for producing a medicament for treating epilepsy, bipolar disorder, migraine, or schizophrenia.

[15] 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorders, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, and Alzheimer's disease.

[16] 17. The compound according to claim 1 or a pharmaceutical salt thereof, or the pharmaceutical composition according to claim 16, for use in the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or intractable epilepsy, or epileptic seizures.

[17] 17. The compound according to claim 1 or a pharmaceutical salt thereof, or the pharmaceutical composition according to claim 16, for use in treating focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epileptic syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with persistent spikes and waves during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or metabolic disorder (such as hyponatremia).

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

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

[20] Focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epilepsy syndromes (such as severe myoclonic epilepsy of infancy, persistent spike-and-wave epilepsy during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome, etc.), or due to stress, hormonal changes, drugs, 10. A method for treating a patient in need thereof suffering from epileptic seizures associated with alcohol, infection, traumatic brain injury, stroke, brain tumor, autism spectrum disorder, or metabolic disorder (such as hyponatremia), or for use in treating epileptic symptoms as part of a neurodegenerative disease such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, or frontotemporal lobar degeneration, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

[21] 10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for treating epilepsy, an epileptic syndrome, an epileptic condition, treatment-resistant or intractable epilepsy, or an epileptic seizure.

[22] 10. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for use in the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal epilepsy, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal convulsions, and other epileptic syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with persistent spikes and waves during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, or metabolic disorders (such as hyponatremia), or for use in the treatment of epileptic symptoms as part of neurodegenerative diseases such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, etc.

[23] 8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or intractable epilepsy, or epileptic seizures.

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

[0076] Experimental section Biological evaluation: Cell culture Synthetic cDNA fragments encoding human Kv7.3 and human Kv7.2, separated by a P2A sequence, were inserted into the pcDNA5 / FRT / TO vector using the BamHI and XhoI restriction sites. The constructs were then transfected into HEK Flp-In 293 cells using Lipofectamine 2000. Transfected cells were grown in DMEM containing 10% (v / v) FBS and 1% PenStrep for 48 hours and subsequently maintained under selection in DMEM containing 10% (v / v) FBS, 1% PenStrep, and 200 μg / mL Hygromycin B at 37°C in a humidified atmosphere of 5% CO2. The resulting stable hKv7.2 / hKv7.3 cell line (HEK-hKv7.2 / hKv7.3) was functionally tested by automated whole-cell patch clamp and showed typical Kv7 currents that were sensitive to XE991 and potentiated by retigabine.

[0077] Thallium influx assay Thallium influx assays for potassium channel activation were performed using the FLIPR Potassium Assay kit (Molecular Devices) as previously described (C.D. Weaver, et al., J. Biomol. Screen 2004, 9, 671-677). HEK-hKv7.2 / hKv7.3 cells were plated onto 96-well black-walled, clear-bottom culture dishes (Corning, Acton, MA, USA) at a density of 80,000 cells / well (100 μl / well) if cells were assayed the following day, or 40,000 cells / well (100 μl / well) if cells were assayed 2 days after plating.

[0078] On the day of the assay, the medium was removed, followed by the addition of 50 μL / well of test compound diluted to 2x final concentration in HBSS containing 20 mM HEPES and 50 μL / well of 2x dye loading buffer. The cells were then incubated for 60 minutes in the dark at room temperature. A 5x final concentration of T1 + and K. +Chloride-free stimulation buffer containing 5x concentration (5mM in both cases) and test compound at 1x final concentration was prepared during incubation. Cells were then assayed in an FDSS7000EX Functional Drug Screening System (Hamamatsu). Following baseline fluorescence signal readings at 0.1Hz for 60 seconds and 1Hz for 10 seconds, 25µL / well of stimulation buffer was added and fluorescence was measured consecutively at 1Hz for 50 seconds, followed by 0.1Hz for 4 minutes. Compound effects were quantified using AUC as the readout and normalized to the reference compound included on each 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: General procedures for the synthesis of intermediates and compounds of general formula I are described in Reaction Scheme 1 and specifically exemplified in the preparative section and examples. Variations of the procedures described, known to those skilled in the art, are within the scope of the invention.

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

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

[0085] Or, R 2 When R is H, compounds of general formula I can be prepared via a second general route, in which an intermediate of general formula V is treated with a suitable reducing agent, such as NaBH4, in a suitable solvent, such as methanol. Intermediates of formula V can be obtained from enantiomerically pure amines of general formula II and carboxylic acids of general formula IV (R = H). This transformation can be achieved using reaction conditions similar to those described above for the condensation of II and III to form I.

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

[0087] Optically active amines of general formula II can be prepared as outlined in Scheme 2a. Scheme 2a [ka] Aldehydes of general formula VI can be condensed with (R)-2-methylpropane-2-sulfinamide in the presence of a drying agent such as titanium(IV) isopropoxide or copper sulfate in a suitable solvent such as dichloroethane. The formed sulfinylimine XV can be condensed with R 3 Treatment with MgBr gives the corresponding substituted (R)-2-methyl-N-((S)-1-aryl-alkyl)propane-2-sulfinamide (VII), which is converted to compounds of general formula II by treatment with an appropriate acid in a suitable solvent, such as HCl in MeOH.

[0088] In a variation of this procedure, R having a functional group 3 The substituents can be further modified by standard functional group transformation methodologies known to chemists of ordinary skill in the art. An example of such a procedure to prepare chiral amines is shown in Scheme 2b. 3 The intermediate XV (wherein XV is aryl) is formed from XV and allyl-MgBr and reacted with R using H2(g) in the presence of a suitable catalyst such as Pd / C in a suitable solvent such as ethyl acetate. 3 Alternatively, compounds of general formula VII (wherein R is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 110, 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 12 3 = allyl) is subjected to dihydroxylation followed by oxidative cleavage to give R 3 The intermediate VII is obtained, which is acetaldehyde. The resulting aldehyde can be further transformed; for example, by exchanging the oxygen for two fluorine atoms by treatment with a suitable reagent such as diethylaminosulfur trifluoride (DAST) in a suitable solvent such as DCM. In the final step, the chiral amine can be obtained by hydrolysis as described above.

[0089] In another embodiment, the compound of formula XVI (wherein R 3An intermediate of XV (wherein XV is acetic acid) can be formed from XV by reaction with ethyl 2-bromoacetate in the presence of CuCl and activated Zn in a suitable solvent such as THF. The ester group can be further derivatized by transformations known to chemists of ordinary skill in the art. For example, the ester can be reduced to a primary alcohol by treatment with a suitable reducing agent such as LiAlH4 in a suitable solvent such as THF. The resulting alcohol can also be further derivatized by transformations known to those skilled in the art. For example, the alcohol can be converted to a leaving group by activation with a reagent such as mesyl chloride in the presence of a suitable base such as triethylamine (TEA) in a suitable solvent such as DCM. The resulting mesylate can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent such as DMSO.

[0090] Scheme 2b: [ka]

[0091] Aldehydes of general formula VI can also be converted to chiral amines of general formula II by an alternative strategy, as shown in Scheme 2c. Scheme 2c: [ka] Following this procedure, appropriately substituted benzaldehydes VI can be converted to the corresponding appropriately substituted styrenes using Wittig methodology known to chemists of ordinary skill in the art. These intermediates can undergo an alkylation-oxidation reaction to form keto intermediates XVII. Intermediates of general formula XVII can be condensed with (R)-2-methylpropane-2-sulfinamide in a suitable solvent, such as dichloroethane, in the presence of a suitable drying agent, such as titanium(IV) ethoxide. The sulfinylimine formed can be reduced with a suitable reducing agent, such as L-Selectride, in a suitable inert solvent, such as THF, to form the corresponding appropriately substituted (R)-2-methyl-N-((S)-1-aryl-alkyl)propane-2-sulfinamide, which can be converted to chiral amines of general formula II by treatment with a suitable acid in a suitable solvent, such as HCl in MeOH.

[0092] Those skilled in the art will recognize that other transformations are possible from each of the intermediates; the present invention is intended to encompass such alternative transformations.

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

[0094] In another procedure, chiral amines of formula II can be obtained from aryl ketones by hydride reduction of the intermediate sulfinyl imine obtained from reaction with (R)-2-methylpropane-2-sulfinamide with a reagent such as L-selectride, as shown in Scheme 3a.

[0095] Scheme 3a [ka] A variation of this procedure is shown in Scheme 3b. In this procedure, an additional R 3 The substituents are incorporated from a common α-bromoacetophenone intermediate XI obtained by bromination of the correspondingly substituted acetophenone. Examples include, but are not limited to, R 3 Examples of suitable fluoroalkyl methylene ether groups include the introduction of a fluoroalkyl methylene ether group as follows: Thus, using this methodology, the correspondingly substituted bromoacetophenone can be reacted with trifluoromethyl trifluoromethanesulfonate and a fluoroalkoxy donor such as KF under Finkelstein conditions in a suitable solvent such as dimethylacetamide (DMA) to give intermediate XII, which can be further converted to a chiral amine as described above. Other examples include, but are not limited to, R 3 Examples include the introduction of alkyl methylene ethers as aryl groups. Thus, the correspondingly substituted bromoacetophenone can be converted to the acyl diazo intermediate XIII by reaction with 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydrazide in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in a suitable solvent, such as THF. Intermediate XIII can undergo carbene formation by treatment with a suitable solvent, such as indium triflate, in a suitable solvent, such as toluene. The formed carbene can be trapped in situ with a suitable alcohol to form the alkoxyketo intermediate XIV. From intermediate XIV, chiral amines of formula II can be obtained by standard procedures as described above.

[0096] Scheme 3b: [ka] The correspondingly substituted ketones or acetophenones used in preparing the compounds of the present invention are either 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 the present invention is intended to encompass such alternative transformations.

[0098] General formula II (wherein, R 3 Another suitable procedure for accessing chiral amines of formula (wherein is an ether) is outlined in Scheme 4. Scheme 4: [ka] In this procedure, as described in JP 2017-095366 A, the glyoxylic acid sulfinyl imine formed during the condensation reaction of a glyoxylic acid ester with (R)-2-methylpropane-2-sulfinamide can be reacted with a suitably substituted boronic acid using a suitable catalyst, such as bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, in a suitable solvent, such as dioxane. The resulting intermediate VIII can be hydrolyzed, reprotected with a suitable protecting group, such as Boc, under standard conditions, and subjected to ester reduction under suitable conditions, such as LiAlH4 in THF, to afford the alcohol intermediate of general formula IX. The intermediate of formula IX can be further derivatized to afford the desired R 3 The substituent can be obtained. For example, the alcohol group in intermediate IX can be difluoromethylated using a suitable reagent such as 2,2-difluoro-2-(fluorosulfonyl)acetic acid under conditions such as CuI activation in a suitable solvent such as acetonitrile; alternatively, the alcohol group in IX can be alkylated using a simple alkyl halide such as methyl iodide in a suitable solvent such as THF in the presence of a suitable base such as NaH. Alternatively, the alcohol in intermediate IX can be converted to a leaving group by activation using a reagent such as mesyl chloride in a suitable solvent such as DCM in the presence of a suitable base such as TEA. The resulting mesylate can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent such as DMSO.

[0099] Those skilled in the art will recognize that other transformations are possible from intermediates of general formula IX, and 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 reacted with alkyl esters of bromoacetic acid activated, for example, with Zn and iodine, to produce the corresponding aldol adducts. In an alternative procedure, the bromoacetic acid ester can be activated with Zn and TMSCl (trimethylsilyl chloride). In the final step, hydrolysis of the alkyl ester is achieved by treatment with a suitable base, such as NaOH or LiOH, in a suitable solvent, such as water, or an alcohol in water, followed by acidification with a suitable acid to give compounds of formula III.

[0101] Carboxylic acid esters of general formula IV (R=Me, Et) are commercially available or can be prepared as outlined in Scheme 6. Scheme 6 [ka] The correspondingly substituted carboxylic acid can be activated using a suitable reagent such as CDI and condensed with potassium 3-ethoxy-3-oxo-propanoate in the presence of MgCl to give intermediates of general formula IV.

[0102] on 400.13MHz with Bruker Avance III400 equipment, or on 300.13MHz with Bruker Avance300 equipment, 1H NMR spectra were recorded. Deuterated dimethyl sulfoxide or deuterated chloroform was used as the solvent. Tetramethylsilane was used as the internal reference standard. Chemical shift values are expressed as ppm relative to tetramethylsilane. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = septet, dd = double doublet, ddd = double double doublet, dt = double triplet, dq = double quartet, tt = triple triplet, m = multiplet, and brs = broad singlet.

[0103] The chromatographic systems and methods for assessing chemical purity (LCMS method) and chiral purity (SFC and HPLC 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: Instrument: Agilent 1200 LCMS system equipped with an ELS detector.

[0109] [Table 5]

[0110] LCMS Method 4: Instrument: Shimadzu LC20ADXR LCMS system equipped with an ESI detector.

[0111]

Table 6

[0112] キラル analysis method: SFC method 1: Apparatus: 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] Chiral 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] To a solution of ethyl 2-oxoacetate (7.5 g, 36.7 mmol) and (R)-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol) in DCM (150 mL) was added CuSO (12.9 g, 80.8 mmol), and the reaction mixture was stirred at 25 °C for 24 h. The solid was filtered off and washed with ethyl acetate (50 mL), and the organic phases were combined and concentrated. The resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate, 5 / 1) to give the desired product (5.1 g, 67.6% yield).

[0165] Step 2: Preparation of ethyl (2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate [ka] To a solution of ethyl 2-[(R)-tert-butylsulfinyl]iminoacetate (7 g, 34.1 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (8.4 g, 40.9 mmol) in dioxane (100 mL) was added [Rh(COD)(MeCN)]BF (1.3 g, 3.4 mmol), and the mixture was stirred at 80° C. for 16 h. The product was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to give 9.8 g (78%).

[0166] Step 3: Preparation of ethyl (2R)-2-amino-2-[3-(trifluoro-methoxy)phenyl]acetate hydrochloride [ka] To a solution of ethyl (2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate (9.8 g, 26.7 mmol) in MeOH (100 mL) was added HCl / MeOH (4 M, 100 mL), and the mixture was stirred at 25° C. for 2 h, then concentrated to give ethyl (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate (7.8 g, crude).

[0167] Step 4: Preparation of ethyl (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(difluoromethoxy)phenyl)acetate [ka] To a mixture of ethyl (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate hydrochloride (6 g) and BocO (8.7 g) in THF (150 mL) was added NaHCO (1.7 g) and stirred for 16 h at 25° C. The mixture was concentrated and purified by chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to give the product (7.2 g).

[0168] Step 5: Preparation of tert-butyl (R)-(1-(3-(difluoromethoxy)phenyl)-2-hydroxyethyl)carbamate [ka] To a suspension of LiAlH4 (1.7 g) in THF (200 mL) was added (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(difluoromethoxy)phenyl)acetate (4 g) in THF (25 mL) with ice cooling. The reaction was warmed to 25 °C and stirred for 2 h. Anhydrous magnesium sulfate was added, followed by the successive addition of a drop of water and ethyl acetate. The insoluble material was filtered off through a Celite pad. The filtrate was concentrated and purified by chromatography on silica (petroleum ether:ethyl acetate = 5:1) (2.1 g).

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

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

[0171] IIa: (R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)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] To a mixture of 4-methylbenzenesulfonohydrazide (70 g) and 4-methylbenzenesulfonyl chloride (93 g) was added DCM (400 mL). The mixture was cooled to 0°C, and pyridine (38.65 g) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour and at 20°C for 7 hours. Water (200 mL) and methyl tert-butyl ether (METB) (200 mL) were added to the mixture, which was then filtered. The filter cake was washed with METB (200 mL) and dried to give 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydrazide (125 g). 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: Preparation of 2-bromo-1-(3-(difluoromethoxy)phenyl)ethan-1-one [ka] To a solution of 1-[3-(difluoromethoxy)phenyl]ethanone (10 g) in dioxane (100 mL) was added a solution of Br (8.58 g) in dioxane (100 mL). The resulting mixture was stirred at 20 °C for 2 h. Saturated aqueous NaHCO (50 mL) and HO (100 mL) were added, and the aqueous phase was extracted with EtOAc (200 mL × 2). The organic phase was washed with brine (200 mL), dried over NaSO, and concentrated to give 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (17 g). 1 H NMR (CDCl3400MHz): δ7.81(d,1H),7.72(s,1H),7.49(t,1H),7.37(d,1H),6.56(t,1H),4.41(s,2H).

[0174] Step 3: Preparation of 1-(3-(difluoromethoxy)phenyl)-2-iminoethan-1-one [ka] To a solution of 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (5.6 g) and 4-methyl-N'-(p-trisulfonyl)benzenesulfonohydrazide (11.51 g) in THF (100 mL) was added DBU (12.87 g) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and at 20 °C for 4 h. The mixture was quenched with saturated aqueous NaHCO (200 mL), diluted with water (200 mL), and then extracted with EtOAc (200 mL × 2). The organic layer was washed with brine (100 mL), dried over NaSO, and concentrated. The crude product was purified by column chromatography on silica gel (20% EtOAc in petroleum ether) to give 1-(3-(difluoromethoxy)phenyl)-2-iminoethan-1-one (6.4 g). 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: Preparation of 2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one [ka] To a solution of cyclopropanol (1.75 g) and 2-diazo-1-[3-(difluoromethoxy)phenyl]ethanone (3.2 g) in toluene (50 mL) was added indium(III) triflate (1.7 g) under N2. The resulting mixture was stirred at 20 °C for 16 h. The mixture was quenched with saturated aqueous NaHCO3 (100 mL), diluted with HO (50 mL), and then extracted with EtOAc (100 × 2). The organic layer was washed with brine (200 mL × 2), dried over Na2SO4, and concentrated. The crude product was purified by column chromatography on silica gel (5% EtOAc in petroleum ether) to give 2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one (6.1 g). 1H NMR(CDCl3,400MHz):δ7.76(d,1H),7.68(s,1H),7.47(t,1H),7.34(d,1H),6.5 5(t,1H),4.74(s,1H),3.55-3.50(m,1H),0.70-0.66(m,2H),0.53-0.49(m,2H).

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

[0177] Step 6: Preparation of (R)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (R,Z)-N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide from the previous step in THF (150 mL) was added a solution of L-selectride (1 M in THF, 50.36 mL) dropwise at −45° C. The mixture was stirred at −45° C. for 1 h, quenched with MeOH (100 mL) and HO (100 mL), and filtered over Celite. The filtrate was extracted with EtOAc (200 mL × 2), and the organic layer was washed with brine (200 mL × 2), dried over NaSO, and concentrated. The crude product was purified by column chromatography on silica gel (30-50% EtOAc in petroleum ether) to give (R)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (2.4 g).

[0178] Step 7: Preparation of (R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride [ka] To a solution of (R)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.46 g) in MeOH (10 mL) was added HCl / MeOH (10 mL). The resulting mixture was stirred at 20° C. for 1 h and concentrated to give (1R)-2-(cyclopropoxy)-1-[3-(difluoromethoxy)phenyl]ethanamine hydrochloride (0.46 g, crude).

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

[0180] IIe: (R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride [ka] Step 1: Preparation of 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone [ka] To a solution of 1-[3-(difluoromethoxy)phenyl]ethanone (5 g) in dioxane (50 mL) was added a solution of Br (4.29 g) in dioxane (50 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour, diluted with EtOAc (200 mL), and washed with water (100 mL × 3). The organic phase was dried over anhydrous Na SO and concentrated. The residue was purified by chromatography on a silica gel column (petroleum ether: EtOAc = 10:1) to give 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (5 g).

[0181] Step 2: Preparation of 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-one [ka] To a solution of KF (712 mg) in DMA (20 mL) was added trifluoromethyl trifluoromethanesulfonate (4.11 g) at 0 °C. The reaction mixture was stirred in a sealed tube for 1 h, and then 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (2.5 g, 9.43 mmol) and KI (157 mg) were added to the solution at 0 °C, brought to 20 °C, and stirred for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (50 mL × 3). The organic phase was concentrated to give the product, which was purified by acidic preparative HPLC (1.4 g). 1H 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: Preparation of (R)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethylidene)-2-methylpropane-2-sulfinamide [ka] A mixture of 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-one (900 mg), (R)-2-methylpropane-2-sulfinamide (606 mg), and Ti(OEt) (2.28 g) in THF (50 mL) was stirred at 60° C. under N for 16 h. The product (1.2 g, crude) in THF (70 mL) was obtained and used directly in the next step.

[0183] Step 4: Preparation of (R)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (R)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethylidene)-2-methylpropane-2-sulfinamide (1.2 g) in THF (70 mL) was added L-selectride (1 M in THF, 3.86 mL) at −60° C. The mixture was stirred at −60° C. for 0.5 h, then diluted with EtOAc (100 mL) and washed with water (50 mL × 3). The organic phase was dried, filtered, and concentrated. The crude product was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give (R)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide (600 mg). 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: Preparation of (R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride [ka] To a solution of (R)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide (600 mg) in MeOH (10 mL) was added HCl / MeOH (4 M in MeOH, 8.0 mL). The mixture was stirred at 15° C. for 1 h and then concentrated to give ((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride (500 mg, crude). 1H 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] Prepared as described for IIe using 1-[3-(trifluoromethoxy)phenyl]ethanone as starting material. 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 [ka] Step 1: Preparation of (R)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 3-(difluoromethoxy)benzaldehyde (3 g) and (R)-2-methylpropane-2-sulfinamide (2.54 g) in DCE (120 mL) was added CuSO (13.91 g). The mixture was stirred at 55 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 10:1) to give the product (3 g).

[0187] Step 2: Preparation of (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide [ka] To a solution of (R)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (1 g) in DCM (40 mL) was slowly added allyl(bromo)magnesium (1 M solution in THF, 10.9 mL) in THF at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and at 25 °C for 2 h. The reaction mixture was quenched by the addition of saturated NH Cl (10 mL) at 0 °C, diluted with HO (50 mL), and extracted with DCM (40 mL × 3). The combined organic phase was washed with HO (40 mL), dried over Na SO , filtered, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1:2) to give (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (580 mg). 1 H NMR (CDCl3400MHz): δ7.31(t,1H),7.15(d,1H),7.08(s,1H),7.01(d,1H),6.48(t,1H),5.73-5.66(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,1H),1.19(s,9H).

[0188] Step 3: Preparation of (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (R)—N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (580 mg) in EtOAc (20 mL) was added Pd / C (0.4 g, 10% purity) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (18 psi) at 25° 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-sulfinamide (560 mg).

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

[0190] IIh: (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride [ka] Step 1: Preparation of 1-(difluoromethoxy)-3-vinyl-benzene [ka] To a solution of methyltriphenylphosphonium iodide (7.05 g) in DME (50 mL) was added K2CO3 (2.41 g). The resulting mixture was stirred at 20 °C for 1 h, and then 3-(difluoromethoxy)benzaldehyde (1.5 g) was added and stirring was continued at 80 °C for 15 h. 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) to give 1-(difluoromethoxy)-3-vinyl-benzene (1.4 g). 1 H NMR (CDCl3400MHz): δ7.32(t,1H),7.25(d,1H),7.16(s,1H),7.01(d,1H),6.70(t,1H),6.52(t,1H),5.77(d,1H),5.32(d,1H).

[0191] Step 2: Preparation of 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one [ka] To a solution of 1,1-difluoro-2-iodo-ethane (1 g), 1-(difluoromethoxy)-3-vinyl-benzene (1.33 g), bis[(Z)-1-methyl-3-oxo-but-1-eneoxy]copper (273 mg), and AgSO (325 mg) in ACN (20 mL) was added EtN (527 mg) and tert-butyl hydroperoxide (TBHP) (2.01 g, 70% in water). The resulting mixture was stirred at 80 °C for 24 h. The reaction was quenched with saturated aqueous NaSO and extracted with DCM (10 mL × 3). The organic phases were combined, washed with brine (5 mL × 2), dried over NaSO, and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one (300 mg). 1H NMR (CDCl3400MHz): δ7.82(d,1H),7.73(s,1H),7.50(t,1H),7.36(d,1H),6.57(t,1H),6.02(tt,1H),3.18(t,2H),2.35-2.27(m,2H).

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

[0193] Step 4: Preparation of N-[(1S)-1-[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2-methyl-propane-2-sulfinamide [ka] To a solution of (S)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutylidene)-2-methylpropane-2-sulfinamide (423 mg) in THF at −48 °C, L-selectride (1 M in THF, 3.59 mL) was added. The reaction mixture was stirred for 0.5 h, then brought to 0 °C, and HO (ca. 10 mL) was added. The resulting mixture was extracted with EtOAc (35 mL × 2). The organic extract was washed with brine (10 mL), dried over NaSO, and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to give N-[(1S)-1-[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2-methyl-propane-2-sulfinamide (140 mg).

[0194] Step 5: (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride [ka] N-[(1S)-1-[3-(difluoromethoxy)phenyl]-4,4-difluoro-butyl]-2-methyl-propane-2-sulfinamide (140 mg) in MeOH (10 mL) and HCl / MeOH (5 mL, 4 M) was stirred for 1 h at 20° C. The mixture was concentrated to give (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride (110 mg).

[0195] IIi: (S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropan-1-amine hydrochloride [ka] Step 1: Preparation of (S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 3-(difluoromethoxy)benzaldehyde (5 g) and (R)-2-methylpropane-2-sulfinamide (4.22 g) in DCE (150 mL) was added CuSO (23 g). The reaction mixture was stirred at 55 °C for 20 h, filtered, and concentrated. The crude product was purified by chromatography on silica (SiO, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give (S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (6.9 g). 1H NMR (CDCl3400MHz): δ8.55(s,1H),7.65(d,1H),7.62(s,1H),7.47(t,1H),7.25(d,1H),6.55(t,1H),1.25(s,9H).

[0196] Step 2: Preparation of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide [ka] To a solution of (S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2 g) in DCM (60 mL) was added allyl(bromo)magnesium (1 M solution in THF, 21.79 mL) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and at 25 °C for 2 h. The reaction was quenched by the addition of saturated aqueous NH Cl (10 mL) at 0 °C, then diluted with HO (50 mL) and extracted with DCM (40 mL × 3). The combined organic phase was washed with HO (40 mL), dried over Na SO , filtered, and concentrated. The residue was purified by chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 2) to give (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.3 g). 1 H NMR (CDCl3400MHz): δ7.31(t,1H),7.15(d,1H),7.08(s,1H),7.01(d,1H),6.49(t,1H),5.71-5.65(m,1H ),5.19-5.15(m,2H),4.48-4.44(m,1H),3.66(s,1H),2.59-2.54(m,1H),2.46-2.40(m,1H),1.18(s,9H).

[0197] Step 3: Preparation of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide [ka] To a stirred solution of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (2.5 g), 2,6-lutidine (1.69 g), and sodium periodate (5.05 g) in a mixture of dioxane (10 mL) and HO (3 mL), potassium dioxide (dioxo)osmium hydrate (276 mg) was added in one portion. The reaction mixture was stirred at 20 °C for 1 h and then diluted with DCM (100 mL) and water (20 mL). The aqueous layer was extracted with DCM (25 mL × 2). The combined organic extracts were dried over NaSO. The crude reaction mixture was used directly in the next step.

[0198] Step 4: Preparation of (S)—N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (2 g) in DCM (200 mL) was added diethylaminosulfur trifluoride (DAST) (3.03 g) dropwise at -78 °C. The reaction mixture was brought to 20 °C and stirred for 2 h. The solution was poured into saturated aqueous NaHCO (50 mL), and the organic phase was separated. The solution was dried over anhydrous NaSO and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide (500 mg).

[0199] Step 5: Preparation of (1S)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoro-propan-1-amine hydrochloride [ka] To a solution of (S)—N—((S)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide (380 mg) in MeOH (15 mL) at 0° C. was added HCl / MeOH (25 mL, 4 M) and the reaction was stirred for 0.5 h, allowing it to reach 25° C. The reaction mixture was concentrated to give (1S)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoro-propan-1-amine hydrochloride (300 mg, crude, HCl salt). It was used directly without further purification.

[0200] IIj: (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride [ka] Step 1: Preparation of ((S,E)-N-(3-(difluoro-methoxy)benzylidene)-2-methylpropane-2-sulfinamide [ka] To a mixture of 3-(difluoromethoxy)benzaldehyde (2 g) and (R)-2-methylpropane-2-sulfinamide (1.7 g) in DCE (60 mL) was added CuSO (9.3 g) at 55 °C under N. The reaction mixture was stirred at 55 °C for 12 h, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column (petroleum ether / ethyl acetate = 20:1 to 10:1) to give ((S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (4.5 g).

[0201] Step 2: Preparation of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of ((S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2 g) in DCM (30 mL) was added bromo(methyl)magnesium (3 M in EtO, 4.8 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and at 20 °C for 16 h. The reaction was quenched with saturated aqueous NH Cl (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic extracts were washed with brine (40 mL × 2), dried over anhydrous Na SO , filtered, concentrated, and the crude product was purified by chromatography on a silica gel column (petroleum ether / ethyl acetate = 5:1 to 1:1) to give (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (960 mg).

[0202] Step 3: Preparation of (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride [ka] To a solution of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8 g) in MeOH (4 mL) was added HCl / MeOH (4 M, 2 mL). The resulting mixture was stirred at 25° C. for 3 h and concentrated to give (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (1.6 g, crude).

[0203] IIk: (R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride [ka] Step 1: Preparation of ethyl (R,E)-2-((tert-butylsulfinyl)imino)acetate [ka] To a solution of ethyl 2-oxoacetate (7.5 g) and (R)-2-methylpropane-2-sulfinamide (4.90 g) in DCM (150 mL) under nitrogen, CuSO (12.9 g) was added, and the reaction mixture was stirred at 25 °C for 24 h. The solid was filtered off and washed with ethyl acetate (50 mL), and the organic layer was concentrated. The residue was purified by chromatography (SiO, hexane / ethyl acetate, 5 / 1) to give ethyl (R,E)-2-((tert-butylsulfinyl)imino)acetate (5 g).

[0204] Step 2: Preparation of ethyl (R)-2-(((S)-tert-butylsulfinyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate [ka] To a solution of ethyl (R,E)-2-((tert-butylsulfinyl)imino)acetate (5 g) and [3-(trifluoromethoxy)phenyl]boronic acid (6.02 g) in dioxane (80 mL) was added bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (CAS: 32679-02-0) (1.85 g), and the mixture was stirred at 80 °C for 16 h. The solution was filtered, and the organic phase was concentrated. The residue was purified by chromatography (SiO, petroleum ether: EtOAc = 6:1) to give ethyl (R)-2-(((S)-tert-butylsulfinyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (5.1 g).

[0205] Step 3: Preparation of ethyl (R)-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate [ka] To a solution of ethyl (R)-2-(((S)-tert-butylsulfinyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (4.6 g) in MeOH (30 mL) was added HCl / MeOH (4 M, 25.04 mL) at 0° C. The reaction mixture was stirred at 25° C. for 1 h and concentrated to give ethyl (R)-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate as the hydrochloride salt (3.3 g).

[0206] Step 4: Preparation of ethyl (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate [ka] To a mixture of ethyl (R)-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate hydrochloride (3.3 g) in THF (80 mL) was added BocO (4.81 g) and NaHCO (925 mg), and the reaction was stirred at 25 °C for 16 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), washed with water (20 mL), and then concentrated. The residue was purified by chromatography (SiO; petroleum ether: EtOAc = 10:1) to give ethyl (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (3.8 g).

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

[0208] Step 6: Preparation of tert-butyl (R)-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1 g) in hexane (15 mL) was added diethyl sulfate (960 mg), tetrabutyl ammonium chloride (TBAC) (87 mg), and a solution of NaOH (324 mg) and HO (1.5 mL). The resulting mixture was stirred at 25 °C for 20 h. The reaction mixture was diluted with EtOAc (200 mL), washed with water (100 mL) and brine (100 mL), dried over NaSO, and concentrated. The crude was purified by chromatography (SiO, 10% ethyl acetate in petroleum ether) to give tert-butyl (R)-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (5.9 g).

[0209] Step 7: Preparation of (R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride [ka] To a solution of tert-butyl (R)-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (5.9 g) in MeOH (100 mL) was added HCl / MeOH (4 M, 63.33 mL) at 25° C., and the mixture was stirred for 16 h at 25° C. The solution was concentrated to give (R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride (4.5 g).

[0210] IIl: (S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride [ka] Step 1: Preparation of (S,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide: [ka] A mixture of 3-(trifluoromethoxy)benzaldehyde (10.0 g), (R)-2-methylpropane-2-sulfinamide (7.7 g), and CuSO (12.6 g) in DCE (200 mL) was stirred at 55 °C for 16 h. The mixture was filtered, and the filter cake was washed with DCM (200 mL). The filtrate was concentrated. The residue was purified by chromatography (SiO, 0–10% ethyl acetate / petroleum ether gradient) to give (S,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (12.6 g).

[0211] Step 2: Preparation of (S)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide [ka] To a solution of (S,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (2.0 g) in DCM (40 mL) at 0 °C, EtMgBr (3 M in EtO, 9.1 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h and at 20 °C for 3 h. The mixture was cooled to 0 °C, and saturated aqueous NH Cl (100 mL) was added. The mixture was extracted with DCM (100 mL × 2), the phases were separated, and the organic layer was washed with brine (200 mL), dried over Na SO , and concentrated. The residue was purified by chromatography (SiO , 0–50% ethyl acetate / petroleum ether gradient) to give the product (1.4 g).

[0212] Step 3: Preparation of (S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride [ka] To a solution of (S)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide (1.4 g) in MeOH (40 mL) was added HCl / MeOH (4 M, 20 mL). The resulting mixture was stirred at 30° C. for 12 h and then concentrated to give crude (S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride, which was used without further purification (1 g).

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

[0214] Step 2: Preparation of (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate [ka] To a solution of tert-butyl (R)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (2 g) in DCM (20 mL) was added EtN (756 mg) followed by methanesulfonyl chloride (1.75 g) at 0° C. The mixture was stirred at 20° C. for 16 h. The reaction mixture was washed with saturated aqueous NH4Cl (15 mL), dried over Na2SO4, filtered, and concentrated to give (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate (2.50 g, crude), which was used in the next step without purification.

[0215] Step 3: Preparation of (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propanenitrile hydrochloride [ka] To a solution of (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate (420 mg) in DMSO (5 mL) was added KCN (225 mg) at 20 °C. The mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with 10% Na2CO3 solution (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 4 / 1) to give tert-butyl (S)-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (665 mg). 1H 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] To a solution of tert-butyl (S)-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (400 mg) in MeOH (8 mL) was added HCl / MeOH (4 M, 4.00 mL) 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-(trifluoromethoxy)phenyl)propanenitrile hydrochloride (280 mg, crude).

[0217] IIn: (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride [ka] Step 1: Preparation of (R,E)-2-methyl-N-(3-(trifluoro-methoxy)benzylidene)propane-2-sulfinamide [ka] To a solution of 3-(trifluoromethoxy)benzaldehyde (30 g) and (R)-2-methylpropane-2-sulfinamide (23.0 g) in DCE (600 mL) was added CuSO (37.8 g). The mixture was stirred at 55 °C for 24 h and filtered. The filter cake was washed with DCM (300 mL). The filtrates were combined and concentrated, and the residue was purified by chromatography (SiO, petroleum ether / ethyl acetate = 0 / 1 to 5:1) to give (R,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (41.8 g).

[0218] Step 2: Preparation of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate [ka] A solution of (R,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (5 g) in THF (60 mL) was added to a suspension of activated Zn (11.15 g), CuCl (2.5 g), and ethyl 2-bromoacetate (7.1 g) in THF (60 mL) at 0 °C. The reaction mixture was stirred at 50 °C for 2 h and filtered. The filter cake was washed with DCM (400 mL), and the combined organic filtrate was concentrated. The residue was purified by chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7 g, crude). 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: Preparation of (R)-N-((S)-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide [ka] To a solution of ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7 g) in THF (70 mL) was added LiAlH (696 mg) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and then quenched at 0° C. by the sequential addition of HO (0.7 mL), 10% NaOH (0.7 mL) solution, and HO (2.1 mL). The mixture was filtered. The residue was concentrated to give crude (R)-N-((S)-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide (4.2 g).

[0220] Step 4: Preparation of (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride [ka] The crude (R)-N-((S)-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide (4 g) from the previous reaction step 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 h and concentrated to give (S)-3-amino-3-(3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride (3.2 g, crude).

[0221] Step 5: Preparation of tert-butyl (S)-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate [ka] The crude ethyl (S)-3-(((R)-tert-butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (3.2 g) from the previous reaction step was dissolved in THF (35 mL), and BocO (10.28 g) and NaHCO (2 g) were added. The reaction mixture was stirred at 20 °C for 16 h. The mixture was concentrated, and the residue was diluted with water (70 mL) and extracted with DCM (100 mL × 3). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to give tert-butyl (S)-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (3.2 g).

[0222] Step 6: Preparation of (S)-3-((tert-butoxycarbonyl)amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate [ka] To a solution of tert-butyl (S)-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (1 g) in DCM (30 mL) was added EtN (905 mg) and methanesulfonyl chloride (683 mg) at 0° C. The reaction mixture was stirred at 20° C. for 16 h, washed with ice water (15 mL), dried over anhydrous NaSO, filtered, and concentrated to give ((S)-3-((tert-butoxycarbonyl)amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate (1.2 g).

[0223] Step 7: Preparation of tert-butyl (S)-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate [ka] The ((S)-3-((tert-butoxycarbonyl)amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate obtained in the previous step was dissolved in DMSO (35 mL), and KCN (661 mg) was added at 20 °C. The reaction mixture was stirred at 50 °C for 16 h, then diluted with 10% NaCO solution (40 mL) and extracted with EtOAc (70 mL × 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give tert-butyl (S)-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (990 mg).

[0224] Step 8: Preparation of (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride [ka] To a solution of tert-butyl (S)-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (900 mg) in MeOH (14 mL) was added HCl / MeOH (4 M, 6.53 mL). The mixture was stirred at 20° C. for 16 h and concentrated to give (S)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride (850 mg).

[0225] IIo: (S)-3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride [ka] Prepared as described for IIi using 3-(trifluoromethoxy)benzaldehyde as starting material.

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

[0227] Step 2: Preparation of tert-butyl (R)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate [ka] To a solution of ethyl (R)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (10 g) in EtOH (90 mL) was added NaBH (4.17 g) at 0 °C. The mixture was removed from the cold bath and stirred for 2 h. The reaction was quenched with water (20 mL) and concentrated. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give the product (13.6 g). 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: Preparation of tert-butyl (R)-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1 g) and MeI (4 g) in THF (70 mL) was added NaH (149 mg, 60% in mineral oil) at 0 °C. The mixture was stirred at 0 °C for 1 h and at 25 °C for 16 h. Water (1 mL) was added to quench the reaction. THF was removed, and EtOAc (200 mL) was added to the residue. The solution was washed with water (50 mL × 3) and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 5 / 1) to give tert-butyl (R)-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (3.2 g). 1 H NMR (CDCl3400MHz): δ7.36(t,1H),7.25(m,1H),7.19(s,1H),7.12(d,1H),5.34(s,1H),4.83(s,1H),3.63-3.56(m,2H),3.35(s,3H),1.43(s,9H).

[0229] Step 4: Preparation of (R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride [ka] To a solution of tert-butyl (R)-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (2.7 g) in MeOH (40 mL) was added HCl / MeOH (4 M, 40 mL) at 25° C. 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] It is prepared according to the literature described in Wang Z. et al: Tetrahedron: Asymmetry 10 (1999) 225-228.

[0231] IIIb: 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid [ka] Step 1: Preparation of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate [ka] To a solution of 3,3-difluorocyclobutanone (0.2 g), Zn (198 mg), and I (10 mg) in THF (13 mL) under N was added dropwise ethyl 2-bromoacetate (378 mg). The mixture was stirred at 55 °C for 6 h. H SO (10%, 10 mL) was carefully added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic extract was washed with NaHCO (saturated aqueous solution, 10 mL), dried over Na SO 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] To a solution of ethyl 2-(3,3-difluoro-1-hydroxycyclobutyl)acetate (0.26 g) in MeOH (10 mL) and HO (2 mL) was added NaOH (107 mg) at 0 °C. The mixture was stirred at 20 °C for 8 h. The reaction solution was cooled to 0 °C, and 1 N HCl was added to the solution until the pH reached 1-2. The residue was diluted with brine (10 mL) and extracted with methyl tert-butyl ether (30 mL × 5). The combined organic extracts were dried over NaSO, filtered, and concentrated. The crude product (0.24 g) was used without further purification.

[0233] IIIc: 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid [ka] Step 1: Preparation of ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butanoate [ka] A solution of 1-(1-fluorocyclopropyl)ethanone (0.5 g), Zn (512 mg), and I (62 mg) in THF (30 mL) was stirred at 20 °C until the solution turned colorless, and ethyl 2-bromoacetate (981 mg) was added dropwise. The resulting mixture was stirred at 20 °C for 0.5 h and at 65 °C for 4.5 h. The reaction was washed with 10% aqueous HSO (20 mL) and extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (100 mL), dried over NaSO, and concentrated to give ethyl 3-(1-fluorocyclopropyl)-3-hydroxybutanoate (0.83 g, crude).

[0234] Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-butanoic acid [ka] To a solution of ethyl 3-(1-fluorocyclopropyl)-3-hydroxybutanoate (0.83 g) in EtOH (10 mL) was added a solution of NaOH (350 mg) in HO (3 mL). The reaction mixture was stirred at 20 °C for 2 hours and then extracted with EtOAC (50 mL × 2). The aqueous layer was acidified to pH = 3 with 10% HCl and extracted with EtOAC (50 mL × 2). The combined organic extracts were washed with brine (100 mL), dried over NaSO, and concentrated to give 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid (0.57 g, crude).

[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), and the resulting mixture was stirred at 20 °C for 15 min and then heated to 70 °C. Heating was discontinued, and methyl 2-bromoacetate (21.8 g) was added dropwise at such a rate that the solution gently boiled. The resulting mixture was stirred at 70 °C for 1 h, then at 20 °C for 1 h, followed by the addition of a solution of 1-cyclopropylethanone (10 g) in THF (50 mL). The reaction was stirred at 20 °C for 16 h. The mixture was poured into NH₃·H₂O (100 mL, 28%) on ice and extracted with ethyl acetate (150 mL × 2). The organic extract was washed with water (150 mL) and brine (150 mL), 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] A mixture of crude methyl 3-cyclopropyl-3-hydroxybutanoate (8.9 g) and LiOH·HO (11.8 g) in THF (100 mL) and HO (50 mL) was stirred at 20 °C for 16 h. HO (50 mL) was added and extracted with ethyl acetate (100 mL × 2). The organic extracts were discarded. The pH of the aqueous layer was adjusted to approximately 5 with 2 N HCl and extracted with ethyl acetate (100 mL × 3). The combined organic fractions were washed with brine (100 mL × 10), dried over NaSO, filtered, and concentrated to give the desired product (5.1 g) in 30% overall yield. 1H 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: Preparation of ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate [ka] To a mixture of Zn (6.9 g) and I2 (89 mg) in THF (80 mL) was added 4,4,4-trifluorobutan-2-one (4.4 g) and ethyl 2-bromoacetate (6.4 g) at 15 °C. The mixture was stirred at 60 °C for 6 h. The reaction mixture was cooled to 0 °C and quenched with H2SO4 (100 mL, 10% aqueous solution). The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. The product was obtained (11.00 g, crude) and used directly without further purification.

[0238] Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid [ka] A mixture of ethyl 5,5,5-trifluoro-3-hydroxy-3-methyl-pentanoate (11 g, crude) and NaOH (4.1 g) in HO (150 mL) was stirred at 15 °C for 16 h. The pH was adjusted to about 2 with saturated KHSO at 0 °C, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic extracts were washed with brine (300 mL), dried over NaSO, filtered, and concentrated to give the product (10 g, crude).

[0239] Using the relevant starting materials, the following were prepared by the same methodology as described in IIIe:

[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: Preparation of ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxy-propanoate [ka] To a solution of ethyl 3-(3,3-dimethylcyclobutyl)-3-oxopropanoate (IVd) (1 g) in MeOH (8 mL) was added NaBH (95 mg). The mixture was stirred at 0 °C for 10 min, quenched by the addition of HO (1 mL), concentrated, then diluted with EtOAc (30 mL), dried over NaSO, filtered, and evaporated. The residue was purified by chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 4 / 1) to give ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoate (907 mg). 1 H NMR(DMSO-d6 400MHz):δ4.70(d,1H),4.06-4.00(m,2H),3.71-3.68(m,1H),2.26-2.23(m,1H),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] To a solution of ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoate (900 mg) in MeOH (10 mL) was added a solution of NaOH (377 mg) in HO (5 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was adjusted to pH = 3-4 by the addition of 10% HCl solution, diluted with HO (30 mL), extracted with EtOAc (30 mL × 2), and the combined organic layers were dried over NaSO, filtered, and concentrated to give 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoic acid (760 mg). 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),1.00(s,3H).

[0244] Using the relevant starting materials, the following were prepared by the same methodology as described in IIIh: 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-propanoate [ka] Step 1: Preparation of ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propanoate [ka] EtN (2.34 g) and MgCl (1.8 g) were added to a suspension of (3-ethoxy-3-oxopropanoyl)oxypotassium salt (2.6 g) in MeCN (30 mL) and stirred at 20 °C for 2 h. A pre-stirred mixture of carbonyldiimidazole (CDI) (1.4 g) and 1-(difluoromethyl)cyclopropanecarboxylic acid (1 g) in MeCN (20 mL) was added at 0 °C and stirred at 20 °C for 14 h. The reaction mixture was diluted with HO (30 mL) and extracted with ethyl acetate (80 mL × 2). The combined organic extracts were washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (SiO, elution with a 0–10% ethyl acetate / petroleum ether gradient). The product was obtained (0.98 g).

[0246] Using the relevant starting materials, the following was prepared by the same methodology as described in IVa: IVb: Ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate [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] 1H 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: Preparation of (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide [ka] A solution of (R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (IIa) (0.6 g), methyl 4,4-dimethyl-3-oxo-pentanoate (750 mg), TEA (2.40 g), and DMAP (58 mg) in toluene (10 mL) was stirred at 90 °C for 16 h. The mixture was diluted with EtOAc (50 mL), washed with water (30 mL) and brine (50 mL), dried over Na SO , and concentrated. The crude was purified by chromatography (SiO, 30% EA in petroleum ether) to give (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide (0.28 g).

[0250] The following intermediates were prepared by methodology similar to Va using related intermediates: Vb: (R)-N-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)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-(trifluoro-methyl)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-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanamide [ka] Prepared from IVc and IIa.

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

[0255] Vg: (S)-3-(3,3-difluorocyclobutyl)-N-(1-(3-(difluoromethoxy)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-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] and Example 1b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] To a solution of (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide (Va) (0.28 g) in MeOH (10 mL) was added NaBH (56 mg) at 0° C. The resulting 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 NaSO, and concentrated.

[0258] Step 2: Separation of (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was separated by chromatography.

[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),6.50(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 examples were prepared by analogous methodology to that described for 1a and 1b using relevant intermediates: Example 2a: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] and Example 2b: N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: Preparation of N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Prepared from Vb.

[0262] Step 2: Separation of (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide and (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide [ka] N-((R)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was separated by chromatography.

[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-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide [ka] and Example 3b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide [ka] Prepared from Vc.

[0266] Step 2: Separation of (R)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide and (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoro-methyl)cyclopropyl)propanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide was 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),6.21(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,4H). LC-MS: R =2.51 min (LCMS method 1), m / z=434.1[M+H] + . SFC:t R = 1.58 min (SFC method 3), ee% = 90,0%.

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

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

[0271] Example 4a: 1H NMR (CDCl3400MHz): δ7.41(t,1H),7.27(s,1H),7.18(m,2H),6.41(s,1H),6.23(t,1H) ),5.30(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) ),5.30(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-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] and Example 5b: 3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] Step 1: Preparation of (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanamide [ka] Prepared from Ve.

[0274] Step 2: Separation of (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] (R)-3-(3,3-difluorocyclobutyl)-N-(2-(trifluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanamide was 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),3.64(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),4.1 8-4.15(m,1H),4.11-4.07(m,1H),4.02-3.98(m,1H),2.64-2.51(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-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] and Example 6b: 3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] Step 1: Preparation of (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropanamide [ka] Prepared from Vf.

[0278] Step 2: Separation of (R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] (R)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropanamide was 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),5.33-5.28(m,1H),4.20-4.16(m,1H) ),4.13-4.10(m,1H),4.01-4.00(s,1H),3.56(d,2H),2.61-2.54(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: 1H 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),2.61-2.57(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-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide [ka] and Example 7b: 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide [ka] Step 1: Preparation of 3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide [ka] Prepared from Vg.

[0282] Step 2: Separation of (S)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide and (R)-3-(3,3-difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide [ka] 3-(3,3-Difluorocyclobutyl)-N-((S)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide was separated by chiral SFC.

[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),1.33-1.28(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),1.33-1.28(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-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide [ka] and Example 8b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide [ka] Prepared from Vh.

[0286] Step 2: Separation of (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide and (R)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide was separated 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),6.44(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),2.49-2.41(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-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] and Example 9b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] To a solution of (R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (IIa) (400 mg) and 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid (IIIc) (307 mg) in DCM (20 mL) was added N-hydroxybenzotriazole (HOBt) (213 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (363 mg), and EtN (320 mg). The mixture was stirred at 25 °C for 16 h, diluted with water (10 mL), and extracted with EtOAc (20 mL × 3). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by basic preparative HPLC to give N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide (250 mg).

[0290] Step 2: Separation of (R)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide and (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide was separated 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),6.25(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] The following examples were prepared by similar methodology as described for Example 9a and Example 9b using the relevant intermediates: Example 10a: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] and Example 10b: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] Prepared from IIb and IIIc.

[0294] Step 2: Separation of (S)—N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide and (R)—N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide was 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: Preparation of 3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] Prepared from IIb and IIId.

[0298] Step 2: Separation of (R)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide and (S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide [ka] 3-Cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide was separated by chiral SFC.

[0299] Example 11a: 1H 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),0.90-0.88(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),0.90-0.87(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)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide [ka] and Example 12b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide [ka] Prepared from IIa and IIIe.

[0302] Step 2: Separation of (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide was separated by chiral SFC.

[0303] Example 12a: 1H 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)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide [ka] and Example 13b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide [ka] Prepared from IIa and IIIg.

[0306] Step 2: Separation of (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide and (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide was separated by chiral SFC.

[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),1.84-1.76(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),6.51(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)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] and Example 14b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] Prepared from IIa and IIIf.

[0310] Step 2: Separation of (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide and (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide was separated using chiral SFC.

[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),6.48(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: 1H NMR (CDCl3400MHz): δ7.35(t,1H),7.16(d,1H),7.08(s,1H),7.04(d,1H),6.79(d,1H),6.48(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)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide [ka] and Example 15b: N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide [ka] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide [ka] Prepared from IIa and IIIh.

[0314] Step 2: Separation of (S)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide and (R)—N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide [ka] N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide was 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,1 H),4.61(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,3H),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: 1H NMR(DMSO-d6 400MHz): δ8.43(d,1H),7.40(t,1H),7.24(d,1H),7.22(t,1H),7.18(s,1H),7.08(d,1H),6.67(t,1H),5.14-5.10(m,1 H),4.63(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,3H),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: Preparation of 3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] Prepared from IIa and IIIi.

[0318] Step 2: Separation of (S)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and (R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide [ka] 3-Cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide was separated by chiral SFC.

[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,1H),7.08(d,1H),6.66(t,1H),5.16-5.1 4(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: 1H NMR(DMSO-d6 400MHz): δ8.41(d,1H),7.36(d,1H),7.20(d,1H),7.18(t,1H),7.15(s,1H),7.04(m,1H),6.63(t,1H),5.13-5.07( m,1H),4.59(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),1.60-1.33(m,8H). LC-MS: R =2.27 min (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: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide [ka] Prepared from IIp and IIIc.

[0322] Step 2: Separation of (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 [ka] Chiral SFC was used to separate 3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide.

[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),5.18-5.13(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,1H),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,1 H),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-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] Step 1: Preparation of (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide [ka] To a solution of (R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (IIc) (0.2 g), (3S)-3-hydroxy-4,4-dimethyl-pentanoic acid (IIIa) (144 mg), and HATU (375 mg) in DCM (10 mL) was added DIEA (319 mg). The mixture was stirred at 20° C. for 16 hours and concentrated. The crude product was purified to give (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide. 1 H NMR (CDCl3400MHz): δ7.33(t,1H),7.17(d,1H),7.08(s,1H),7.03(d,1H),6.49(m,1H),6.51(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,1H),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 examples were prepared by analogous methodology to that described for Example 17 using relevant intermediates.

[0327] Example 18: (S)—N—((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide [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),2.36-2.29(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-dimethylpentanamide [ka] 1H 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)-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),1.36-1.29(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),5.84( 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,1 H),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)-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:tR = 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),5.19-5.13(m,1H ),3.75-3.71(m,1H),2.82(d,1H),2.45-2.40(m,3H),2.30-2.27(m,1H),2.23-2.16(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. 1H 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)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide [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) ,4.92(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)acetamide [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),6.39(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,2H),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),5.32(m,1H),4.63(s,1H),4.23(m,2H),2.76-2.57(6H). LC-MS: R =2.48 min (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) ),5.04(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)acetamide [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),5.90 (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),4.99(brs,1 H),4.89(q,1H),2.77-2.70(m,2H),2.63(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),5.34-5.29 (m,1H),4.44(s,1H),3.09-3.03(m,1H),2.91-2.89(m,1H),2.77-2.73(m,2H),2.70-2.53(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)acetamide [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),5.8 3(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: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】 (In the formula, R １ is C １ ~C ６ Alkyl, CF ３ , C.H. ２ CF ３ , C.F. ２ CHF ２ , and C ３ ~C ８ cycloalkyl, wherein said C ３ ~C ８ Cycloalkyl is C １ ~C ３ Alkyl, F, CHF ２ and CF ３ and R ２ is H, C １ ~C ６ Alkyl or CF ３ or R １ and R ２ is bonded to one or two F, CHF ２ , or CF ３ C optionally substituted with ３ ~C ５ forming a cycloalkyl; and R ３ is C １ ~C ３ Alkyl, CH ２ O-C １～３ Alkyl or CH ２ O-cyclopropyl, １ ~C ３ Alkyl or CH ２ O-C １～３ alkyl is substituted with C≡N or 3 F; R ４ is OCF ３ and OCHF ２ selected from the group consisting of or a pharmaceutically acceptable salt of any of these compounds.

2. R ４ OCF ３ or OCHF ２ 2. The compound of claim 1, wherein:

3. R ３ But CH ２ O-CF ３ , C.H. ２ O-cyclopropyl, and CH ２ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: -C≡N.

4. R １ But one or two C １ ~C ３ Alkyl, F, CHF ２ or CF ３ C optionally substituted with ３ ~C ４ 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

5. R １ and R ２ are joined to form a cyclobutyl optionally substituted with one or two F, and R ４ OCF ３ or OCHF ２ 5. The compound according to any one of claims 1 to 4, wherein:

6. (S)-N-((R)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N-((R)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N-((S)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (S)—N-((S)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide; (R)—N-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)—N-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)acetamide; (S)—N-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1-hydroxycyclobutyl)acetamide; and A compound selected from the group consisting of (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)acetamide, or a pharmaceutically acceptable salt of any of these compounds.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for treating a patient suffering from epilepsy, bipolar disorder, migraine, or schizophrenia.

9. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for treating a patient suffering from psychosis, mania, stress-related disorders, acute stress reaction, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorders, personality disorders, schizophrenia-type disorders, aggression, chronic pain, neurological disorders, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, or Alzheimer's disease.

10. Use of a compound according to claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia.

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

12. A pharmaceutical composition comprising a compound according to claims 1 to 6 or a pharmaceutically acceptable salt thereof for the treatment of epilepsy, epilepsy syndromes, epileptic symptoms, treatment-resistant or intractable epilepsy, or epileptic seizures.

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

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the treatment of epileptic symptoms as part of a neurodegenerative disease such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, or frontotemporal lobar degeneration.

15. 10. Use of a compound according to claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or intractable epilepsy, or epileptic seizures.

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

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