EA048113B1 - ALCOHOL DERIVATIVES AS COMPOUNDS INDUCING THE OPENING OF Kv7 POTASSIUM CHANNELS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to novel compounds that activate Kv7 potassium channels. Certain aspects of the present invention are directed to pharmaceutical compositions containing said compounds and uses of the compounds for treating disorders responsive to activation of Kv7 potassium channels.

Background of the invention

Voltage-gated potassium (Kv) channels allow potassium ions (K+) to pass across cell membranes in response to changes in membrane potential, and thereby can control cellular excitability by modulating (increasing or decreasing) the cell's electrical activity. Functional Kv channels exist as multimeric structures formed by the association of four alpha and four beta subunits. The alpha subunits contain six transmembrane domains, a pore-forming loop, and a voltage sensor, and are arranged symmetrically around a central pore. Beta or accessory subunits interact with the alpha subunits and can modify the properties of the channel complex to provide unlimited changes in the electrophysiological or biophysical properties of the channels, expression levels, or expression profiles.

Nine families of Kv channel alpha subunits have been identified and are designated Kv1 through Kv9. For this reason, there is enormous diversity in Kv channel function, which arises from the multiple subfamilies, the formation of both homomeric and heteromeric subunits within the subfamilies, and the additive effects of association with beta subunits (Christie, 25 Clinical and Experimental Pharmacology and Physiology, 1995, 22, 944-951).

The Kv7 channel family consists of at least five members, which include one or more of the following mammalian channels: Kv7.1, Kv7.2, Kv7.3, Kv7.4, Kv7.5, and any mammalian or non-mammalian equivalents or variants (including splice variants) thereof. Alternatively, members of this family are referred to by the names of their genes, which are KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5, respectively (DalbyBrown, et al., Current Topics in Medicinal Chemistry, 2006, 6, 9991023).

As mentioned above, neuronal Kv7 potassium channels play roles in controlling neuronal excitation. Kv7 channels, particularly the Kv7.2/Kv7.3 heterodimers, underlie the M-current (Wang et al. Science. 1998 Dec 4; 282(5395):1890-3). The M-current has a characteristic time- and voltage-dependence that results in stabilization of the membrane potential in response to multiple excitatory stimuli.

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-activating potassium current found in a variety of nerve cell types. In each cell type, it is the predominant form of membrane excitability control, being the only sustained current within the range that initiates an action potential (Marrion, Annual Review Physiology 1997, 59, 483-504).

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)phenyl)carbamic acid ethyl ester) is a compound that binds to Kv7 potassium channels (Wuttke, et al., Molecular Pharmacology, 2005, 67, 1009-1017). Retigabine activates K ⁺ current in nerve cells, and the pharmacology of this induced current is consistent with the published pharmacology of the M channel, which has been correlated with the heteromultimeric K' channel Kv7.2/3, indicating that activation of Kv7.2/3 channels accounts for at least some of the anticonvulsant activity of this drug (Wickenden, et al., Molecular Pharmacology 2000, 58, 591-600). Retigabine is effective in reducing the incidence of seizures in patients with epilepsy (Bialer, et al., Epilepsy Research 2002, 51, 31-71). Retigabine has a broad spectrum of activity and potent anticonvulsant properties. It is active after oral and intraperitoneal administration in rats and mice in a number of anticonvulsant tests (Rostock, et al., Epilepsy Research 1996, 23, 211-223).

The five members of this ion channel family differ in their expression patterns. Kv7.1 expression is restricted to the heart, peripheral epithelium, and smooth muscle, while Kv7.2, Kv7.3, Kv7.4, and Kv7.5 expression appears to be predominant in the nervous system, including neurons in the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion (for review, see Greene & Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495–508).

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

In addition, mRNA molecules corresponding to Kv7.3 and 5, in addition to those corresponding to Kv7.2, are expressed in astrocytes and glial cells. Thus, the Kv7.2, Kv7.3 and

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Kv7.5 may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of compounds that induce KCNQ channel opening (Noda, et al., Society for Neuroscience Abstracts 2003, 53. 9), which may be relevant for the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's chorea.

mRNA corresponding to the Kv7.2 and Kv7.3 subunits has been detected in brain regions associated with anxiety and emotional behaviors such as depression and bipolar disorder, such as the hippocampus, ventral tegmental area, and amygdala (Saganich, et al. Journal of Neuroscience 2001, 21, 4609-4624; Friedman et al., Nat Commun. 2016; 7: 11671), and retigabine has been reported to be active in animal models of anxiety-like behavior (Korsgaard et al. J Pharmacol Exp Ther. 2005 Jul; 314(1):282-92. Epub 2005 Apr 6.). Thus, Kv7 channels are significant for the treatment of emotion-related disorders such as, but not limited to, bipolar depression, major depressive disorder, anxiety, suicidal behavior, panic attacks, social phobia.

Increased expression of Kv7.2/3 channels has also been reported in models of neuropathic pain (Wickenden, et al., Society for Neuroscience Abstracts 2002, 454. 7), and potassium channel modulators have been suggested to be active in both neuropathic pain and epilepsy (Schroder, et al., Neuropharmacology 2001, 40, 888-898).

In addition to a role in neuropathic pain, expression of Kv7.25 mRNA in the trigeminal and dorsal ganglia and in the trigeminal nucleus caudalis suggests that compounds that induce opening of such channels may also affect the processing of sensory information from migraine pain sites (Goldstein, et al. Society for Neuroscience Abstracts 2003, 53.8). Taken together, this evidence points to the importance of compounds that induce opening of the KCNQ channel for the treatment of chronic pain and neuropathy-related disorders.

WO 07/90409 relates to the use of compounds that induce the opening of the Kv7 channel for the treatment of schizophrenia. Compounds that induce Kv7 channel opening modulate dopaminergic system function (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 2006 Jun 14), which may be of significance for the treatment of mental disorders such as, but not limited to, psychosis, mania, stress-related disorders, acute stress reactions, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulse control disorders, personality disorders, schizotypal disorder, aggression, autism spectrum disorders. WO 01/96540 discloses the use of modulators of the M-current generated by the expression of the KCNQ2 and KCNQ3 genes in insomnia, while WO 01/092526 discloses that Kv7.5 modulators can be used to treat sleep disorders. WO 09/015667 discloses the use of compounds that induce Kv7 opening in the treatment of sexual dysfunction.

Although patients suffering from the above disorders may have treatment options available, many of these options lack the required efficacy and are accompanied by unwanted side effects. Consequently, there is an unmet need for new therapies to treat these disorders.

In an attempt to identify new therapies, the present inventors have identified a series of novel compounds represented by formula I. Accordingly, the present invention provides novel compounds as drugs for the treatment of disorders that are modulated by KCNQ potassium channels.

The essence of the invention

The present invention relates to a compound of formula I,

formula I;

where R ¹ is selected from the group consisting of C ₁ -C6 alkyl, CF ₃ , CH ₂ CF ₃ , CF2CHF2, ^-^-cycloalkyl, wherein said ^-^-cycloalkyl may be substituted with 1 or 2 of ^-^-alkyl, F, CHF2 or CF ₃ , and

R ² is H, ^-^-alkyl or CF ₃ ; or

R ¹ and R ² are combined (together with the carbon atoms to which they are attached) to form a C ₃ -cycloalkyl optionally substituted with 1 or 2 F, CHF2, or CF ₃ ; and

R ³ is O2-alkyl or CH ₂ O-C _1-3 alkyl, wherein said O2-alkyl or CH ₂ O-C _1-3 alkyl are substituted by C=N, 3 F, or C ₃ -C ₅ -cycloalkyl;

R ⁴ is selected from the group consisting of OCF ₃ or OCHF2.

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According to another aspect of the present invention, the present invention relates to novel compounds according to the present invention.

The present invention also provides a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier or excipient.

Furthermore, the present invention provides a method for treating a patient as described in the claims and embodiments, and also provides treatment options for patients suffering from epilepsy, bipolar disorder, migraine and schizophrenia, comprising administering to a subject a therapeutically effective amount of a compound according to the present invention.

Detailed description of the invention

According to one embodiment, the compound of formula I may comprise a group R ⁴ that is OCF3 or OCHF2.

According to another embodiment, the compound according to formula I may comprise a group R ³ selected from the group consisting of CH ₂ -O-CF ₃ , CH ₂ -O-cyclopropyl, CH2C=N.

According to a further embodiment, the compound according to formula I may comprise a group R ¹ which is C ₃ -C ₄ -cycloalkyl optionally substituted with 1 or 2 C ₁ -C ₃ -alkyl, F, CHF2 or CF3.

In another embodiment, a compound according to any formula I may comprise an R ¹ group and an R ² group that are combined to form cyclobutyl optionally substituted with 1 or 2 F, and wherein R ⁴ is OCF3 or OCHF2.

According to a particular embodiment of the present invention, the compound according to the present invention is selected from the group consisting of (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)-3hydroxy-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-1hydroxycyclobutyl)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 a pharmaceutically acceptable salt of either compound.

Another aspect of the present invention relates to a compound selected from the group consisting of

- 3 048113 (R)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide;

(S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide;

(R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide;

(R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide;

(S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide;

(R)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide (S)-3-(3,3-difluorocyclobutyl)-N-((R)-2-(difluoromethoxy)1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

- 4 048113 (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)-3hydroxypropanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3hydroxypropanamide;

(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-hydroxy4,4-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;

- 5 048113 (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)-3hydroxybutanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide;

(S)-N-((R)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide;

(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;

- 6 048113 (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)-3hydroxypropanamide;

(R)-N-((R)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3hydroxypropanamide;

(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-methoxy1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((R)-2methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide or a pharmaceutically acceptable salt of any of these compounds.

Reference to compounds encompassed by the present invention includes racemic mixtures as well as optically pure isomers of the compounds, where applicable, as well as tautomeric forms of the compounds, where applicable. Furthermore, the compounds of the present invention can potentially exist in polymorphic and amorphous forms or as unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.

The present invention also provides isotopically labeled forms of the compounds of the present invention, such as with deuterium. The compound may also contain positron-active isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-active isotopes that may be included in the compounds of the present invention are 11C, ^13N , ^15O and ^18F . Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples using a suitable isotopically labeled reagent in place of a non-isotopically labeled reagent.

The compound of the present invention may be in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier.

In one embodiment, the present invention relates to a compound according to the present invention for use in therapy.

In another embodiment, the present invention relates to 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 according to the present invention.

In 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 reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease, comprising administering to the subject a therapeutically effective amount of a compound according to the present invention.

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According to one embodiment, the compound of the present invention is used in therapy.

The use of the compound according to the present invention is provided for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia or, in another embodiment, for the treatment of psychosis, mania, disorders associated with exposure to stress factors, acute reactions to stress, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease.

In another embodiment, the compound of the present invention is for the manufacture of a medicament for the treatment of epilepsy, fragile X syndrome, Angelman syndrome, bipolar disorder, migraine or schizophrenia, or, in another embodiment, for the manufacture of a medicament for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease.

In the context of the present invention, optionally substituted means that the indicated fragment may or may not be substituted, and if substituted, it contains one or two substituents. It is understood that if no substituents are indicated for an optionally substituted fragment, the position is occupied by a hydrogen atom.

A given range may be interchangeably denoted by - (hyphen) or from ... to, for example, the term C _1-3 alkyl is equivalent to C1 to C ₃ alkyl.

The terms C1- _C3 alkyl and C1- _C6 alkyl refer to a saturated hydrocarbon with a straight or branched chain containing from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and tert-butyl.

The term C1- _C3 -alkoxy refers to a moiety of the formula -OR, where R is C1-C3- _alkyl as defined above.

The terms _C3 - _C4- cycloalkyl, _C3 -C5-cycloalkyl, _C3 - _C8- cycloalkyl or cyclopropyl refer to a saturated monocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Routes of administration.

Pharmaceutical compositions containing a compound of the present invention as defined above may be specially formulated for administration 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.

It should be taken into account that the route will depend on the general health and age of the subject being treated, the nature of the condition being treated and the active ingredient.

Pharmaceutical compositions and excipients Hereinafter, the term excipient or pharmaceutically acceptable excipient refers to pharmaceutical excipients, including but not limited to fillers, anti-adhesive agents, binders, coatings, colorants, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, carrier media, and auxiliaries.

The present invention also provides a pharmaceutical composition comprising a compound of the present invention, such as one of the compounds disclosed in the experimental section herein. The present invention also provides a method for preparing a pharmaceutical composition comprising a compound of the present invention. The pharmaceutical compositions of the present invention can be formulated with pharmaceutically acceptable excipients according to conventional techniques, such as those disclosed in Remington, The Science and Practice of Pharmacy, 22nd ed. (2012), edited by Allen, Loyd V., Jr.

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 and granules to be dissolved or suspended in a suitable liquid.

Solid dosage forms for oral administration may be presented 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. If necessary, solid dosage forms may be

- 8 048113 are coated with coatings such as enteric coatings, or they can be formulated so as to provide modified release of the active ingredient, such as delayed or prolonged release, according to methods well known in the art. If necessary, the solid dosage form can be a dosage form that disintegrates under the action of saliva, such as, for example, an orodispersible tablet.

Examples of excipients suitable for an oral solid formulation include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, sodium croscarmellose, sucrose, cyclodextrin, talc, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, the solid formulation may include excipients for delayed or extended release formulations known in the art, such as glyceryl monostearate and hypromellose. If a solid material is used for oral administration, the formulation may be prepared, for example, by mixing the active ingredient with the solid excipients and then compressing the mixture in a standard tabletting machine; or the formulation, for example in the form of a powder, granule, or minitablet, may be placed in, for example, a hard capsule. The amount of solid excipient in a standard dose will vary considerably, but will generally range from about 25 mg to about 1 g.

Liquid dosage forms for oral administration may be presented as, for example, tinctures, syrups, oral drops or liquid-filled capsules. Liquid dosage forms for oral administration may also be presented as powders for solution or suspension in an aqueous or non-aqueous liquid. Examples of excipients suitable for oral liquid formulation include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylene glycols, poloxamers, sorbitol, polysorbate, mono- and diglycerides, cyclodextrins, coconut oil, palm oil and water. Liquid dosage forms for oral administration 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 a liquid emulsion of the oil-in-water or water-in-oil type.

In solid and liquid oral formulations, additional excipients such as colorants, flavorings and preservatives, etc. may be used.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, and sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion before use. Examples of excipients suitable for parenteral formulation 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.

Other types of pharmaceutical compositions include suppositories, inhalation formulations, creams, gels, skin patches, implants, and buccal or sublingual formulations.

It is essential that the excipients used in any pharmaceutical formulation are appropriate for the intended route of administration and compatible with the active ingredients.

Doses.

In one embodiment, the compound of the present invention is administered in an amount of from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day. In particular, the daily dosage may be in the range of from 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The exact dosages will depend on the frequency and route of administration, the sex, age, weight, and general health of the subject being treated, the nature and severity of the condition being treated and any concomitant diseases being treated, the desired effect of the treatment, and other factors known to those skilled in the art.

A typical dosage of a compound of the present invention for oral administration to adults will be in the range of 0.1-1000 mg/day, such as 1-500 mg/day, such as 1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of the present invention are administered in a unit dosage form containing said compounds in an amount of from about 0.1 to 500 mg, such as 10 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, of a compound of the present invention.

Isomeric and tautomeric forms.

Where the compounds of the present invention contain one or more chiral atoms, unless otherwise indicated, reference to the compounds shall include the enantiomerically or diastereomerically pure compound as well as mixtures of enantiomers or diastereomers in any ratio.

The improved stereochemical representation of MDL is applied to the description of unknown

- 9 048113 the stereochemistry of the compounds of the present invention. Thus, the designation or1 at a chiral carbon atom is used to indicate that the absolute stereoconformation at that atom is unknown; for example, the stereoconformation at a given carbon atom is either (S) or (R).

Furthermore, the representations of a chiral bond extending from an or1-designated carbon atom using an upward wedge or a downward wedge are equivalent; for example, the two representations have the same value, where the value implies that the absolute stereoconformation at the or1-designated carbon atom is unknown and may be (S) or (R).

Thus, the use of upward wedge-shaped bonds and downward wedge-shaped bonds extending from the or1-designated atoms is intended only to provide a visual cue that the images represent different stereoisomers in which the conformation at the or1-designated carbon atom is unknown.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms, and it is intended that the present invention include any tautomeric forms that the compounds may form.

Therapeutically effective amount

In the context of the present invention, the term therapeutically effective amount of a compound means an amount sufficient to alleviate, arrest, partially arrest, eliminate or delay the clinical manifestations of a given disease and its complications when a therapeutic intervention involves the administration of said compound. An amount sufficient to do this is defined as a therapeutically effective amount. Effective amounts for each purpose will depend on the severity of the disease or injury, as well as the weight and general health of the subject. It should be understood that the determination of the appropriate dosage can be accomplished using conventional experimentation, by constructing a matrix of values and testing various points in the matrix, which is within the competence of a skilled physician.

Treatment and implementation of treatment.

In the context of the present invention, treatment or carrying out treatment is intended to mean the management and care of a patient with the aim of alleviating, stopping, partially stopping, eliminating or delaying the development of a clinical manifestation of a disease. The patient to be treated is preferably a mammal, in particular a human.

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

Use in epilepsy, epileptic syndromes, epileptic symptoms or seizures.

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

In another embodiment, the present invention relates to a method of treating a patient in need thereof suffering from focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ-associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with continuous spike-and-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome) or seizures associated with exposure to stress factors, hormonal changes, drug use (such as amphetamines or cocaine), alcohol use, infection or metabolic disorders (such as hyponatremia), or intended for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, comprising administering to a subject a therapeutically effective amount of a compound of the present invention.

The use of the compound according to the present invention is provided 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, generalized idiopathic epilepsy, grand mal seizures, epileptic status

- 10 048113 sa, neonatal seizures, KCNQ-associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with continuous spike-and-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome) or seizures associated with exposure to stress factors, hormonal changes, drug use, alcohol use, infection, traumatic brain injury, stroke, forms of brain cancer, autism spectrum disorders or metabolic disorders (such as hyponatremia), or use is provided for epileptic symptoms that are a component neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration.

In another embodiment, the compound of the present invention is for the manufacture of a medicament for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures, including focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ-associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as other epileptic syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with continuous spike-and-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome) or seizures associated with stress, hormonal changes, drug use, alcohol use, infection, traumatic brain injury, stroke, forms of brain cancer, autism spectrum disorders or metabolic disorders (such as hyponatremia), or is intended for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration.

The classification of epilepsy forms can be based on ICD-10 (2016, published by WHO), and its description is provided in sections G40 and G41, and it is also taken into account in the treatment of epilepsy according to the present invention.

G40.0. Localized (focal)(partial) idiopathic epilepsy and epileptic syndromes with focal-onset seizures.

G40.1. Localized (focal)(partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures.

G40.2. Localized (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures.

G40.3. Generalized idiopathic epilepsy and epileptic syndromes.

G40.4. Other generalized epilepsy and epileptic syndromes.

G40.5. Special epileptic syndromes.

G40.6. Grand mal seizures, unspecified (with or without minor seizures).

G40.7. Unspecified minor seizures without major seizures.

G40.8. Other forms of epilepsy.

G40.9. Epilepsy, unspecified.

G41. Status epilepticus.

Treatment of seizures.

A seizure is a sudden, uncontrolled disruption of electrical activity in the brain. It can cause changes in behavior, movement, or sensation, as well as in levels of consciousness. If a person has two or more seizures or a tendency to have seizures periodically, then the diagnosis is epilepsy.

There are many types of seizures that vary in severity. Seizure types vary in where and how they occur in the brain. Most seizures last between 30 seconds and 2 minutes.

Focal seizures.

Focal seizures are caused by abnormal electrical activity in one area of the brain. Focal seizures may occur with or without loss of consciousness and include:

Focal seizures with impaired awareness. These seizures involve a change or loss of consciousness or awareness. The person may stare into space and not respond to their surroundings in the usual way, or engage in repetitive movements such as rubbing their hands, chewing, swallowing, or walking in circles.

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Focal seizures without loss of consciousness.

These seizures may alter emotions or change the way things look, smell, feel, taste, or sound, but the person does not lose consciousness. These seizures may also cause involuntary jerking of a body part, such as an arm or leg, and spontaneous sensory symptoms such as tingling, dizziness, and flashing lights.

Generalized convulsive seizures.

Seizures that appear to involve all areas of the brain are called generalized seizures. Different types of generalized seizures include: absence seizures. Absence seizures, previously known as petit mal seizures, often occur in children and are characterized by a blank stare or subtle body movements such as blinking or lip smacking. These seizures may occur in clusters and cause a brief loss of awareness.

Tonic seizures. Tonic seizures cause muscles to become stiff. These seizures usually affect the muscles of the back, arms, and legs.

Atonic seizures: Atonic seizures, also known as drop seizures, cause a loss of muscle control that can lead to sudden collapse or falling.

Clonic seizures. Clonic seizures are associated with repetitive or rhythmic jerking movements of muscles. These seizures usually involve the neck, face, and arms.

Myoclonic seizures Myoclonic seizures usually appear as sudden, brief jerks or twitches of the arms and legs.

Tonic-clonic seizures. Tonic-clonic seizures, previously known as grand mal seizures, are the most severe type of epileptic seizure and can cause sudden loss of consciousness, stiffness and shaking of the body, and in some cases loss of bladder control or tongue biting.

In many cases, seizures may be associated with or caused by the following factors:

high body temperature, which may be associated with an infection such as meningitis;

lack of sleep;

low sodium levels in the blood (hyponatremia), which can occur with diuretic therapy;

taking medications, such as certain painkillers, antidepressants, or nicotine addiction therapies, that lower the seizure threshold;

head injury that results in bleeding into the brain;

stroke;

the presence of a brain tumor;

use of drugs such as amphetamines or cocaine;

alcohol consumption.

Headings and subheadings are used herein for convenience only and are not to be construed as limiting the present invention in any way.

The use of all kinds of examples or introductory words before examples (including such as, for example, for instance and actually) in this description is intended solely to better illustrate the present invention and does not imply limiting the scope of the present invention, unless otherwise stated.

The citation and inclusion of patent documents in this document is for convenience only and does not reflect any assessment of the significance, patentability and/or legal effect of such patent documents.

The present invention includes all modifications and equivalents of the subject matter of the invention set forth in the claims appended hereto in accordance with applicable law.

Experimental section.

Biological assessment.

Cell culture.

The synthesized cDNA fragment encoding human Kv7.3 and human Kv7.2 separated by the P2A sequence was inserted into the pcDNA5/FRT/TO vector using BamHI and XhoI restriction sites. The construct was then transfected into HEK Flp-In 293 cells using Lipofectamine 2000. Transfected cells were grown for 48 h in DMEM containing 10% (v/v) FBS and 1% PenStrep and then maintained under selection in DMEM containing 10% (v/v)

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FBS, 1% PenStrep and 200 μg/mg 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 using whole-cell automated patch clamps and showed a typical Kv7 current that was sensitive to XE991 and enhanced by retigabine.

Analysis of thallium intake.

The thallium influx assay for potassium channel activation was performed similar to the published procedure (CD Weaver, et al., J Biomol Screen 2004, 9, 671-677') using the FLIPR potassium assay kit (Molecular Devices). HEK-hKv7.2/hKv7.3 cells were seeded in 96-well, black-walled, clear NaCl culture plates (Opioid, 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 two days after seeding. On the day of the assay, the medium was removed and 50 μl/well of test compound was diluted to 2x the final concentration in HBSS containing 20 mM HEPES and 50 μl/well of 2x dye loading buffer was added. Cells were then incubated for 60 min at room temperature in the dark. Chloride-free stimulation buffer containing Tl ⁺ and K ⁺ at a final concentration of 5x (5x concentration: 5 mM in both cases) and test compound at a final concentration of 1x were prepared during the incubation. Cells were then analyzed on a FDSS7000EX Functional Drug Screening System (Hamamatsu). After 60 sec, the baseline fluorescence signal was read at 0.1 Hz and 10 sec. At 1 Hz, 25 μl/well of stimulation buffer was added and fluorescence was measured continuously for 50 sec at 1 Hz, then for 4 min at 0.1 Hz. The effect of the compound was quantified using AUC as the readout and normalized to the reference compound included in each plate.

Connection effects.

In the assay described above, the compounds of the present invention were characterized by the following biological activity.

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Synthesis of the compounds of the present invention: general methods.

General procedures for synthesizing intermediates and compounds of general formula I are described in Reaction Scheme 1 and are specifically illustrated in the preparation methods and examples. Variations of the described procedures that are known to those skilled in the art are within the scope of the present invention.

The compounds of the present invention are prepared as described in Scheme 1. Several compounds of general formula I contain two chiral carbon atoms and are formed as a mixture of diastereomers. In this case, the diastereomers can be separated to give individual stereoisomers Ia and Ib.

Scheme 1

Scheme I shows the preparation of a compound of general formula I via two general routes. The first route is the synthesis of compounds of formula I via the reaction of an enantiomerically pure amine of general formula II and an acid of general formula III, via a technique well known in the art for converting an acid and an amine into an amide. This technique involves the formation of reactive derivatives of the acid of formula III, including but not limited to activated esters and reactive mixed anhydrides, followed by condensation with amines of general formula II. One such procedure is to carry out the condensation in the presence of (N-bis-dimethylamino-ethylene-methyl-2-yl-deoxy-triazolo-N-pyridinium 3-oxide hexafluorophosphate (HATU) and a suitable base such as diisopropylethylamine (DIPEA) in a solvent such as dichloromethane (DCM). Alternatively, when R ² is H, compounds of general formula I can be prepared via a second general route in which intermediates of general formula V are treated with a suitable reducing agent such as NaBH ₄ in a suitable solvent such as methanol.

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Intermediates of formula V can be prepared from enantiomerically pure amines of general formula II and a carboxylic acid of general formula IV (R = H). This transformation can be accomplished using reaction conditions similar to those described above for the condensation of compounds II and III to form compound I. A variation of this procedure is a direct coupling reaction between a chiral amine of general formula II and a carboxylic acid ester of general formula IV (R = Me, Et). This reaction can be accomplished by refluxing the reactants in a suitable solvent such as toluene, in the presence of a suitable base such as DIPEA, and in the presence of a catalytic amount of a suitable catalyst such as 4-dimethylaminopyridine (DMAP).

Optically active amines of general formula II can be prepared as described in Scheme 2a.

Scheme 2a

Aldehydes of general formula VI can be condensed with (S)-2-methylpropane-2-sulfinamide in a suitable solvent such as dichloroethane in the presence of a drying agent such as titanium isopropoxide (TII) or copper sulfate. The resulting sulfinylimine XV is treated with R ³ MgBr in a suitable inert solvent such as THF to afford the appropriately substituted (S)-2-methyl-N(S)-1-aryl-alkyl)propane-2-sulfinamides VII, which are converted to compounds of general formula II by treatment with a suitable acid in a suitable solvent such as HCl in MeOH.

In variations of this procedure, the R ³ substituent bearing the functional group may be further modified using standard functional group transformation procedures known to those skilled in the art. Examples of such manipulations to prepare chiral amines are illustrated in Scheme 2b. An intermediate of general formula VII, in which R ³ = allyl, may be formed from compound XV and allyl-MgBr, and may be catalytically reduced to R ³ = n-propyl using H2(g) in the presence of a suitable catalyst such as Pd/C in a suitable solvent such as ethyl acetate. Alternatively, the intermediate of general formula VII, wherein ^R3 = allyl, can be dihydroxylated followed by oxidative cleavage to give the intermediate VII, wherein ^R3 = acetaldehyde, by treatment with suitable catalysts such as _K2OsO4 and NaIO4, in the presence of a suitable base such as 2,6-lutidine and in a suitable solvent such as dioxane/ _H2O . The resulting aldehyde can undergo further transformations; for example, exchange of oxygen for two fluorine atoms by treatment with a suitable reagent such as (diethylamino)sulfur trifluoride (DAST) in a suitable solvent such as DCM. In the final step, chiral amines can be obtained by hydrolysis as described above.

As another example, an intermediate of general formula XVI, in which R ³ is an acetic acid ester, can be formed from compound XV during 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 transformed by transformations known to those skilled in the art of chemistry. 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 transformed by transformations known to the skilled practitioner. 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 mesylates can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent such as DMSO.

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Scheme 2b

Aldehydes of general formula VI can also be converted to chiral amines of general formula II via an alternative strategy illustrated in Scheme 2c.

Scheme 2c

Following this procedure, appropriately substituted benzaldehydes VI can be converted to the corresponding appropriately substituted styrenes using the Wittig procedure known to those skilled in the art of chemistry. Such intermediates can undergo an alkylation-oxidation reaction to form keto intermediates XVII. Intermediates of general formula XVII can be condensed with (K)-2-methylpropane-2

- 16 048113 sulfinamide in a suitable solvent such as dichloroethane in the presence of a suitable drying agent such as titanium(IV)ethoxide. The resulting sulfinyl imine can be reduced with a suitable reducing agent such as L-selectride in a suitable inert solvent such as THF to give the corresponding appropriately substituted (N)-2-methyl-N((8)-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.

One skilled in the art will appreciate that other transformations are possible from several of the intermediates; the present invention is intended to include such alternative transformations.

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.

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

Scheme 3a

A variation of this procedure is illustrated in Scheme 3b. In this procedure, additional R ³ substituents, which are ethers, can be installed from a common alpha-bromoacetophenone intermediate XI prepared by bromination of an appropriately substituted acetophenone. Examples include, but are not limited to, the introduction of fluoroalkylmethylene ether groups as R ³ . Thus, using this procedure, an appropriately substituted bromoacetophenone can be reacted with a fluoroalkoxy donor such as trifluoromethyl trifluoromethanesulfonate and KF under Finkelstein conditions in a suitable solvent such as dimethylacetamide (DMA) to provide intermediate XII, which can be further converted to chiral amines as described above. Other examples include, but are not limited to, the introduction of alkylmethylene ethers as R ³ . Thus, an appropriately substituted bromoacetophenone can be converted to the acyldiazo intermediate XIII by reaction with 4-methyl-N-(p-tolylsulfonyl)benzenesulfonohydrazide in the presence of a suitable base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and in a suitable solvent such as THF. Intermediate XIII can undergo carbene formation by treatment with a suitable catalyst such as indium triflate in a suitable solvent such as toluene. The formed carbene can be trapped in situ with a suitable alcohol to afford the alkoxyketo intermediates XIV. From intermediate XIV, chiral amines of formula II can be prepared by standard manipulations as described above.

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Scheme 3b

The appropriately substituted ketones or acetophenones used to prepare the compounds of the present invention are commercially available or can be prepared by methods known to those skilled in the art.

It will be apparent to those skilled in the art that other transformations are possible from the intermediates of general formula XI; the present invention is intended to include such alternative transformations.

Another procedure suitable for the preparation of chiral amines of general formula II in which R ³ is an ester, is described in Scheme 4.

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Scheme 4

In this procedure, the sulfinyl imine glyoxylate formed by the condensation reaction between the glyoxyl ester and (D)-2-methylpropane-2-sulfinamide can be reacted with an appropriately substituted boronic acid using a suitable catalyst such as bis(acetonitrile)-cyclooctadiene-dium fluorotetrafluoroborate in a suitable solvent such as dioxane, as described in JP 2017/095366A. The resulting intermediates 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 intermediates of general formula IX, which is an alcohol. The intermediates of formula IX can be further modified to provide the desired R ³ substituent. For example, the alcohol group in intermediates 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, or the alcohol group in IX can be alkylated using simple alkyl halides such as methyl iodide in the presence of a suitable base such as NaH in a suitable solvent such as THF. Alternatively, the alcohol of intermediates IX 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 TEA in a suitable solvent such as DCM. The resulting mesylates can be reacted with a suitable nucleophile such as potassium cyanide in a suitable solvent such as DMSO.

It will be apparent to those skilled in the art that other transformations are possible from the intermediates of general formula IX; the present invention is intended to include such alternative transformations.

Carboxylic acids of general formula III can be prepared as described in Scheme 5.

Scheme 5

O o ^Ζπ · <2. THF on O ^NaOH _r 2? ^H 9 _R A _R 2 ⁺ Br^A _o ,alkyl - ^-O^o-alkyl ri^OH

X ¹¹¹

Ketones of general formula X are reacted with an alkyl bromoacetic acid ester,

- 19 048113 activated with, for example, Zn and iodine to give the corresponding aldol adduct. In an alternative procedure, the bromoacetic acid ester can be activated using Zn and TMSCl (trimethylsilyl chloride). In the final step, hydrolysis of the alkyl ester is accomplished by treatment with a suitable base such as NaOH or LiOH in a suitable solvent such as water or alcohol in water, followed by acidification with a suitable acid to give compounds of formula III.

The carboxylic acid ester of general formula IV (R = Me, Et) is commercially available or can be prepared as described in Scheme 6.

Scheme 6

R = Me, Et

Suitably substituted carboxylic acids can be activated using a suitable reagent such as CDI and subjected to a condensation reaction with potassium 3-ethoxy-3-oxopropanoate in the presence of MgCl2 to give intermediates of general formula IV.

1H NMR spectra were recorded at 400.13 MHz on a Bruker Avance III 400 or at 300.13 MHz on a Bruker Avance 300. Deuterated dimethyl sulfoxide or deuterated chloroform were used as solvent. Tetramethylsilane was used as an internal standard sample. Chemical shift values are expressed in ppm relative to tetramethylsilane. The following abbreviations are used for multiple NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, ddd = double doublet of doublets, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet, and brs = broad signal.

Chromatographic systems and methods for assessing chemical purity (LCMS methods) and chiral purity (SFC and HPLC methods) are described below.

LCMS Method 1. Device: Agilent 1200 LCMS system with E1S detector.

Column Waters XBridge C18, 50 x 2 mm, 5 µm Flow rate 0.8 ml/min. Run time 4.5 min. Wavelength 2 54 nm Tempo, columns: 50°С. Ion source ESI Solvent A Water + 0.04% TEA Solvent B MeCN + 0.02% TEA Gradient Time (min.) A% IN% 0 99 1 3,4 0 100 4 0 100 4.01 99 1 4,5 99 1

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LCMS Method 2. Device: Agilent 1200 LCMS system with ElS detector.

Column Waters XBridge ShieldRP18, 50 x 2.1 mm, 5 µm Flow rate 0.8 ml/min. Run time 4.5 min. Wavelength 2 54 nm Tempo, columns: 40°С. Ion source ESI Solvent A Water + 0.05% NH3.H2O Solvent B MeCN Gradient Time (min.) A% IN% 0 95 5 3,4 0 100 4 0 100 4.01 95 5 4,5 95 5

LCMS Method 3. Device: Agilent 1200 LCMS system with E1S detector.

Column Waters XBridge C18, 50 x 2 mm, 5 µm Flow rate 0.8 ml/min. Run time 4.5 min. Wavelength 2 54 nm Tempo, columns: 50°С. Ion source ESI Solvent A Water + 0.04 % TEA Solvent B MeCN + 0.02% TEA Gradient Time A% IN% (min.) 0 90 10 3, 4 0 100 4 0 100 4, 01 90 10 4,5 90 10

LCMS Method 4. Device: Shimadzu LC20ADXR LCMS system with ESI detector.

Column Poroshell NRN-S18, 50x2.7 mm, 3 microns Flow rate 1.2 ml/min. Run time 3 min. Wavelength 190-400 nm Tempo, columns: 40°С. Ion source ESI Solvent A Water + 0.04% NH4HCO3 Solvent B MeCN Gradient Time (min.) A% IN% 0 95 5 2,2 5 95 2.8 5 95 3 95 5

Chiral methods of analysis.

SFC Method 1. Device: Waters UPC2

Column Chiralpak AD-3 150 > internal diameter, 3 µm < 4.6 mm Flow rate 2.5 ml/min.

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Run time 8 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A EtOH + 0.05% diethylamine Gradient Time (min.) A% 0 5 4,5 40 7 40 7.01 5 8 5

SFC Method 2. Device: Agilent 1260

Column (S,S)Whelk-01 100x4.6 mm inner diameter, 5 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A EtOH + 0.05% diethylamine Gradient Time (min.) A% 0 5 5, 5 40 5, 51 5 7 5

SFC Method 3. Device: Agilent 1260

Column Chiralpak AS-3 150 χ 4.6 mm internal diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 40°С Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 5, 5 40 5, 51 5 7 5

SFC Method 4. Device: Agilent 1260

Column Chiralpak AD-3 150 χ 4.6 mm internal diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A iPrOH + 0.05% diethylamine Gradient Time A% 0 5 5, 5 40 5, 51 5 7 5

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SFC Method 5. Device: Agilent 1260

Column Lux Cellulose-2 150x4.6 mm internal diameter, 3 microns Flow rate 2.5 ml/min. Run time 10 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A MeOH + 0.05% diethylamine Gradient Time A% 0 5 5, 5 40 8.5 40 8.51 5 10 5

SFC Method 6. Device: Agilent 1260

Column Chiralpak AD-3 150 χ 4.6 mm internal diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A EtOH + 0.05% diethylamine Gradient Time (min.) A% 0 5 5, 5 40 5, 51 5 7 5

SFC Method 7. Device: Waters UPC2

Column Chiralpak AS-3 150 χ 4.6 mm internal diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 35°С Solvent A EtOH + 0.05% diethylamine Gradient Time (min.) A% 0 5 5 40 5, 5 40 7 5

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SFC Method 8. Device: Waters UPC2

Column ChiralPak AD-3 150x4.6 mm inner diameter, 3 µm Flow rate 2.5 ml/min. Run time 10 min. Wavelength 210 nm Tempo, columns: 35°С. Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 7.5 40 7.51 5 10 5

SFC Method 9. Device: Waters UPC2

Column Chiralcel OJ-3 150x4.6 mm inner diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A MeOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 5, 5 5 7 5

SFC Method 10. Device: Agilent, 1260

Column Chiralpak AY-3 150 χ 4.6 mm internal diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 5, 5 40 5, 51 5 7 5

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SFC Method 11. Device: Agilent 1260

Column (R,R)Whelk-01 100x4.6 mm inner diameter, 3 µm Flow rate 2.5 ml/min. Run time 10 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A MeOH + 0.05% diethylamine Gradient Time (min.) A% 0 5 5, 5 40 8.5 40 8.51 5 10 5

SFC Method 12. Device: Waters UPC2

Column (S,S)Whelk-01 100x4.6 mm inner diameter, 3 µm Flow rate 2.8 ml/min. Run time 8 min. Wavelength 2 54 nm Tempo, columns: 35°С. Solvent A 1PgOH + 0.05% diethylamine Gradient Time (min.) A% 0 5 4 40 6, 5 40 8.51 5 8 5

SFC Method 13. Device: Waters UPC2

Column ChiralPak AS-3 150x4.6 mm ID, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A iPrOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 5, 5 5 7 5

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SFC Method 14. Device: Waters UPC2

Column ChiralPak IG-3 100x4.6 mm inner diameter, 3 µm Flow rate 2.8 ml/min. Run time 8 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 4 40 6, 5 40 6, 51 5 8 5

Method SFC 15. Device: Waters UPC2

Column Cellulose-2 150x4.6 mm inner diameter, 5 µm Flow rate 2.5 ml/min. Run time 10 min. Wavelength 2 54 nm Tempo, columns: 35°С. Solvent A iPrOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 7.5 40 7.51 5 10 5

Method SFC 16. Device: Waters UPC2

Column Cellulose-2 150x4.6 mm inner diameter, 5 µm Flow rate 2.5 ml/min. Run time 10 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 7.5 40 7.51 5 10 5

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SFC Method 17. Device: Waters UPC2

Column Cellulose-2 150x4.6 mm inner diameter, 5 µm Flow rate 2.5 ml/min. Run time 10 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A MeOH + 0.05% diethylamine Gradient Time A% 0 5 5 40 7.5 40 7.51 5 10 5

Method SFC 18. Device: Agilent.

Column Lux Cellulose-4 100x4.6 mm internal diameter, 3 microns Flow rate 2 ml/min. Run time 6.5 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A EtOH Gradient Time A% 0 5 2 20 5 20 6, 5 5

Method SFC 19. Device: Agilent

Column Chiralpak OD-3 150x4.6 mm inner diameter, 3 µm Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 5, 5 40 5, 51 5 7 5

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Method SFC 20. Device: Waters UPC2

Column ChiralPak AD-3 150x4.6 mm inner diameter, 3 µm Flow rate 2.5 ml/min. Run time 10 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A EtOH + 0.05% diethylamine Gradient Time A% 0 5 5 5 5, 5 40 7.5 40 7.51 5 10 5

Method SFC 21.

Device: Waters UPC2

Column Cellulose 2 100x4.6 mm inner diameter, 3 µm Flow rate 2.8 ml/min. Run time 8 min. Wavelength 22 0 nm Tempo, columns: 35°С. Solvent A MeOH + 0.05% diethylamine Gradient Time A% 0 5 4 40 6, 5 40 6, 51 5 8 5

Method SFC 22.

Device: Agilent 1260

Column Lux Cellulose-2 150x4.6 mm internal diameter, 3 microns Flow rate 2.5 ml/min. Run time 7 min. Wavelength 22 0 nm Tempo, columns: 40°С. Solvent A MeOH + 0.05% diethylamine Gradient Time A% 0 5 5, 5 40 5, 51 5 7 5

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Chiral HPLC Method 1. Device: SHIMADZU LC-20AB

Column Chiralpak AS-RH 150*4.6 mm inner diameter, 5 microns Flow rate 0.8 ml/min. Run time 25 min. Wavelength 22 0 nm Tempo, columns: 30°С. Solvent A Water + 0.069% TFA Solvent B MeCN Gradient Time (min.) A% IN% 0 90 10 25 20 80

Chiral HPLC Method 2. Device: SHIMADZU LC-20AB

Column ChiralCel OD-RH 150x4.6 mm internal diameter, 5 µm Flow rate 0.8 ml/min. Run time 25 min. Wavelength 22 0 nm Tempo, columns: 30°С. Solvent A Water + 0.07% TFA Solvent B MeCN Gradient Time A% IN% 0 90 10 14 20 80 15 90 10 25 90 10

Chiral HPLC Method 3. Device: SHIMADZU LC-20AB

Column ChiralCel OD-RH 150x4.6 mm internal diameter, 5 µm Flow rate 0.8 ml/min. Run time 25 min. Wavelength 22 0 nm Tempo, columns: 100°С. Solvent A Water + 0.07% TFA Solvent B MeCN Gradient Time A% IN% 0 90 10 14 20 80 15 90 10 25 90 10

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Chiral HPLC Method 4. Device: SHIMADZU LC-20AB

Column ChiralPak AD-RH 150x4.6 mm internal diameter, 5 µm Flow rate 0.8 ml/min. Run time 25 min. Wavelength 22 0 nm Tempo, columns: 30°С. Solvent A Water + 0.07% TFA Solvent B MeCN Gradient Time A% IN% 0 90 10 14 20 80 15 90 10 25 90 10

Obtaining intermediate compounds.

IIb: (^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine

Step 1. Obtaining ethyl 2-[^)-tert-butylsulfinyl]iminoacetate

To a solution of ethyl 2-oxoacetate (7.5 g, 36.7 mmol) and ((S)-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol) in DCM (150 mL) was added _CuSO4 (12.9 g, 80.8 mmol), and the reaction mixture was stirred at 25 °C for 24 h. The solid was filtered, 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).

Step 2. Obtaining ethyl (2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3(trifluoromethoxy)phenyl]acetate

To a solution of ethyl 2-[^)-tert-butylsulfinyl]iminoacetate (trifluoromethoxy)phenyl]boronic acid (8.4 g, 40.9 mmol) (7 g, 34.1 mmol) and [3 in dioxane (100 ml) was added

[Rh(COD)(MeCN) ₂ ]BF ₄ (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 yield 9.8 g (78%).

Step 3. Obtaining ethyl (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate hydrochloride

To a solution of ethyl (2R)-2-[[^)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate

- 30 048113 (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 and then concentrated to give ethyl (2R)-2-amino-2-[3(trifluoromethoxy)phenyl]acetate (7.8 g, crude).

Step 4. Obtaining ethyl-(^)-2-((tert-butoxycarbonyl)amino)-2-(3(difluoromethoxy)phenyl)acetate

To a mixture of ethyl (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate hydrochloride (6 g) in THF (150 ml) and Boc ₂ O (8.7 g) was added NaHCO ₃ (1.7 g), and stirring was carried out at 25 °C for 16 h. The mixture was concentrated and purified by silica chromatography (petroleum ether:ethyl acetate = 10:1) to give the product (7.2 g).

Step 5. Obtaining tert-butyl-^)-(1-(3-(difluoromethoxy)phenyl)-2-hydroxyethyl)carbamate

To a suspension of LiAlH ₄ (1.7 g) in THF (200 ml) was added ethyl ((t)-2-((tert-butoxycarbonyl)amino)-2-(3-(difluoromethoxy)phenyl)acetate (4 g) in THF (25 ml) under ice-cooling. The reaction mixture was warmed to 25°C and stirred for 2 h. Anhydrous magnesium sulfate was added, followed by the successive addition of one drop of water and ethyl acetate. The insoluble materials were filtered through a pad of celite. The filtrate was concentrated and purified by silica chromatography (petroleum ether:ethyl acetate = 5:1) (2.1 g).

Step 6. Obtaining tert-butyl-^)-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of tert-butyl ((D))-(1-(3-(difluoromethoxy)phenyl)-2-hydroxyethyl)carbamate (1.5 g) in MeCN (20 mL) was added CuI (360 mg), and stirring was performed at 25 °C under N ₂ for 30 min. A solution of 2,2-difluoro-2-fluorosulfonylacetic acid (1.7 g) in MeCN (5 mL) was added at 45 °C over 30 min, and the reaction mixture was stirred at 45 °C for 1 h. The mixture was concentrated, then diluted with ethyl acetate (100 mL), filtered, and concentrated to give the desired product (1.5 g, crude).

Step 7. Obtaining (^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine

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

- 31 048113

Prepared as described for 11b using appropriate reagents.

IIc: (^)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1. Obtaining 4-methyl-N'-(p-tolylsulfonyl)benzenesulfonohydrazide

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 and the reaction mixture was stirred at 0 °C for 1 h and at 20 °C for 7 h. Water (200 ml) and methyl tert-butyl ether (METB) (200 ml) were added to the mixture and it was filtered. The filter cake was washed with METB (200 ml) and dried to give 4-methyl-N-(ptolylsulfonyl)benzenesulfonohydrazide (125 g).

1H NMR (DMSO- _d6 , 400 MHz): δ 9.55 (s, 2H), 7.61 (d, 4H), 7.35 (d, 4H), 2.36 (s, 6H).

Step 2. Obtaining 2-bromo-1-(3-(difluoromethoxy)phenyl)ethan-1-one

To a solution of 1-[3-(difluoromethoxy)phenyl]ethanone (10 g) in dioxane (100 ml) was added a solution of Br2 (8.58 g) in dioxane (100 ml). The resulting mixture was stirred at 20 °C for 2 h. Saturated aqueous _NaHCO3 (50 ml) and _H2O (100 ml) were added, and the aqueous phase was extracted with EtOAc (200 ml x 2).

The organic phase was washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated to give 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (17 g).

1H NMR (CDCl3, 400 MHz): δ 7.81 (d, 1H), 7.72 (s, 1H), 7.49 (t, 1H), 7.37 (d, 1H), 6.56 ( t, 1H), 4.41 (s, 2H).

Step 3. Obtaining 1-(3-(difluoromethoxy)phenyl)-2-iminoethan-1-one o

Vg

TsNHNHTs

DBU, THF o

To a solution of 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (5.6 g) and 4-methyl-N-(ptolylsulfonyl)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 sat. aq. NaHCO ₃ (200 mL) and diluted with water (200 mL), then extracted with EtOAc (200 mL x 2). The organic layer was washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (20% EtOAc in petroleum ether) to give 1-(3-(difluoromethoxy)phenyl)-2-iminoethan-1-one (6.4 g).

1H NMR (CDCl3, 400 MHz): δ 7.57 (dt, 1H), 7.55 (s, 1H), 7.46 (t, 1H), 7.31 (dd, 1H), 6.56 ( t, 1H), 5.90 (s, 1H).

Step 4. Obtaining 2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one

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) and diluted with

- 32 048113 with H2O (50 mL) and then extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (200 mL x 2), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (5% EtOAc in petroleum ether) to give 2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-one (6.1 g).

1H NMR (CDC13, 400 MHz): δ 7.76 (d, 1H), 7.68 (s, 1H), 7.47 (t, 1H), 7.34 (d, 1H), 6.55 ( t, 1H), 4.74 (s, 1H), 3.55-3.50 (m, 1H), 0.70-0.66 (m, 2H), 0.53-0.49 (m, 2H).

Step 5. Obtaining methylpropane-2-sulfinamide (R, Z)-\-(2-iiuk.ioi ipoi 1oxy-1 -(3 -(difluoromethoxy)phenyl)ethylidene)-2-

To a solution of 2-(cyclopropoxy)-1-[3-(difluoromethoxy)phenyl]ethanone (6.1 g) and ((S)-2-methylpropane-2-sulfinamide (4.6 g) in THF (100 ml) was added Ti(OEt)4 (11.5 g). The resulting mixture was stirred at 60°C for 8 h and then used directly in the next step.

Step 6. Obtaining (^)-N-(^)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (2-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide in THF (150 mL) from the previous step was added dropwise a solution of L-selectride (1 M in THF, 50.36 mL) at -45 °C. The mixture was stirred at -45 °C for 1 h and quenched with MeOH (100 mL) and H2O (100 mL) and filtered on Celite. _The filtrate was extracted with EtOAc (200 mL x 2), the organic layer was washed with brine (200 mL x 2), dried over _Na2SO4 and concentrated.

The crude product was purified by column chromatography (30~50% EtOAc in petroleum ether) to give (N)-(N)-(N)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (2.4 g).

Step 7. Preparation of (^)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

To a solution of (N)-(N)-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 (N)-2-(cyclopropoxy)-1-[3(difluoromethoxy)phenyl]ethanamine hydrochloride (0.46 g, crude).

IId: (^)-2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Prepared as described for IIc using 1-[3-(trifluoromethoxy)phenyl]ethanone as starting material.

IIe: (^)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-amine hydrochloride

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To a solution of 1-[3-(difluoromethoxy)phenyl]ethanone (5 g) in dioxane (50 ml) was added a solution of Br2 (4.29 g) in dioxane (50 ml) at 20 °C. This mixture was stirred at 20 °C for 1 h, then diluted with EtOAc (200 ml) and washed with water (100 ml x 3). The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1) to give 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (5 g).

Step 2. Obtaining 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-one

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, then 2-bromo-1-[3-(difluoromethoxy)phenyl]ethanone (2.5 g, 9.43 mmol) and KI (157 mg) were added to this solution at 0 °C and the temperature was adjusted to 20 °C and stirred for 16 h. The mixture was diluted with EtAOc (100 mL) and washed with water (50 mL x 3). The organic phase was concentrated to give the product, which was purified by acidic preparative HPLC (1.4 g).

^1H NMR ( _CDCl3 , 400 MHz): δ 7.72 (d, 1H), 7.66 (s, 1H), 7.51 (t, 1H), 7.40 (d, 1H), 6. 56 (t1H), 5.13 (s, 2H). 19F NMR (CDCl ₃ , 400 MHz): δ -61.11, -81.52, -81.71.

Stage 3. Obtaining da-Щ1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethylidene)-2methylpropane-2-sulfinamide

A mixture of 1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1-one (900 mg), (I)-2-methylpro11ane-2sulfinamide (606 mg) and Ti(OEt) ₄ (2.28 g) in THF (50 mL) was stirred at 60°C under N2 for 16 h.

The product (1.2 g, crude) in THF (70 ml) was obtained and used directly in the next step.

Step 4. Obtaining (^)-N-(^)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2methylpropane-2-sulfinamide

To a solution of (I)-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 and then diluted with EtOAc (100 mL) and washed with water (50 mL x 3). The organic phase was dried, filtered and concentrated. The crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1) to give da-N-(da-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2-sulfinamide (600 mg).

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1H NMR ( _CDCl3 , 400 MHz): δ 7.37 (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).

Step 5. Obtaining hydrochloride (^)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethan-1amine

To a solution of (R)-N-((R)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-2-methylpropane-2sulfinamide (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 ( _CDCl3 , 400 MHz): δ 9.17 (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).

IIf: (R)-2-(trifluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Prepared as described for IIe using 1-[3-(trifluoromethoxy)phenyl]ethanone as starting material.

1H NMR (CDCl3, 400 MHz): δ 9.18 (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).

IIg: ^)-1-(3-(difluoromethoxy)phenyl)butan-1-amine hydrochloride

Step 1. Obtaining (^)-N(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a solution of 3-(difluoromethoxy)benzaldehyde (3 g) and ((S)-2-methylpropane-2-sulfinamide (2.54 g) in DCE (120 ml) was added CuSO ₄ (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 ₂ , petroleum ether/ethyl acetate = 100/1 to 10:1) to give the product (3 g).

Step 2. Obtaining (^)-N(^)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2sulfinamide

To a solution of (3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (1 g) in DCM (40 mL) was slowly added allylmagnesium bromide (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 adding saturated NH4Cl solution (10 mL) at 0 °C, then diluted with _H2O (50 mL) and extracted with DCM (40 mL x 3). _The combined organic phases were washed with _H2O (40 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 1:2) to give (R)-N(^)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (580 mg).

1H NMR (CDCl3, 400 MHz): δ 7.31 (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).

Step 3. Obtaining (^)-N(^)-1-(3-(difluoromethoxy)phenyl)butyl)-2-methylpropane-2-sulfinamide

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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 N2. The suspension was degassed under vacuum and purged with _H2 several times. The mixture was stirred under _H2 (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).

Step 4. Obtaining hydrochloride (^)-1-(3-(difluoromethoxy)phenyl)butan-1-amine

To a solution of (N)-(N)-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 (N)-1-[3-(difluoromethoxy)phenyl]butan-1-amine hydrochloride (250 mg).

IIh: (S)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride

Step 1. Obtaining 1-(difluoromethoxy)-3-vinylbenzene

K ₂ CO ₃ , DME

To a solution of methyltriphenylphosphonium iodide (7.05 g) in DME (50 ml) was added K ₂ CO ₃ (2.41 g). The resulting mixture was stirred at 20 °C for 1 h, 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 (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to give 1(difluoromethoxy)-3-vinylbenzene (1.4 g).

^1H NMR (CDCl3, 400 MHz): δ 7.32 (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).

Step 2. Obtaining 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one

To a solution of 1,1-difluoro-2-iodoethane (1 g), 1-(difluoromethoxy)-3-vinylbenzene (1.33 g), 6uc[(Z)-1methyl-3-oxobut-1-enoxy]copper (273 mg) and Ag ₂ SO ₄ (325 mg) in ACN (20 mL) were added Et ₃ N (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 mixture was quenched with saturated aqueous Na ₂ S ₂ O ₃ and extracted with DCM (10 mL x 3). The organic phases were combined, washed with brine (5 mL x 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to give 1-(3(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one (300 mg).

1H NMR (CDCl3, 400 MHz): δ 7.82 (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).

Stage 3. Obtaining ^^-i-^^-^ifluoromethox^phenyl^D-difluorobutylidene^-methylpropane-2-sulfinamide

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To a solution of 1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-one (300 mg) and (N)-2-methylpropane-2sulfinamide (218 mg) in THF (10 ml) was added Ti(OEt) ₄ (547 mg). The mixture was stirred at 60°C for 6 h. The reaction mixture was used directly in the next step.

Step 4. Obtaining N[(^)-1-[3-(difluoromethoxy)phenyl]-4,4-difluorobutyl]-2-methylpropane-2sulfinamide

L-selectride (1 M in THF, 3.59 mL) was added to a solution of (1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutylidene)-2-methylpropane-2-sulfinamide (423 mg) in THF at -48°C.

The reaction mixture was stirred for 0.5 h, then its temperature was brought to 0°C and _H2O (~10 ml) was added.

The resulting mixture was extracted with EtOAc (35 mL x 2). The organic extracts were washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to give N[(^)-1-[3-(difluoromethoxy)phenyl]-4,4-difluorobutyl]-2-methylpropane-2-sulfinamide (140 mg).

Step 5. (^)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride

^[(^)-1-[3-(difluoromethoxy)phenyl]-4,4-difluorobutyl]-2-methylpropane-2-sulfinamide (140 mg) in MeOH (10 mL) and HCl/MeOH (5 mL, 4 M) was stirred at 20°C for 1 h. The mixture was concentrated to give ^)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutan-1-amine hydrochloride (110 mg).

IIi: (^)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropan-1-amine hydrochloride

Step 1. Obtaining (S, E)^-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a solution of 3-(difluoromethoxy)benzaldehyde (5 g) and (S)-2-methylpropane-2-sulfinamide (4.22 g) in DCE (150 ml) was added CuSO ₄ (23 g). The reaction mixture was stirred at 55 °C for 20 h, then filtered and concentrated. The crude product was purified by silica chromatography (SiO ₂ , 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 ( _CDCl3 , 400 MHz): δ 8.55 (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).

Step 2. Obtaining ^)-^(^)-1-(3-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2sulfinamide

To a solution of (E)-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2 g) in DCM (60 mL) was slowly added allylmagnesium bromide (1 M solution in THF, 21.79 mL) at 0°C. The reaction

- 37 048113 the mixture was stirred at 0 °C for 1 h and at 25 °C for 2 h. The reaction mixture was quenched by adding sat. aq. NH4Cl (10 mL) at 0 °C and then diluted with H2O (50 mL) and extracted with DCM (40 mL x 3). The combined organic phases were washed with H2O (40 mL), dried over Na2SO4, 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).

1H NMR ( _CDCi3 , 400 MHz): δ 7.31 (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).

Stage 3. sulfinamide

Preparation of ^)^-(^)-1-(3-(difluoromethoxy)phenyl)-3-oxopropyl)-2-methylpropane-2-

2,6-lutidine, dioxane/HgO

_{K2OsO4 .} 2H ₂ O, H ₂ O, NalO ₄

Potassium osmate (276 mg) was added in one portion 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 H ₂ O (3 ml). 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 x 2). The combined organic extracts were dried over Na ₂ SO ₄ . The crude reaction mixture was used directly in the next step.

Step 4. Obtaining (^)-((3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2sulfinamide

To a solution of (^)^-(^)-1-(3-(difluoromethoxy)phenyl)-3-oxopropyl)-2-methylpropane-2-sulfinamide (2 g) in DCM (200 mL) was added dropwise diethylaminosulfur trifluoride (DAST) (3.03 g) at -78 °C. The temperature of the reaction mixture was allowed to drop to 20 °C and it was stirred for 2 h. The solution was poured into saturated aqueous NaHCO ₃ solution (50 mL) and the organic phase was separated. This solution was dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to give (^)^-(^)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide (500 mg).

Step 5. Obtaining (^)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoropropan-1-amine hydrochloride

HCI/MeOH

solution h ₂ n

HCI (B)-M-((B)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-2-methylpropane-2-sulfinamide (380 mg) in MeOH (15 mL) was added HCl/MeOH (25 mL, 4 M) at 0 °C and the reaction mixture was stirred for 0.5 h and allowed to cool to 25 °C. The reaction mixture was concentrated to give (B)-1-[3-(difluoromethoxy)phenyl]-3,3-difluoropropan-1-amine hydrochloride (300 mg, crude, HCl salt). It was used directly without further purification.

IIj: ^)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1. Obtaining (^,E)-^(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

To a mixture of 3-(difluoromethoxy)benzaldehyde (2 g) and ((D))-2-methylpropane-2-sulfinamide (1.7 g) in DCE (60 mL) was added CuSO ₄ (9.3 g) at 55 °C under N2. The reaction mixture was stirred at 55 °C for

- 38 048113 for 12 h, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20:1-10:1) to give ((S,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (4.5 g).

Step 2. Obtaining (^)-Ы-(^)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of (N,E)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2 g) in DCM (30 mL) was added dropwise methylmagnesium bromide (3 M in _Et2O , 4.8 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 h and at 20°C for 16 h. The reaction mixture was quenched with aq.

saturated NH4Cl solution (10 ml) and the aqueous phase was extracted with ethyl acetate (30 ml x 3). The combined organic extracts were washed with brine (40 ml x 2), dried over anhydrous _{Na2SO4 ,} filtered, concentrated and purified by silica gel chromatography (petroleum ether/ethyl acetate = 5:1-1:1) to give (N)-(N)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (960 mg).

Step 3. Obtaining ^)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

To a solution of (^)-Ы-(^)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8 g) in

MeOH (4 mL) was added to HCl/MeOH (4 M, 2 mL). The resulting mixture was stirred at 25 °C for 3 h and concentrated to give ((D)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (1.6 g, crude).

IIk: (^)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Stage 1. Obtaining ethyl-((E)-2-((tert-butylsulfinyl)imino)acetate

To a solution of ethyl 2-oxoacetate (7.5 g) and ((E)-2-methylpropane-2-sulfinamide (4.90 g) in DCM (150 mL) under N2 was added _CuSO4 (12.9 g) and the reaction mixture was stirred at 25 °C for 24 h. The solid was filtered, washed with ethyl acetate (50 mL) and the organic layer was concentrated. The residue was purified by chromatography ( _SiO2 , hexane/ethyl acetate, 5/1) to give ethyl ((E)-2-((tert-butylsulfinyl)imino)acetate (5 g).

Step 2. Obtaining ethyl (^)-2-((^)-tert-butylsulfinyl)amino)-2-(3(trifluoromethoxy)phenyl)acetate

To a solution of ethyl ((D,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 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 ₂ , petroleum ether:EtOAc = 6:1) to give ethyl ((D)-2-((D)-tert-butylsulfinyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (5.1 g).

Step 3. Obtaining ethyl (^)-2-amino-2-(3-(trifluoromethoxy)phenyl)acetate

- 39 048113

To a solution of ethyl ((N)-2-((N)-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 (N)-2-amino-2-(3(trifluoromethoxy)phenyl)acetate as a hydrochloride salt (3.3 g).

Step 4. Obtaining ethyl-^)-2-((tert-butoxycarbonyl)amino)-2-(3(trifluoromethoxy)phenyl)acetate

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

Step 5. Obtaining tert-butyl-^)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a suspension of LiAlH4 (2.1 g) in THF (200 ml) was added ethyl ((t)-2-((tert-butoxycarbonyl)amino)-2(3-(trifluoromethoxy)phenyl)acetate (5 g) in THF (20 ml) under ice-cooling, and the mixture was stirred at 0 to 25°C for 2 h. Anhydrous magnesium sulfate was added, followed by the addition of water (5 ml) and ethyl acetate (100 ml), and the insoluble materials were 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 ((t)-(2-hydroxy-1(3-(trifluoromethoxy)phenyl)ethyl)carbamate (3.37 g).

Step 6. Obtaining tert-butyl-^)-(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of tert-butyl ((3-)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (1 g) in hexane (15 mL) were added diethyl sulfate (960 mg), tetrabutylammonium chloride (TBAC) (87 mg), and a solution of NaOH (324 mg) in H ₂ O (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 Na ₂ SO ₄ , and concentrated. The crude product was purified by chromatography (SiO ₂ , 10% ethyl acetate in petroleum ether) to give tert-butyl ((3-trifluoromethoxy)phenyl)ethyl)carbamate (5.9 g).

Step 7. Obtaining (^)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

- 40 048113

To a solution of tert-butyl ((1\)-(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 at 25 °C for 16 h. The solution was concentrated to give ((1\)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride (4.5 g).

IIl: ^)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

Step 1. Obtaining (S,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide

A mixture of 3-(trifluoromethoxy)benzaldehyde (10.0 g), (N)-2-methylpropane-2-sulfinamide (7.7 g) and CuSO ₄ (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 ₂ , gradient consisting of 0-10% ethyl acetate/petroleum ether) to give (S,E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (12.6 g).

Step 2. Obtaining (^)-2-methyl-N-(^)-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2sulfinamide

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 was added dropwise EtMgBr (3 M in Et2O, 9.1 mL). 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 aq. NH4Cl (100 mL) was added. The mixture was extracted with DCM (100 mL _x 2), the phases were separated and the organic layer was washed with brine (200 mL), dried over _Na2SO4 and concentrated. The residue was purified by chromatography (SiO ₂ , gradient included 0-50% ethyl acetate/petroleum ether) to give the product (1.4 g).

Step 3. Obtaining ^)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

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).

IIm: (^)-3-amino-3-(3-(trifluoromethoxy)phenyl)propanenitrile hydrochloride

Step 1. Obtaining tert-butyl-(^)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate.

This intermediate was prepared as described for intermediate IIk, steps 1-5.

Step 2. Obtaining ^)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)- 41 048113 ethyl methanesulfonate

To a solution of tert-butyl (N)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (2 g) in DCM (20 mL) was added Et ₃ N (756 mg), followed by the addition of 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 anhydrous Na ₂ SO ₄ , filtered and concentrated to give (N)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)ethyl methanesulfonate (2.50 g, crude), which was used in the next step without further purification.

Step 3. Obtaining (^)-3-amino-3-(3-(trifluoromethoxy)phenyl)propanenitrile hydrochloride

To a solution of ((t)-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% Na ₂ CO ₃ solution (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 4/1) to give tert-butyl ((3-(trifluoromethoxy)phenyl)ethyl)carbamate (665 mg).

1H NMR (400 MHz, CDCl·/): δ 7.46 (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) .

To a solution of tert-butyl ((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. Then, the reaction mixture was concentrated to give ((3-trifluoromethoxy)phenyl)propanenitrile hydrochloride (280 mg, crude).

IIn: hydrochloride (^)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile N Ί ¹

G F

A DH DF

HCl F

Step 1. Preparation of (R, E)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide o II

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 ₄ (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 ₂ , 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).

Step 2. Obtaining ethyl (^)-3-((^)-tert-butylsulfinyl)amino)-3-(3(trifluoromethoxy)phenyl)propanoate

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 filtrates were concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 5/1) to give ethyl (5)-3-((^)-tert-butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7 g, crude).

- 42 048113

1H NMR (CDC13, 400 MHz): δ 7.36 (t, 2H), 7.20 (s, 1H), 7.14 (d, 1H), 5.78 (d, 1H), 5.14- 5.10 (m, 1H), 4.14-4.10 (t, 2H), 3.05-2.89 (m, 2H), 1.31 (s, 9H), 1.18 (t, 3H).

Stage 3. Obtaining ^)-^(^)-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2sulfinamide o on

To a solution of ethyl (R)-3-((R)-tert-butylsulfinyl)amino)-3-(3-(trifluoromethoxy)phenyl)propanoate (7 g) in THF (70 mL) was added LiAlH4 (696 mg) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h and then quenched by successive addition of H ₂ O (0.7 mL), 10% NaOH solution (0.7 mL), and H ₂ O (2.1 mL) at 0 °C. The mixture was filtered. The residue was concentrated to give crude (R)-N(R)-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2-sulfinamide (4.2 g).

Step 4. Obtaining (^)-3-amino-3-(3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride

Crude (^)-^(^)-3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)-2-methylpropane-2sulfinamide (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 (^)-3-amino-3-(3-(trifluoromethoxy)phenyl)propan-1-ol hydrochloride (3.2 g, crude).

Step 5. Obtaining tert-butyl-^)-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate

OH OH ___________ I O S ^H 2N'7f^V°><^ NaHCO ₃ THF

NS! [IJ f ^h ' ^H O F ^h

Crude ethyl ((N)-3-((N)-tert-butylsulfinyl)amino)-3-(3(trifluoromethoxy)phenyl)propanoate from the previous reaction step (3.2 g) was dissolved in THF (35 mL) and Boc ₂ O (10.28 g) and NaHCO ₃ (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), extracted with DCM (100 mL x 3), and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 2/1) to give tert-butyl ((3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (3.2 g).

Step 6. Obtaining ^)-3-((tert-butoxycarbonyl)amino)-3-(3(trifluoromethoxy)phenyl)propyl methanesulfonate

To a solution of tert-butyl ((N)-(3-hydroxy-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate (1 g) in DCM (30 mL) were added Et3N (905 mg) and methanesulfonyl chloride (683 mg) at 0 °C. The reaction mixture was stirred at 20 °C for 16 h and then washed with ice water (15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give ((N)-3-((tert-butoxycarbonyl)amino)-3-(3-(trifluoromethoxy)phenyl)propyl methanesulfonate (1.2 g).

Step 7. Preparation of tert-butyl-^)-(3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)carbamate

The (^)-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 and then diluted with 10% Na ₂ CO ₃ solution (40 mL) and extracted with EtOAc (70 mL x 3). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum

- 43 048113 ether/ethyl acetate from 1/0 to 3/1) to obtain tert-butyl-(^)-(3-cyano-1-(3(trifluoromethoxy)phenyl)propyl)carbamate (990 mg).

Step 8. Obtaining (^)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride

To a solution of 1ret-butyl ((5)-(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 (5)-4-amino-4-(3-(trifluoromethoxy)phenyl)butanenitrile hydrochloride (850 mg).

IIo: (^)-3,3-difluoro-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

Prepared as described for Hi, using 3-(trifluoromethoxy)benzaldehyde as starting material.

IIp: (^)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

Stage

1.

(trifluoromethoxy)phenyl)acetate

Preparation of ethyl-^)-2-((tert-butoxycarbonyl)amino)-2-(3-

This intermediate was prepared as described for Ilk, steps 1-4.

Step 2. Obtaining 1ret-butyl-^)-(2-hydroxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of ethyl ((t)-2-((tert-butoxycarbonyl)amino)-2-(3-(trifluoromethoxy)phenyl)acetate (10 g) in EtOH (90 mL) was added NaBH4 (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 ( _SiO2 , petroleum ether/ethyl acetate = 1/0 to 3/1) to give the product (13.6 g).

^1H NMR ( _CDCl3 , 400 MHz): δ 7.39 (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).

Step 3. Obtaining tert-butyl-^)-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate

To a solution of 1-ret-butyl ((3-)-(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 stirred 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 x 3) and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate

- 44 048113 = from 0/1 to 5/1) to obtain tert-butyl-(^)-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)carbamate (3.2 g).

^1H NMR (CDCl3, 400 MHz): δ 7.36 (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).

Step 4. Obtaining (^)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride

To a solution of tert-butyl ((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).

IIIa: (^)-3-hydroxy-4,4-dimethylpentanoic acid

Obtained in accordance with available literature data, as described in Wang Z. et al: Tetrahedron: Asymmetry 10 (1999) 225-228.

IIIb: 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid

Step 1. Obtaining ethyl 2-(3,3-difluoro-1-hydroxycyclobutyl)acetate

To a solution of 3,3-difluorocyclobutanone (0.2 g), Zn (198 mg) and I ₂ (10 mg) in THF (13 ml) under N 2 atmosphere was added dropwise ethyl 2-bromoacetate (378 mg). The mixture was stirred at 55 °C for 6 h. H ₂ SO ₄ (10%, 10 ml) was carefully added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate (20 ml x 3).

The organic extract was washed with _NaHCO3 (sat. aq., 10 mL), dried over _Na2SO4 and concentrated. _The crude product (0.26 g) was used directly without further purification.

Step 2. Obtaining 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid

To a solution of ethyl 2-(3,3-difluoro-1-hydroxycyclobutyl)acetate (0.26 g) in MeOH (10 mL) and H ₂ O (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 pH 1-2. The residue was diluted with brine (10 mL) and extracted with methyl tert-butyl ether (30 mL x 5). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude product (0.24 g) was used without further purification.

IIIc: 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid

Step 1. Obtaining ethyl 3-(1-fluorocyclopropyl)-3-hydroxybutanoate

A solution of 1-(1-fluorocyclopropyl)ethanone (0.5 g), Zn (512 mg) and 1 g (62 mg) in THF (30 ml) was stirred at 20 °C until the solution became colourless 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

- 45 048113

The reaction mixture was washed with 10% aq. H2SO4 (20 mL) and extracted with EtOAc (50 mL x 2). The organic extracts were washed with brine (100 mL), dried over _Na2SO4 and concentrated to give ethyl 3-(1-fluorocyclopropyl)-3-hydroxybutanoate (0.83 g _, crude).

Step 2. Obtaining 3-(1-fluorocyclopropyl)-3-hydroxybutanoic acid

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 H2O (3 mL). The reaction mixture was stirred at 20 °C for 2 h and then extracted with EtOAC (50 mL x 2). The aqueous layer was acidified with 10% HCl to pH 3 and extracted with EtOAC (50 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over _Na2SO4 and concentrated to give 3-( ₁ -fluorocyclopropyl)-3-hydroxybutanoic acid (0.57 g, crude).

IIId: 3-cyclopropyl-3-hydroxybutanoic acid

Step 1. Obtaining methyl 3-cyclopropyl 3-hydroxybutanoate

Zn (12.4 g) in THF (150 ml) was added to TMSCl (1.3 g) and the resulting mixture was stirred at 20 °C for 15 min and then heated to 70 °C. The heating was stopped and methyl 2-bromoacetate (21.8 g) was added dropwise at such a rate that the solvent was subjected to gentle reflux. The resulting mixture was stirred at 70 °C for 1 h and at 20 °C for 1 h, then a solution of 1-cyclopropylethanone (10 g) in THF (50 ml) was added. The reaction mixture was stirred at 20 °C for 16 h. The mixture was poured into NH3-H2O on ice (100 ml, 28%) and extracted with ethyl acetate (150 ml x 2). The organic extract was washed with water (150 ml) and brine (150 ml), dried over Na ₂ SO ₄ and concentrated to give the desired product (8.9 g, crude).

Step 2. Obtaining 3-cyclopropyl-3-hydroxybutanoic acid

YN.N ₂ O

O' thf/h ₂ o

He

A mixture of crude methyl 3-cyclopropyl 3-hydroxybutanoate (8.9 g) and LiOH _H2O (11.8 g) in THF (100 mL) and _H2O (50 mL) was stirred at 20 °C for 16 h. _H2O (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 2). The organic extracts were removed. The aqueous layer was adjusted to pH ~5 with 2 N HCl, extracted with ethyl acetate (100 mL x 3), and the combined organic fractions were washed with brine (100 mL x 10), dried over _{Na2SO4 ,} filtered, and concentrated to give the desired product in 30% overall yield (5.1 g).

^1H NMR (400 MHz, CDCl ₃ ) δ 2.67-2.51 (m, 2H), 1.25 (s, 3H), 0.90-1.00 (m, 1H), 0.33- 0.50 (m, 4H).

IIIe: 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

Step 1. Obtaining ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate

To a mixture of Zn (6.9 g) and I2 (89 mg) in THF (80 mL) were 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 H ₂ SO ₄ (100 mL, 10% aq.). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic extract was washed with brine (15 mL) and dried over Na ₂ SO ₄ , filtered and concentrated. The product (11.00 g, crude) was obtained and used directly without further purification.

Step 2. Obtaining 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

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A mixture of ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate (11 g, crude) and NaOH (4.1 g) in H2O (150 mL) was stirred at 15 °C for 16 h. The pH was adjusted to ~2 with sat. KHSO4 at 0 °C and the mixture was extracted with ethyl acetate (200 mL x 3). _The combined organic extract was washed with brine (300 mL), dried over _Na2SO4 , filtered and concentrated to give the product (10 g, crude).

The following compounds were prepared by the same procedure as described for IIIe, using the appropriate starting materials.

IIIf: 3-hydroxy-3,4-dimethylpentanoic acid

Ϋ' ¹³¹⁴ H* ^ΌΗ ¹ H NMR (CDCl3, 400 MHz): δ 2.65-2.46 (m, 2H), 2.09 (s, 1H), 1.85-1.76 (m, 1H), 1.20 (s, 3H), 0.93 (dd, 6H).

IIIg: 3-hydroxy-3,5-dimethylhexanoic acid

I OH O ¹ H NMR (CDCl ₃ , 400 MHz): δ 2.64-2.50 (m, 2H), 1.85-1.79 (m, 1H), 1.49 (d, 2H), 1.32 (s, 3H), 1.03-0.97 (m, 6H).

IIIh: 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoic acid OH O

Stage 1. Obtaining ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoate oo on o

II II NaBH ₄ I II

G/^° MeOH *

To a solution of ethyl 3-(3,3-dimethylcyclobutyl)-3-oxopropanoate (IVd) (1 g) in MeOH (8 ml) was added NaBH4 (95 mg). The mixture was stirred at 0 °C for 10 min and quenched by addition of _H2O (1 ml), concentrated and then diluted with EtOAc (30 ml), dried _{over Na2SO4} , filtered and evaporated. The residue was purified by chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 4/1) to give ethyl 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoate (907 mg).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 4.70 (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).

Step 2. Obtaining 3-(3,3-dimethylcyclobutyl)-3-hydroxypropanoic acid

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 H ₂ O (5 mL). The mixture was stirred at 25 °C for 4 h. The reaction mixture was added 10% HCl solution to achieve pH 3-4, then it was diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL x 2), the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 3-(3,3-dimethylcyclobutyl)-3hydroxypropanoic acid (760 mg).

1H NMR (DMSO-d ₆ , 400 MHz): δ 11.96-11.95 (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).

The following compound was prepared by the same procedure as described for IIIh, using the appropriate starting materials.

IIIi: 3-cyclopentyl-3-hydroxypropanoic acid he ο

1H NMR (DMSO-d6, 400 MHz): δ 11.96 (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).

IVa: ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxopropanoate

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Step 1. Obtaining ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxopropanoate

_Et3N (2.34 g) and MgCl2 (1.8 g) were added to a suspension of (3-ethoxy-3-oxopropanoyl)oxy potassium 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 _H2O (30 mL) and extracted with ethyl acetate (80 mL * 2). _The combined organic extracts were washed with brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash chromatography (SiO ₂ , eluent was characterized by a gradient of 0~10% ethyl acetate/petroleum ether) to give the product (0.98 g).

The following compounds were prepared by the same procedure as described for IVa, using the appropriate starting materials.

IVb: ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate

IVc: 3-(3,3-difluorocyclobutyl)-3-oxopropanoate

IVd: ethyl 3-(3,3-dimethylcyclobutyl)-3-oxopropanoate O O ^1H NMR ( _CDCl3 , 400 MHz): δ 4.22-4.16 (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).

IVe: ethyl 3-cyclopentyl 3-oxopropanoate O O

1H NMR ( _CDCl3 , 400 MHz): δ 4.24-4.18 (m, 2H), 3.49 (s, 2H), 3.03-2.95 (m, 1H), 1.84- 1.60 (m, 8H), 1.28 (t, 3H).

IVf: ethyl 3-(1-ethylcyclopropyl)-3-oxopropanoate O O

1H NMR ( _CDCl3 , 400 MHz): δ 4.22-4.16 (m, 2H), 3.33 (s, 2H), 1.64-1.60 (m, 2H), 1.26- 1.20 (m, 6H), 0.94 (t, 3H).

Va: ^)-Ы-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide

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Step 1. Obtaining (1\)-\-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenide)ethide)-4,4-dimethide-3oxopentanamide

A solution of (N)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (IIa) (0.6 g), methyl 4,4-dimethyl-3-oxopentanoate (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 ₂ SO ₄ and concentrated. The crude product was purified by chromatography ( _SiO2 , 30% EA in petroleum ether) to give (R)-N-(2(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide (0.28 g).

The following intermediate was prepared analogously to the procedure for Va using the appropriate intermediates.

Vb: ^)-N(2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide

Obtained from IIk and 4,4-dimethyl-3-oxopentanoic acid.

Vc: (1\)-\-(2-(difluoromethox and)-1-(3 -(difluoromethoxy)phenyl)ethyl)-3-oxo-3 -(1(trifluoromethyl)cyclopropyl)propanamide

Obtained from IIa and IVb.

Vd: (1\)-\-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxo-3-(1trifluoromethyl)cyclopropyl)propanamide

Derived from IVb and IIb.

Ve: (R)-3-(3,3-difluorocyclobutyl)-N(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3 oxopropanamide

Derived from IVc and IIa.

Vf: ^)-3-(3,3-difluorocyclobutyl)-N(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3oxopropanamide

Derived from IVc and IIb.

Vg: (S)-3-(3,3-difluorocyclobutide)-\-(1-(3-(difluoromethoxy)phenyl)butyl)-3-oxopropanamide

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Derived from IVc and IIg.

Vh: (R)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3 oxopropanamide

Derived from IVf and IIa.

Example la.

Examples ^(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide and Example 1b. dimethylpentanamide

^(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-

Step 1. Obtaining N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

(D)-N-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide (Va) (0.28 g) in MeOH (10 mL) was added NaBH ₄ (56 mg) at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The mixture was concentrated and the residue was redissolved in EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ and concentrated.

Stage 2. Separation of (N)-(2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide and (N)-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

^(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was separated by chromatography.

Example 1a.

1H NMR ( _CDCl3 , 400 MHz): δ 7.34 (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: t _R = 2.49 min (LC-MS Method 1), m/z=382.2 [M+H]+.

SFC: tR = 1.94 min (SFC Method 1), ee % = 95.26%.

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Example 1b.

1H NMR (CDCI3, 400 MHz): δ 7.35 (t, 1H), 7.16 (d, 1H), 7.06-7.04 (m, 2H), 6.60 (d, 1H), 6.50 (t, 1H), 6.20 (t, 1H), 5.28 (m, 1H), 4.10 (m, 2H), 3.67 (m, 1H), 3.04 (d, 1H), 2.45 (dd, 1H), 2.28 (dd, 1H), 0.91 (s, 9H) .

LC-MS: t _R = 2.50 min (LC-MS Method 1), m/z = 382.2 [M+H]+.

SFC: tR = 2.03 min (SFC Method 1), ee % = 95.26%.

The following examples were prepared analogously to the procedure described for 1a and 1b, using the appropriate intermediates.

Example 2a. N(^)-2-Ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

and Example 2b.

\-((1\)-2-Ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1. Obtaining N(^)-2-ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Derived from Vb.

Step 2. Separation of (S)-3-hydroxy-4,4-dimethyl-N((8)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide and (S)-3-hydroxy-4,4-dimethyl-N((8)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

\-((1\)-2-Ethoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was separated by chromatography.

Example 2a.

1H NMR (DMSO-d6, 300 MHz): δ 8.34 (d, 1H), 7.48-7.35 (m, 3H), 7.23 (d, 1H), 5.07 (d, 1H ), 4.61 (d, 1H), 3.34-3.54 (m, 5H), 2.31-2.20 (m, 1H), 2.17-2.08 (m, 1H), 1.08 (t, 2H), 0.83 (s, 9H).

LC-MS: t _R = 1.87 min (LC-MS Method 4), m/z = 378.2 [M+H] ⁺ .

SFC: tR = 1.71 min (SFC Method 18), ee % = 96.0%.

Example 2b.

1H NMR (DMSO- _d6 , 300 MHz): δ 8.39 (d, 1H), 7.46 (t, J=7.8 Hz, 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: tR = 1.87 min (LC-MS Method 4), m/z = 378.2 [M+H] ⁺ .

SFC: tR = 1.82 min (SFC Method 18), ee % = 99.1%.

Example 3a. \-((1\)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide

Example 3b. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1 (trifluoromethyl)cyclopropyl)propanamide

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Step 1. Obtaining ^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide

Obtained from Vc.

Stage 2. Separation of ^)-Ы-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy3-(1 -(trifluoromethyl)cyclopropyl)propanamide

^)-\-((1\)-2-(difluoromethoxy)-1 -(3 (difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

Chiral

^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-trifluoromethyl)cyclopropyl)propanamide was separated by chiral SFC.

Example 3a.

^1H NMR (CDCl3, 400 MHz): δ 7.35 (t, 1H), 7.16 (d, 1H), 7.07-7.05 (m, 2H), 6.45 (t, 1H) , 6.33 (s, 1H), 6.22 (t, 1H), 5.28-5.24 (m, 1H), 4.17-4.04 (m, 3H), 3.68 (s, 1H), 2.67 (dd, 1H), 2.55 (dd, 1H), 0.92-0.88 (m, 3H), 0.85-0.82 (m, 1H).

LC-MS: t _R = 2.51 min (LCMS Method 1), m/z = 434.1 [M+H] ⁴ .

SFC: tR = 1.95 min (SFC Method 3), its % = 100%.

Example 3 b.

^1H NMR (CDCl3, 400 MHz): δ 7.36 (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: tR = 2.51 min (LCMS Method 1), m/z = 434.1 [M+H] ⁺ .

SFC: tR = 1.58 min (SFC method 3), ee % = 90.0%.

Example 4a. ^-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide

and example 4b. ^-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide

Step 1. Obtaining ^-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide

Obtained from Vd.

Stage 2. Separation of ^)-Ы-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy3-(1 -(trifluoromethyl)cyclopropyl)propanamide

^)-Ы-(^)-2-(difluoromethoxy)-1-(3 (trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1-(trifluoromethyl)cyclopropyl)propanamide

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\-((1\)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide was separated by chiral SFC.

Example 4a.

^1H NMR (CDCl3, 400 MHz): δ 7.41 (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: tR = 2.53 min (LCMS Method 2), m/z = 452.1 [M+H]+.

SFC: tR = 1.21 min (SFC Method 7), its % = 100%.

Example 4b.

^1H NMR ( _CDCl3 , 400 MHz): δ 7.40 (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: tR = 2.63 min (LCMS Method 1), m/z = 452.1 [M+H] ⁺ .

SFC: tR = 1.57 min (SFC Method 7), ee % = 99.8%.

Example 5a. 3-(3,3-difluorocyclobutyl)-N-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)3-hydroxypropanamide

Example 5b. 3-(3,3-difluorocyclobutyl)-N-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)3-hydroxypropanamide

Step 1. Obtaining (^)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-oxopropanamide

Obtained from Ve.

Step 2. Separation of (3)-3-(3,3-difluorocyclobutyl)-N-(3)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and (3)-3-(3,3-difluorocyclobutyl)-N-(3)-2(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

^)-3-(3,3-difluorocyclobutyl)-N-(2-(trifluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-oxopropanamide was separated by chiral SFC.

Example 5a.

^1H NMR (CDCl3, 400 MHz): δ 7.37 (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), 2.592, 55 (m, 3H), 2.45-2.35 (m, 2H), 2.34-2.26 (m, 1H), 2.21-2.08 (m, 1H). LC-MS: t _R = 2.74 min (LCMS Method 1), m/z = 416.1 [M+H] ⁺ .

SFC: tR = 2.49 min (SFC Method 4), ee % = 97.7%.

Example 5b.

^1H NMR ( _CDCl3 , 400 MHz): δ 7.37 (t, 1H), 7.17 (d, 1H), 7.08-7.07 (m, 2H), 6.51 (t, 1H ), 6.32 (m, 1H), 6.23 (t, 1H), 5.30-5.26 (m, 1H), 4.18-4.15 (m, 1H), 4.11-4.07 (m, 1H), 4.02-3.98 (m, 1H), 2.64-2.51 ( m, 3H), 2.45-2.36 (m, 2H), 2.33-2.25 (m, 1H), 2.21-2.16 (m, 1H).

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LC-MS: tR = 2.73 min (LCMS Method 1), m/z = 416, 1 [M+H]+.

SFC: tR = 2.59 min (SFC Method 4), ee % = 96.1%.

Example 6a. 3-(3,3-difluorocyclobutyl)-N-(^)-2-(difluoromethoxy)-1-(3 (trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

and example 6b. 3-(3,3-difluorocyclobutyl)-N-(^)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

Step 1. Obtaining (^)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-oxopropanamide

Obtained from Vf.

Step 2. Separation of (^)-3-(3,3-difluorocyclobutyl)-N-(^)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and

^)-3-(3,3-difluorocyclobutyl)-Ы~-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3hydroxypropanamide

^)-3-(3,3-difluorocyclobutyl)-N-(2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopropanamide was separated by chiral SFC.

Example 6a.

^1H NMR (CDCl3, 400 MHz): δ 7.41 (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: tR = 2.53 min (LCMS Method 1), m/z = 434.0 [M+H] ⁺ .

SFC: tR = 1.62 min (SFC Method 5), ee % = 92.9%.

Example 6b.

^1H NMR (CDCl3, 400 MHz): δ 7.42 (t, 1H), 7.26 (d, 1H), 7.20-7.18 (m, 2H), 6.34 (d, 1H) , 6.24 (t, 1H), 5.33-5.28 (m, 1H), 4.20-4.16 (m, 1H), 4.13-4.00 (m, 1H), 4.00 (m, 1H), 3.61 (s, 1H), 2.61-2.57 (m, 3H), 2.432.39 (m, 2H), 2.39-2.32 (m, 1H), 2.20 (m, 1H). LC-MS: tR = 2.54 min (LCMS Method 1), m/z = 434.0 [M+H] ⁺ .

SFC: tR = 1.71 min (SFC Method 5), ee % = 97.9%.

Example 7a. 3-(3,3-difluorocyclobutyl)-N~-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide

Example 7b. 3-(3,3-difluorocyclobutyl)-N-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide

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Stage 1. Obtaining 3-(3,3-difluorocyclobutyl)-N-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3hydroxypropanamide

Obtained from Vg.

Stage 2. Separation of (^)-3-(3,3-difluorocyclobutyl)-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide and (^)-3-(3,3-difluorocyclobutyl)-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide

3-(3,3-difluorocyclobutyl)-^-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide was separated by chiral SFC.

Example 7a.

¹ H NMR (CDCl3, 400 MHz): δ 7.32 (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: tR = 2.41 min (LC-MS Method 1), m/z = 378.0 [M+H]+.

SFC: tR = 2.37 min (SFC method 6), ee % = 92.4%

Example 7b.

¹ H NMR (CDCl3, 400 MHz): δ 7.31 (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: tR = 2.45 min (LC-MS Method 1), m/z = 378.0 [M+H] ⁺ .

SFC tR = 2.49 min (SFC Method 6), its % = 99.5%

Example 8a. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3hydroxypropanamide

Example 8b. ^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3hydroxypropanamide

Step 1. Obtaining ^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide

Obtained from Vh.

Stage 2. Separation of (N)-(N)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide and (N)-(N)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3-hydroxypropanamide

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N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3hydroxypropanamide was separated by chiral SFC.

Example 8a.

1H NMR (CDCl3, 400 MHz): δ 7.28 (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 (t, 2H), 1.34-1.31 (m, 1H), 0.83-0.80 (m, 3H), 0.38-0.29 (t, 4N).

LC-MS: t _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%

Example 8b.

^1H NMR (CDCl3, 400 MHz): δ 7.29 (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: t _R = 2.38 min (LCMS Method 1), m/z = 394.0 [M+H] ⁺ .

SFC t = 2.60 min (SFC Method 1), its % = 98.7%.

Example 9a. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide

Example 9b. X-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide

Step 1. Obtaining N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1fluorocyclopropyl)-3-hydroxybutanamide

To a solution of (N)-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) were added N-hydroxybenzotriazole (HOBt) (213 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (363 mg) and Et3N (320 mg). The mixture was stirred at 25 °C for 16 h and then diluted with water (10 ml) and extracted with EtOAc (20 ml x 3). _The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by basic preparative HPLC to give N(II)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1fluorocyclopropyl)-3-hydroxybutanamide (250 mg).

Step 2. Separation of (N)-(N)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide and (N)-\'-((1\)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide

\'-((1\)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide was separated by chiral SFC.

Example 9a.

1H NMR (CDCl3, 400 MHz): δ 7.38 (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 ). L.C.

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MS: tR = 2.48 min (LCMS Method 1), m/z = 398.2 [M+H]+.

SFC t _R = 2.46 min (SFC Method 12), its % = 100%.

Example 9b.

1H NMR ( _CDCl3 , 400 MHz): δ 7.39 (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), 0.990.85 (m, 4H).

LC-MS: t _R = 2.47 min (LCMS Method 1), m/z = 398.1 [M+H] ⁺ .

SFC: tR = 2.65 min (SFC Method 12), ee % = 98.8%.

The following examples were prepared analogously to the procedure described for Example 9a and Example 9b, using the appropriate intermediates.

Example 10a. Ы-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)3-hydroxybutanamide

Example 10b. Ы-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)3-hydroxybutanamide

Step 1. Obtaining Ы-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1fluorocyclopropyl)-3-hydroxybutanamide

Obtained from IIb and IIIc.

Stage 2. Separation of (N)-(N)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide and (N)-(N)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3-hydroxybutanamide

Ы-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide was separated using chiral SFC.

Example 10a.

1H NMR (CDC13, 400 MHz): δ 7.48 (t, 1H), 7.35 (d, 1H), 7.27-7.25 (m, 2H), 6.64 (d, 1H), 6.31 (t, 1H), 5.40-5.38 (m, 1H), 4.86 (s, 1H), 4.26-4.18 (m, 2H), 2.78 (d, 1H), 2.60 (d, 1H), 1.42 (s, 3H), 0.86-0.57 (m, 4H). LC-MS: t _R = 2.64 min (LCMS Method 1), m/z = 416.2 [M+H] ⁺ .

SFC tR = 2.38 min (SFC Method 2), its % = 100%.

Example 10b.

1H NMR ( _CDCl3 , 400 MHz): δ 7.42 (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: t _R = 2.659 min (LCMS Method 1), m/z = 416.2 [M+H] ⁺ .

SFC tR = 2.561 min (SFC Method 6), ee % = 95.9%.

Example 11a. 3-cyclopropyl-N-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3hydroxybutanamide

- 57 048113 example 11b. 3-cyclopropyl-N-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3hydroxybutanamide

Step 1. Obtaining 3-cyclopropyl-N-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)3-hydroxybutanamide

Derived from IIb and IIId.

Step 2. Separation of (N)-3-cyclopropyl-N-(N)-2-(difluoromethoxy)-1-(3(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide and (N)-3-cyclopropyl-N-(N)-2-(difluoromethoxy)-1(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide

3-Cyclopropyl-N-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxybutanamide was separated by chiral SFC.

Example 11a.

^1H NMR (CDCl3, 400 MHz): δ 7.38 (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: 1r = 2.42 min (LCMS Method 1), m/z = 420, 1 [M + Na] ⁺ .

SFC tR = 2.17 min (SFC Method 13), its % = 100%.

Example 11b.

1H NMR (CDCl3, 400 MHz): δ 7.39 (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: tR = 2.95 min (LCMS Method 1), mass/charge = 420.1 [M + Na] ⁺ .

SFC tR = 2.48 min (SFC Method 13), its % = 100%.

Example 12a. N(^)-2-(difluoromethoxy)-1-(3 -(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3 hydroxy-3-methylpentanamide

Example 12b. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide

Step 1. Obtaining N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3hydroxy-3-methylpentanamide

Obtained from IIa and IIIe.

Stage 2. Separation of (N)-M-(N)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide and (N)-M-(N)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3-methylpentanamide

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^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-5,5,5-trifluoro-3-hydroxy-3methylpentanamide was separated by chiral SFC.

Example 12a.

1H NMR (CDCl3, 400 MHz): δ 7.38 (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: tR = 2.52 min (LCMS Method 1), m/z = 422.1 [M+H]+.

SFC: tR = 1.10 min (SFC Method 14), ee % = 100%.

Example 12b.

¹ H NMR (CDCl3, 400 MHz): δ 7.39 (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). LCMS: tR = 2.52 min (LCMS Method 1), m/z = 422.1 [M+H] ⁺ .

SFC: tR = 1.24 min (SFC Method 14), ee % = 95.8%.

Example 13 a. ^-((K_)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide

Example 13b. ^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide

Step 1. Obtaining N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide

Derived from IIa and IIIg

Stage 2. Separation of (F)-VI-(F)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy3,5-dimethylhexanamide and (F)-N-(F)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy3,5-dimethylhexanamide

Chiral

ABOUT.

N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,5-dimethylhexanamide was separated by chiral SFC.

Example 13a.

1H NMR (CDCl3, 400 MHz): δ 7.37 (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: t _R = 2.54 min (LCMS Method 1), m/z = 396.1 [M+H] ⁺ .

SFC tR = 2.40 min (SFC Method 15), its % = 99.3%.

Example 13b.

1H NMR (CDCl3, 400 MHz): δ 7.37 (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).

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LC-MS: t _R = 2.54 min (LC-MS Method 1), m/z = 396.1 [M+H]+.

SFC tR = 2.66 min (SFC Method 15), its % = 98.8%.

Example 14a. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide

Example 14b. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide

Step 1. Obtaining N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide

Derived from IIa and IIIf

Step 2. Separation of (N)-Na(Na)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide and (N)-Na((Na)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-

3,4- dimethylpentanamide

N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3,4-dimethylpentanamide was separated by chiral SFC.

Example 14a.

^1H NMR ( _CDCl3 , 400 MHz): δ 7.34 (t, 1H), 7.16 (d, 1H), 7.07 (s, 1H), 7.04 (d, 1H), b.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: tR = 2.41 min (LCMS Method 1), m/z=382.0 [M+H]+.

SFC: tR = 2.44 min (SFC Method 15), ee % = 100%.

Example 14b.

1H NMR ( _CDCl3 , 400 MHz): δ 7.35 (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: tR = 2.41 min (LCMS Method 1), m/z = 382.0 [M+H]+.

SFC: tR = 2.68 min (SFC Method 15), ee % = 97.4%.

Example 15a. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide

Example 15b. N(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide

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Step 1. Obtaining \-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide

Obtained from IIa and IIIh.

Step 2. Separation of (I)-\-((I)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide and (I)-\-((I)-2-(difluoromethoxy)-1-(3(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3-hydroxypropanamide

\-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3hydroxypropanamide was separated by chiral SFC.

Example 15a.

1H NMR (DMSO-d6, 400 MHz): δ 8.41 (d, 1H), 7.40 (t, 1H), 7.26 (d, 1H), 7.21 (t, 1H), 7. 20 (s, 1H), 7.09 (d, 1H), 6.67 (t, 1H), 5.17-5.12 (m, 1H), 4.61 (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: tR = 2.35 min (LC-MS Method 3), m/z = 408.1 [M+H]+.

SFC tR = 2.32 min (SFC Method 16), its % = 99.7%.

Example 15b.

1H NMR (DMSO-d6, 400 MHz): δ 8.43 (d, 1H), 7.40 (t, 1H), 7.24 (d, 1H), 7.22 (t, 1H), 7. 18 (s, 1H), 7.08 (d, 1H), 6.67 (t, 1H), 5.14-5.10 (m, 1H), 4.63 (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: tR = 2.34 min (LCMS Method 3), m/z = 408.1 [M+H] ⁺ .

SFC tR = 2.64 min (SFC Method 16), its % = 98.7%.

Example 16a. 3-cyclopentyl-^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3hydroxypropanamide

and example 16b.

hydroxypropanamide

3-cyclopentyl^-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-

Stage 1. Obtaining 3-cyclopentyl-\-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)3-hydroxypropanamide

Obtained from IIa and IIIi.

Step 2. Separation of (^)-3-cyclopentyl-\-(^)-2-(difluoromethoxy)-1-(3- 61 048113 (difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide and (^)-3-cyclopentyl-N-(^)-2-(difluoromethoxy)-1(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide

Chiral

3-Cyclopentyl-N-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxypropanamide was separated by chiral SFC.

Example 16a.

1H NMR (DMSO-d6, 400 MHz) δ 8.43 (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), 5.16-5.14 (m, 1H), 4.61 (d, 1H), 3.99-3.97 (m, 2H), 3.69-3.65 (m, 1H), 2.26-2.25 (m, 2H), 1.80-1.76 (m, 1H ), 1.64-1.22 (m, 8H).

LC-MS: t _R = 2.48 min (LC-MS Method 1), m/z = 394.1 [M+H]+.

SFC: tR = 2.64 min (SFC Method 17), ee % = 98.8%.

Example 16b.

1H NMR (DMSO- _d6 , 400 MHz): δ 8.41 (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: tR = 2.27 min (LC-MS Method 2), m/z = 394.2 [M+H] ⁺ .

SFC: t _R = 3.08 min (SFC Method 17), ee % = 100%

Example 36a. 3-(1-Fluorocyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1-(3(trifluoromethoxy)phenyl)ethyl)butanamide

Example 36b. 3-(1-Fluorocyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1-(3(trifluoromethoxy)phenyl)ethyl)butanamide

I

Step 1. Obtaining 3-(1-fluorocyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1-(3(trifluoromethoxy)phenyl)ethyl)butanamide

Derived from IIp and IIIc.

Stage 2. Separation

^)-3-(1-fluorocyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1-(3(trifluoromethoxy)phenyl)ethyl)butanamide and ^)-3-(1-fluorocyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1(3-(trifluoromethoxy)phenyl)ethyl)butanamide

3-(1-Fluorocyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide was separated by chiral SFC.

Example 36a.

1H NMR ( _CDCi3 , 400 MHz): δ 7.38 (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), 0.810.53 (m, 4H). LC-MS: t _R = 2.43 min (LCMS Method 1), m/z = 380.0 [M+H] ⁺ .

SFC: t _R = 1.29 min (SFC Method 21), ee % = 99.6%.

Example 36b.

1H NMR (CDC13, 400 MHz): δ 7.38 (t, 1H), 7.28-7.27 (m, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 6.58 (d, 1H), 5.18-5.14 (t, 1H), 4.93 (s, 1H), 3.70-3.62 (m, 2H), 3.38 (s, 3H), 2.71 (dd, 1H), 2.52 (dd, 1H), 1.35 (s, 3H), 1.00

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0.86 (m, 4H). LC-MS: t _R = 2.53 min (LCMS Method 1), m/z = 380.0 [M+H]+.

SFC: t _R = 1.76 min (SFC Method 22), ee % = 81.4%.

Example 17. (^)-N(^)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1. Obtaining ^)-^(^)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy4,4 - dimethylpentanamide

To a solution of (N)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride (IIc) (0.2 g), (3S)-3-hydroxy-4,4-dimethylpentanoic 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 h and concentrated. The crude product was purified to give (N)-Na(Na)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3hydroxy-4,4-dimethylpentanamide.

1H NMR ( _CDCl3 , 400 MHz): δ 7.33 (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: t _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%.

The following examples were prepared analogously to the procedure described for Example 17, using the appropriate intermediates.

Example 18. ^)-N(^)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Derived from IIe and IIIa.

1H NMR (CDCl3, 400 MHz): δ 7.41-7.36 (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: t _R = 2.38 min (LCMS Method 3), mass/charge = 400.0 [M+H] +.

SFC t _R = 2.11 min, (SFC Method 4), ee % = 96.4%.

Example 19. ^)-N(^)-1-(3-(Trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.35 (t, 1H), 7.21-7.19 (t, 1H), 7.13-7.11 (m, 2H), 6.65 (d, 1H), 5.32-5.27 (m, 1H), 4.21-4.13 (m, 1H), 3.64-3.61 (m, 1H), 2.83 (d, 1H), 2.41-2.36 (m, 1H), 2.29-2.25 (m, 1H), 0.86 (s, 9H).

LC-MS: t _R = 2.56 min (LCMS Method 3), m/z = 418.0 [M+H]+.

HPLC: tR = 13.54 min (HPLC Method 2), ee % = 65.9%

Example 20. ^)-N(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide

Obtained from IIg and IIIa.

^1H NMR ( _CDCl3 , 400 MHz): δ 7.33 (t, 1H), 7.14 (d, 1H), 7.03-7.00 (m, 2H), 6.52 (t, 1H ), 6.22-6.20 (m,

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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: tR = 2.30 min (LCMS Method 3), m/z = 344.1 [M+H]+.

SFC tR = 2.13 min (SFC Method 1), its % = 98.7%.

Example 21. ^)^-(^)-1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)-3-hydroxy-4,4dimethylpentanamide

Obtained from IIh and IIIa.

^1H NMR ( _CDCl3 , 400 MHz): δ 7.36 (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: tR = 2.43 min (LCMS Method 1), m/z = 380.0 [M+H] ⁺ . HPLC: tR = 14.01 min (HPLC Method 3), ee % = 95.7%.

Example 22. ^)-U-(^)-1-(3-(difluoromethoxy)phenyl)-3,3-difluoropropyl)-3-hydroxy-4,4-dimethylpentanamide

F

Derived from IIi and IIIa.

1H NMR ( _CDCl3 , 400 MHz): δ 7.35 (t, 1H), 7.14 (d, 1H), 7.05-7.03 (m, 2H), 6.50 (t, 1H), 6.53-6.50 (m, 1H), 5.80 (tt, 1H), 5.30-5.24 (m, 1H), 3.66 (dd, 1H), 2.89 (s, 1H), 2.40-2.22 (m, 4H), 0.89 (s, 9H). LC-MS: tR = 2.63 min (LCMS Method 1), m/z = 366.2 [M+H] ⁺ .

HPLC: tR = 13.43 min (HPLC Method 1), ee % = 96.7%.

Example 23. ^)-U-(^)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Derived from IIj and IIIa.

1H NMR ( _CDCl3 , 400 MHz): δ 7.34-7.30 (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 , 9Н).

LC-MS: tR = 2.155 min (LCMS Method 2), m/z = 316.1 [M+H] ⁺ .

SFC tR = 2.416 min (SFC Method 8), its % = 100%.

Example 24. ^)-U-(^)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Derived from IIm and IIIa.

1H NMR (400 MHz, DMSO-d6): δ 8.66 (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: tR = 2.42 min (1SMS Method 1), m/z = 359.2 [M+H] ⁺ . HPLC: tR = 12.56 min (HPLC Method 4), ee % = 100%.

Example 25. ^)-U-(^)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide

N

Obtained from IIn and IIIa.

1H NMR ( _CDCl3 , 400 MHz): δ 7.42 (t, 1H), 7.24 (m, 1H), 7.18 (d, 1H), 7.13 (s, 1H), 6.49 (d, 1H), 5.195.13 (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: tR = 2.44 min (LCMS Method 1), m/z = 373.2 [M+H] ⁺ .

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SFC: tR = 1.47 min (SFC Method 9), ee % = 95.8%.

Example 26. (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3 (difluoromethoxy)phenyl)ethyl)acetamide

Obtained from IIa and IIIb.

^1H NMR ( _CDCl3 , 400 MHz): δ 7.37 (t, 1H), 7.15 (d, 1H), 7.09-7.06 (m, 2H), 6.50 (t, 1H ), 6.32 (t, 1H), 6.23 (t, 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: tR = 2.39 min (LCMS Method 1), m/z = 402.1 [M+H]+.

SFC: tR = 1.87 min (SFC Method 1), its % = 100%

Example 27. (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(2-(difluoromethoxy)-1-(3 (trifluoromethoxy)phenyl)ethyl)acetamide

Derived from IIb and IIIb.

^1H NMR (CDCl3, 400 MHz): δ 7.35 (t, 1H), 7.14-7.09 (m, 3H), 6.18 (t, 1H), 6.21 (d, 1H) , 5.23 (m, 1H), 4.66 (br s, 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: tR = 2.53 min (LC-MS Method 1), mass/charge = 420.2 [M+H] ⁺ .

HPLC: t _R = 12.77 min (HPLC Method 2), ee % = 86.7%.

Example 28. ^)-Н-(2-Cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1hydroxycyclobutyl)acetamide

Derived from IId and IIIb.

^1H NMR (CDCl3, 400 MHz): δ 7.37 (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: tR = 2.53 min (LC-MS Method 1), m/z = 410.0 [M+H] ⁺ .

SFC tR = 1.50 min (SFC Method 7), its % = 99.7%

Example 29. ^)-Н-(2-Cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1hydroxycyclobutyl)acetamide

Derived from IIe and IIIb.

1H NMR (CDCl3, 400 MHz): δ 7.35 (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: tR = 2.40 min (LC-MS Method 1), m/z = 392.1 [M+H] ⁺ .

SFC: tR = 2.32 min (SFC Method 6), ee % = 100.00%.

Example 30. ^)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-2(trifluoromethoxy)ethyl)acetamide

Derived from IIe and IIIb.

- 65 048113

1H NMR (CDC13, 400 MHz): δ 7.39 (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: tR = 2.48 min (LC-MS Method 1), m/z = 420.0 [M+H]+.

SFC tR = 12.96 min (HPLC Method 2), ee % = 75.5%

Example 31. ^)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3(difluoromethoxy)phenyl)butyl)acetamide

Obtained from IIg and IIIb.

1H NMR (CDCl3, 400 MHz): δ 7.35 (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: tR = 2.44 min (LC-MS Method 1), m/z = 364.0 [M+H] ⁺ .

SFC: tR = 1.71 min (SFC Method 10), ee % = 94.8%.

Example 32. ^)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-difluorobutyl)acetamide

Derived from IIh and IIb.

1H NMR (CDCl3, 400 MHz): δ 7.38 (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: tR = 2.50 min (LCMS Method 1), m/z = 400.1 [M+H] ⁺ . HPLC: tR = 12.48 min (HPLC Method 2), ee % = 98.3%.

Example 33. ^)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3(trifluoromethoxy)phenyl)propyl)acetamide

Obtained from IIl and IIIb.

1H NMR (CDCl3, 400 MHz): δ 7.38 (t, 1H), 7.20 (d, 1H), 7.14 (d, 1H), 7.10 (s, 1H), 5.89 ( d, 1H), 4.99 (brs, 1H), 4.89 (q, 1H), 2.77-2.70 (m, 2H), 2.63 (d, 2H), 2.60-2 .50 (t, 2H), 1.87-1.80 (m, 2H), 0.92 (t, 3H).

LC-MS: tR = 2.57 min (LCMS Method 1), m/z = 368.1 [M+H] ⁺ .

SFC: tR = 13.09 min (SFC Method 1), its % = 100%.

Example 34. ^)-Ы-(2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1hydroxycyclobutyl)acetamide

Derived from IIm and IIIb.

1H NMR (CDCl3, 400 MHz): δ 7.46 (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: tR = 2.257 min (LC-MS Method 1), m/z = 379.0 [M+H] ⁺ .

SFC: tR = 2.60 min (SFC Method 11), ee % = 100%.

Example 3 5. (S)-N-(3,3-difluoro-1 -(3 -(trifluoromethoxy)phenyl)propyl)-2-(3,3-difluoro-1 hydroxycyclobutyl)acetamide

Obtained from IIo and IIIb.

1H NMR ( _CDCl3 , 400 MHz): δ 7.44 (t, 1H), 7.23 (m, 2H), 7.15 (s, 1H), 6.15 (br d, 1H), 5. 83 (tt, 1H), 5.32 (m, 1H), 4.69 (s, 1H), 2.73 (m, 2H), 2.66 (s, 2H), 2.62-2.34 (4H).

LC-MS: tR = 2.53 min (LC-MS Method 1), m/z = 404.1 [M+H] ⁺ .

SFC tR = 1.66 min (SFC Method 19), its % = 98.5%.

Claims (19)

1. Compound of formula I where R ¹ is selected from the group consisting of Q^-alkyl, CF3, CH2CF3, CF2CHF2, C ₃ -C ₈ -cycloalkyl, wherein said Q-^-cycloalkyl may be substituted with 1 or 2 substituents selected from the group consisting of Q-^-alkyl, F, CHF2 and CF3; and R ² is H, ^-^-alkyl or CF3; or R ¹ and R ² are combined to form ^-^-cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3; and R ³ is CH ₂ -O-cyclopropyl, C ₁ -C ₃ -alkyl or OT^-C^alkyl, wherein said OT^-C^-alkyl or CH ₂ OC ₁ -C ₃ -alkyl are substituted by C=N, 3 F or OT^-C^-cycloalkyl; R ⁴ is selected from the group consisting of OCF3 or OCHF2, or a pharmaceutically acceptable salt of any of these compounds. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is OCF3 or OCHF ₂ . 3. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R ³ is selected from the group consisting of CH2-O-CF3, PI^O-cyclopropyl, CH2-C^N. 4. A compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₃ -C ₄ -cycloalkyl optionally substituted with 1 or 2 of C 3 -C 4 -alkyl, F, CHF2 or CF3. 5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are combined to form cyclobutyl optionally substituted with 1 or 2 F, and R ⁴ is OCF3 or OCHF2. 6. The compound of claim 1, wherein the compound is selected from the group consisting of ^)-I-(^)-2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-I-(^)-1-(3-(difluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-I-(^)-1-(3-(trifluoromethoxy)phenyl)-2-(trifluoromethoxy)ethyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-I-(^)-2-cyano-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-I-(^)-3-cyano-1-(3-(trifluoromethoxy)phenyl)propyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-I-(2-cyclopropoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1 hydroxycyclobutyl)acetamide; ^)-I-(2-cyclopropoxy-1-(3-(difluoromethoxy)phenyl)ethyl)-2-(3,3-difluoro-1 hydroxycyclobutyl)acetamide; (R)-2-(3,3-difluoro-1-hydroxycyclobutyl)-I-(1-(3-(difluoromethoxy)phenyl)-2(trifluoromethoxy)ethyl)acetamide or ^)-I-(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. A compound selected from the group consisting of ^)-I-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-I-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-3-hydroxy-4,4-dimethyl-I-(^)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; ^)-3-hydroxy-4,4-dimethyl-I-(^)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide; ^)-I-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide; ^)-I-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1 (trifluoromethyl)cyclopropyl)propanamide; ^)-I-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide; ^)-I-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-3-(1(trifluoromethyl)cyclopropyl)propanamide; ^)-3-(3,3-difluorocyclobutyl)-I-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3hydroxypropanamide; ^)-3-(3,3-difluorocyclobutyl)-I-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3hydroxypropanamide; - 67 048113 (R)-3-(3,3-di(|)trifluorocyclobutyl)^-((C)-2-(di(|)trifluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3 hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-H-(^)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3 hydroxypropanamide; (S)-3-(3,3-difluorocyclobutyl)-N-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; (R)-3-(3,3-difluorocyclobutyl)-N-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxypropanamide; ^)-M-(^)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3 hydroxypropanamide; (C)-N-((C)-2-(di(()tormethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-ethylcyclopropyl)-3 hydroxypropanamide; ^)-M-(^)-1-(3-(difluoromethoxy)phenyl)butyl)-3-hydroxy-4,4-dimethylpentanamide; ^)-H-(^)-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; ^)-M-(^)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide; (C)-2-(3,3-di(|)tor-1 -hydroxycyclobutyl)-N(2-(difluoromethoxy)-1 -(3 (di(tormethoxy)(enyl)ethyl)acetamide; (C)-2-(3.3-di(|)tor-1 -hydroxycyclobutyl)-N(2-(difluoromethoxy)-1 -(3 (tri(tormethoxy)(enyl)ethyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-No( 1 -(3 -(di(tormethoxy)(enyl)butyl)acetamide; (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(difluoromethoxy)phenyl)-4,4-di(torbutyl)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-(cyclopropyl)-3 hydroxybutanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(1-fluorocyclopropyl)-3hydroxybutanamide; (S)-N-((R)-2-(difluoromethoxy)-1-(3 -(Ίfluoromethoxy)phenyl)ethyl)-3 -(1 -(cyclopropyl)-3 hydroxybutanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3 -(Ίfluoromethoxy)phenyl)ethyl)-3 -(1 -(cyclopropyl)-3 hydroxybutanamide; (R)-3-cyclopropyl-N-((R)-2-(di(trifluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3 hydroxybutanamide; (S)-3-cyclopropyl-N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3hydroxybutanamide; (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)-3hydroxypropanamide; (R)-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-(3,3-dimethylcyclobutyl)-3hydroxypropanamide; (S)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3hydroxypropanamide; (R)-3-cyclopentyl-N-((R)-2-(difluoromethoxy)-1-(3-(difluoromethoxy)phenyl)ethyl)-3hydroxypropanamide; (R)-3-(1-(cyclopropyl)-3-hydroxy-N-((C)-2-methoxy-1-(3 (tri(methoxy)(enyl)ethyl)butanamide and (S)-3-(1-(cyclopropyl)-3-hydroxy-N-(^)-2-methoxy-1-(3 (tri(methoxy)(enyl)ethyl)butanamide - 68 048113 or a pharmaceutically acceptable salt of any of these compounds. 8. A pharmaceutical composition for the treatment of disorders responsive to activation of Kv7 potassium channels, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. 9. A pharmaceutical composition for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 10. A pharmaceutical composition for the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 11. Use of a compound according to claims 1-7 or a pharmaceutically acceptable salt thereof for the treatment of disorders responsive to activation of Kv7 potassium channels. 12. Use of a compound according to claims 1-7 or a pharmaceutically acceptable salt thereof for the treatment of disorders responsive to activation of Kv7 potassium channels, selected from epilepsy, bipolar disorder, migraine or schizophrenia. 13. Use of a compound according to claims 1-7 or a pharmaceutically acceptable salt thereof for the treatment of disorders responsive to activation of Kv7 potassium channels, selected from psychosis, mania, disorders associated with exposure to stress factors, acute stress reactions, bipolar depression, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, ADHD, PTSD, OCD, impulse control disorders, personality disorders, schizotypal disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease. 14. A pharmaceutical composition for the treatment of epileptic symptoms that are a component of neurodegenerative disorders selected from Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 15. A pharmaceutical composition for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 16. A pharmaceutical composition for the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, grand mal seizures, status epilepticus, neonatal seizures, neonatal seizures, KCNQ-associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as epileptic syndromes selected from severe myoclonic epilepsy of infancy, epilepsy with continuous spike-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome, or seizures associated with exposure to stress factors, hormonal changes, drug use drugs, alcohol use, infection, traumatic brain injury, stroke, forms of brain cancer, autism spectrum disorders or metabolic disorders, or intended for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 17. Use of a compound according to claims 1-7 or a pharmaceutically acceptable salt thereof for the treatment of epileptic symptoms that are a component of neurodegenerative disorders selected from Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration. 18. Use of a compound according to claims 1-7 or a pharmaceutically acceptable salt thereof for the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy or seizures. 19. Use of a compound according to claims 1-7 or a pharmaceutically acceptable salt thereof for the treatment, for use in the treatment of disorders responsive to activation of potassium channels Kv7, selected from focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, generalized idiopathic epilepsy, - 69 048113 grand mal seizures, status epilepticus, neonatal seizures, KCNQ-associated epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures, as well as epileptic syndromes selected from severe myoclonic epilepsy of infancy, epilepsy with continuous spike-and-wave complexes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy, Ohtahara syndrome, or seizures associated with exposure to stress factors, hormonal changes, drug use, alcohol use, infection or metabolic disorders, or for use in the treatment of epileptic symptoms that are a component of neurodegenerative disorders selected from Alzheimer's disease, Lewy body disease, juvenile form of the disease Huntington's, frontotemporal lobar degeneration.