TWI788325B - ALCOHOL DERIVATIVES AS Kv7 POTASSIUM CHANNEL OPENERS - Google Patents

Abstract

The present invention provides novel compounds which activate the Kv7 potassium channels. Separate aspects of the invention are directed to pharmaceutical compositions comprising said compounds and uses of the compounds to treat disorders responsive to the activation of Kv7 potassium channels.

Description

Alcohol derivatives as Kv7 potassium channel openers

The present invention relates to novel compounds that activate Kv7 potassium channels. Individual aspects of the invention relate to pharmaceutical compositions comprising said compounds and the use of these compounds to treat disorders responsive to Kv7 potassium channel activation.

Voltage-dependent potassium (Kv) channels guide potassium ions (K ⁺ ) across the cell membrane in response to changes in membrane potential and can thus regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell. Functional Kv channels exist as multimeric structures formed by combinations of four α-subunits and four β-subunits. The α subunit includes six transmembrane domains, a pore-forming loop, and a voltage sensor, and is arranged symmetrically around the central pore. The beta or accessory subunit interacts with the alpha subunit and can modify the properties of the channel complex to include, but not limited to, changes in the channel's electrophysiological or biophysical properties, expression level, or expression pattern.

Nine families of Kv channel alpha subunits have been identified and termed Kv1-Kv9. Thus, there is enormous diversity in Kv channel function, which arises from the multiplicity of subfamilies, the formation of homologous and heteromeric subunits within subfamilies, and additive effects associated with beta subunits (Christie, 25 Clinical and Experimental Pharmacology and Physiology [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 The following mammalian channels: Kv7.1 , Kv7.2, Kv7.3, Kv7.4, Kv7.5 and any mammalian or non-mammalian equivalent or variant (including splice variants) thereof. Alternatively, these members of the family are designated by the gene names KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5, respectively (Dalby-Brown et al., Current Topics in Medicinal Chemistry, 2006, 6, 9991023).

As mentioned above, the neuronal Kv7 potassium channel plays a role in controlling neuronal excitation. Kv7 channels (specifically Kv7.2/Kv7.3 heterodimers) underlie M currents (Wang et al., Science. 1998 Dec 4;282(5395):1890-3). M currents have characteristic time and voltage dependencies, leading to stabilization of the membrane potential in response to multiple excitatory stimuli.

In this way, M currents are involved in the control of neuronal excitability (Delmas and Brown, Nature, 2005, 6, 850-862). M currents are non-inactivating potassium currents found in many neuronal cell types. In each cell type, it predominantly controls membrane excitability by being the only persistent current in the range of action potential initiation (Marrion, Annual Review Physiology 1997, 59, 483-504).

Retigabine (ethyl N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamate) is a compound that binds to the Kv7 potassium channel (Wuttke et al. Molecular Pharmacology [Molecular Pharmacology], 2005, 67, 1009-1017). Retigabine activates K ⁺ currents in neuronal cells, and the pharmacology of this evoked current was shown to be consistent with the published pharmacology of M-channels with Kv7.2 /3 K ⁺ channel heteromultimer association, suggesting that activation of Kv7.2/3 channels is responsible for at least some of the anticonvulsant activity of the agent (Wickenden et al., Molecular Pharmacology [Molecular Pharmacology] 2000, 58, 591-600 ). Retigabine is effective in reducing the incidence of seizures in epileptic patients (Bialer et al., Epilepsy Research 2002, 51, 31-71). Retigabine has broad-spectrum and potent anticonvulsant properties. In a series of anticonvulsant tests, retigabine was active following oral and intraperitoneal administration in rats and mice (Rostock et al., Epilepsy Research 1996, 23, 211-223).

The five members of this family differ in their mode of expression. Expression of Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle, whereas expression of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 appear to be expressed in areas including the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion nerves Predominant in the nervous system of the cell (for a review, see Greene and Hoshi, Cellular and Molecular Life Sciences [Cell 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 localize to pyramidal neurons of the human cortex and hippocampus, brain regions associated with seizure generation and proliferation (Cooper et al., Proceedings National Academy of Science U S A [Proceedings of the National Academy of Sciences of the United States] 2000, 97 , 4914-4919).

Furthermore, mRNAs of Kv7.3 and 5 were expressed in astrocytes and glial cells in addition to mRNAs of Kv7.2. Kv7.2, Kv7.3 and Kv7.5 channels may thus help regulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (Noda et al., Society for Neuroscience Abstracts 2003, 53.9), the KCNQ channel opener will be related to the treatment of neurodegenerative disorders (such as but not limited to Alzheimer's disease, Parkinson's disease and Huntington's disease).

Found in mRNAs of the Kv7.2 and Kv7.3 subunits in brain regions associated with anxiety and affective behaviors (e.g., depression and bipolar disorder) (e.g., hippocampus, ventral tegmental area, and amygdala) (Saganich et al. Journal of Neuroscience [Neuroscience Journal] 2001, 21, 4609-4624; Friedman et al., Nat Commun. [Nature Communication] 2016; 7: 11671), and retigabine has been reported to be effective in animal models of anxiety-like behavior. Activity (Korsgaard et al., J Pharmacol Exp Ther. 2005 Jul;314(1):282-92. Epub 2005 Apr 6). Thus, Kv7 channels are relevant for the treatment of affective related disorders such as but not limited to bipolar depression, major depression, anxiety, suicide, panic disorder, social phobia.

Kv7.2/3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators have been postulated to play a role in neuropathic pain. It is active in both epilepsy and epilepsy (Schroder et al., Neuropharmacology [Neuropharmacology] 2001, 40, 888-898). In addition to its role in neuropathic pain, mRNA expression of Kv7.2-5 in the trigeminal and dorsal root ganglia and in the caudate nucleus of the trigeminal nerve implies that openers of these channels may also affect sensory processing in migraine (Goldstein et al., Society for Neuroscience Abstracts 2003, 53.8). Taken together, this evidence suggests the relevance of KCNQ channel openers for the treatment of chronic pain and neuropathy-related disorders.

WO 07/90409 relates to the use of Kv7 channel openers for the treatment of schizophrenia. Kv7 channel openers modulate the function of the dopamine system (Friedman et al. Nat Commun. [Nature Communications] 2016; Scotty et al. J Pharmacol Exp Ther. 2009 Mar; 328(3) :951-62.doi:10.1124/jpet.108.146944.Epub 19 Dec 2008; 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 Oct 19 2017; Hansen et al., J Pharmacol Exp Ther. 2006 Sep; 318(3): 1006-19. Epub 14 Jun 2006), the opener will be relevant to the treatment of mental disorders , such as, but not limited to, psychosis, mania, stress-related disorders, acute stress response, attention-deficit/hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive disorder, personality disorder, schizophrenia Disorders, aggressive behavior, autism-like disorders. WO 01/96540 discloses the use of M current regulators formed by expressing the KCNQ2 and KCNQ3 genes for insomnia, while WO 01/092526 discloses the use of Modulators of Kv7.5 for the treatment of sleep disorders. WO 09/015667 discloses the use of Kv7 openers for the treatment of sexual dysfunction.

While patients with the above-mentioned disorders may have available treatment options, many of these options lack the desired efficacy and are associated with undesirable side effects. Therefore, there remains an unmet need for novel therapies for the treatment of this disease.

In an effort to identify new therapeutics, the inventors have identified a series of novel compounds represented by Formula I that act as Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channel openers. Accordingly, the present invention provides novel compounds as drugs for the treatment of disorders regulated by KCNQ potassium channels.

其中R1選自下組，該組由以下組成：C₁-C₆烷基、CF₃、CH₂CF₃、CF₂CHF₂、C₃-C₈環烷基，其中所述C₃-C₈環烷基可以被1個或2個F、CHF₂或CF₃取代，並且R2是H、C₁-C₆烷基或CF₃；或者R1和R2組合以形成視需要被F、CHF₂或CF₃取代的C₃-C₅環烷基；R3是視需要被F取代的C₁-C₃烷基或CH₂O-C_1-3烷基；R4選自下組，該組由以下組成：OCF₃、OCH₂CF₃或OCHF₂； 本發明還涉及包含根據本發明所述的化合物的醫藥組合物以及藥學上可接受的載體或賦形劑。 The present invention relates to compounds of formula I

Wherein R1 is selected from the group consisting of: C ₁ -C ₆ alkyl, CF ₃ , CH ₂ CF ₃ , CF ₂ CHF ₂ , C ₃ -C ₈ cycloalkyl, wherein said C ₃ -C ₈ Cycloalkyl can be substituted by 1 or 2 F, CHF ₂ or CF ₃ , and R2 is H, C ₁ -C ₆ alkyl or CF ₃ ; or R1 and R2 are combined to form optionally substituted by F, CHF ₂ or C ₃ -C ₅ cycloalkyl substituted by CF ₃ ; R 3 is C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl optionally substituted by F; R 4 is selected from the group consisting of : OCF ₃ , OCH ₂ CF ₃ or OCHF ₂ ; The present invention also relates to a pharmaceutical composition comprising the compound according to the present invention and a pharmaceutically acceptable carrier or excipient.

Furthermore, the present invention relates to methods of treating patients as described in the claims and examples, and includes treating patients with epilepsy, bipolar disorder, migraine and schizophrenia, comprising administering to a subject or a therapeutically effective amount of a compound according to the invention.

According to one embodiment of the invention, R4 is OCF ₃ or OCHF ₂ , and according to another embodiment, R2 is H or CH ₃ .

In a specific example, R1 is _C3 - _C4cycloalkyl optionally substituted with 1 or 2 F, _CHF2 or _CF3 .

According to certain embodiments, R1 is tertiary butyl, and R2 is H, and R4 is one of _OCF3 , _OCH2CF3 or _{OCHF2 .}

According to another specific embodiment, R1 and R2 combine to form cyclobutyl _optionally substituted with 1 or 2 Fs, and R4 is one of _OCF3 , _OCH2CF3 or _OCHF2 .

According to a specific embodiment of the present invention, the compound according to the present invention is selected from the group consisting of ( S )-3-hydroxy-4,4-dimethyl- N -[( 1S ) -1-[3-(Trifluoromethoxy)phenyl]ethyl]pentanamide, ( R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[ 3-(Trifluoromethoxy)phenyl]ethyl]pentanamide, ( 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)pentamide, ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl) -3-Hydroxy-4,4-dimethylpentanamide, ( R )- N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy- 4,4-Dimethylpentanamide, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl ) pentamide, ( R )-3-hydroxy-4,4-dimethyl- N -((S)-1-(3-(trifluoromethyl)phenyl) ethyl) pentamide, ( S )-3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, ( R )-3- Hydroxy-4,4-dimethyl-N-(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, ( S )-3-(3,3- Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( R )-3-(3,3 -Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( S )-3-hydroxy-4 -Methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, ( R )-3-hydroxy-4-methan Base- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, ( S )-3-(1-(difluoroform Base) cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)propionamide, ( R )-3-(1- (Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( R )-3- Hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, ( S ) -3-Hydroxy- N -(( S )-1-(3 -(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, ( S )-3-hydroxy-4-methyl- N- ( ( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3 -(trifluoromethoxy)phenyl)ethyl)pentanamide, N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl) Ethyl)-3-( R )-hydroxy-4,4-dimethylpentanamide, N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy base)phenyl)ethyl)-3-( S )-hydroxy-4,4-dimethylpentamide, ( S )-3-hydroxy- N -(( R )-2-methoxy-1 -(3-(Trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, ( R )-3-hydroxy- N -(( R )-2-methoxy- 1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, ( S )-2-(3,3-difluoro-1-hydroxycyclobutyl ) -N- (1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, ( S )-2-(1-hydroxycyclobutyl) -N- (1-(3- (2,2,2-Trifluoroethoxy)phenyl)ethyl)acetamide, (3 R )-3-hydroxy-4-methyl- N -[(1 S )-1-[3- (2,2,2-Trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide, (3 S )-3-hydroxy-4-methyl- N -[( 1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide, 4,4,4-trifluoro- 3-Hydroxy- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide, ( R )-4,4 ,5,5-Tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( S )- 4,4,5,5-tetrafluoro-3-hydroxyl-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )-5,5,5-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( S )-5,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide , ( R )-3-(1-fluorocyclopropyl)-3-hydroxyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide, ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy Base) phenyl) ethyl) butyramide, ( R )-2-(1-hydroxycyclopentyl) -N- (2-methoxy-1-(3-(trifluoromethoxy)phenyl )ethyl)acetamide, ( R )-3-cyclopropyl-3-hydroxyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl) Ethyl)butyramide, ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl base) butyramide, ( S )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethane Oxyphenyl) ethyl) butyramide, and ( R )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2, 2,2-trifluoroethoxy)phenyl)ethyl)butanamide.

References to compounds encompassed by the present invention include racemic mixtures of these compounds, optical isomers of related compounds thereof, as well as polymorphic and amorphous forms of the compounds of the present invention, and tautomers of compounds related thereto form. Furthermore, the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The present invention covers both the solvated and unsolvated forms of these compounds.

A compound according to the present invention may be in a pharmaceutical composition comprising the compound together with a pharmaceutically acceptable excipient or carrier.

In a particular example, the invention relates to a compound according to the invention for use in therapy.

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

In yet another embodiment, the present invention relates to a method of treating a patient in need thereof suffering from the following disorders: psychosis, mania, stress-related disorder, acute stress response, bipolar depression, major depression , Anxiety, Panic Disorder, Social Phobia, Sleep Disorder, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizoid Disorder, Aggression, Chronic Pain, Neuropathy, Autism-like Disorders, Huntington's Chorea, sclerosis, multiple sclerosis, Alzheimer's disease, the method comprises administering to a subject a therapeutically effective amount of a compound according to the present invention.

According to particular examples, the compounds of the invention are used in therapy.

The use of the compounds according to the invention is for the treatment of epilepsy, bipolar disorders, head pain or schizophrenia, or in another specific example for the treatment of psychosis, mania, stress-related disorder, acute stress response, bipolar depression, major depression, anxiety, panic disorder, social phobia , Sleep Disorders, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizophrenic Disorder, Aggressive Behavior, Chronic Pain, Neuropathy, Autistic Disorders, Huntington's Disease, Sclerosis, Multiple Sclerosis Syndrome, Alzheimer's disease.

In another embodiment, a compound of the invention is used in the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine, or schizophrenia, or in another embodiment for the manufacture of a medicament for the treatment of psychosis, mania mania, stress-related disorder, acute stress response, bipolar depression, major depression, anxiety, panic disorder, social phobia, sleep disorder, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizoid disorder, aggression Behavior, chronic pain, neuropathy, autism-like disorders, Huntington's disease, sclerosis, multiple sclerosis, Alzheimer's disease.

In the context of the present invention, "optionally substituted" means that the moiety referred to may or may not be substituted, and when substituted, is monosubstituted or disubstituted. It is understood that where no substituent is indicated for an "optionally substituted" moiety, then that position is occupied by a hydrogen atom.

A given range may be denoted interchangeably with "-" (dash) or "to", eg the term "C _1-3 alkyl" is equivalent to "C ₁ to C ₃ alkyl".

The terms "C _1- C ₃ alkyl" and "C _1- C ₆ alkyl" refer to unbranched or branched saturated hydrocarbons having from one up 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 "C ₁ -C ₃ alkoxy" refers to a moiety of formula -OR wherein R represents a C ₁ -C ₃ alkyl group as defined above.

The term "C _3- C ₆ cycloalkyl", "C _3- C ₅ cycloalkyl" or "C _3- C ₈ cycloalkyl" refers to a saturated monocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Delivery route:

Pharmaceutical compositions comprising a compound of the invention as defined above may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular and intravenous) routes; oral routes are preferred.

It will be appreciated that the route will depend on the general condition and age of the subject being treated, the nature of the condition being treated and the active ingredient.

Pharmaceutical formulations and excipients:

Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients, including but not limited to fillers, anti-adherents, binders, coatings, colorants, disintegrants , flavoring agents, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

The invention also provides a pharmaceutical composition comprising a compound according to the invention, for example one of the compounds disclosed in the experimental part herein. The invention also provides methods for the manufacture of pharmaceutical compositions comprising compounds according to the invention. Pharmaceutical compositions according to the present invention may be formulated with pharmaceutically acceptable excipients according to conventional techniques, such as those disclosed in: Remington, The Science and Practice of Pharmacy [pharmaceutical science and practice], 22nd Edition (2012), edited by Allen, Loyd, V., Jr.

Pharmaceutical compositions for oral administration include solid oral dosage forms, such as lozenges, capsules, powders, and granules; and liquid oral dosage forms, such as solutions, emulsions, suspensions, and syrups, and to be dissolved or suspended in suitable liquids. Powders and granules.

Solid oral dosage forms can be presented as discrete units (eg, lozenges or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably, one or more suitable excipients. These solid dosage forms may be prepared, where appropriate, with coatings, such as enteric coatings, or they may be formulated to provide modified release of the active ingredient, such as delayed release, according to methods well known in the art. delayed or extended release. Where appropriate, the solid dosage form may be a dosage form that disintegrates in saliva, such as a dispersible lozenge.

Examples of excipients suitable for solid oral formulations include, but are not limited to: microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talc, Gelatin, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Similarly, solid formulations may include excipients known in the art to delay or prolong release formulations, such as glyceryl monostearate or hypromellose. If a solid material is used for oral administration, the formulation can be prepared, for example, by mixing the active ingredient with a solid excipient, and then compressing the mixture in a conventional tablet press; Powder, pill or mini-tablet forms are placed in hard capsules. The amount of solid excipient will vary widely, but will typically range from about 25 mg to about 1 g per dosage unit.

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

Additional excipients (eg, coloring, flavoring, and preservative agents, etc.) can be used in both solid and liquid oral formulations.

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 to be used before use Sterile solution or dispersion for injection or infusion, sterile powder for reconstitution. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solvents. liquid. Aqueous formulations should be suitably buffered as necessary and rendered isotonic with sufficient saline or glucose.

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

Excipients for any pharmaceutical formulation must be compatible with the intended route of administration and with the active ingredient.

dose:

In one embodiment, a compound of the 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 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The precise dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the subject to be treated, the condition to be treated, the nature and severity of any concomitant disease to be treated, the desired therapeutic effect, and Other factors known to those of ordinary skill in the art.

Typical oral dosages for adults are in the range of 0.1-1000 mg/day of a compound of the invention, eg 1-500 mg/day, eg 1-100 mg/day or 1-50 mg/day. Conveniently, the compound of the invention is administered in unit dosage form comprising said compound in an amount of about 0.1 to 500 mg, eg 10 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg of the compound of the invention.

Isomeric and tautomeric forms:

When compounds of the present invention contain one or more chiral centers, reference to any of these compounds shall encompass enantiomerically or diastereomerically pure compounds and in any ratio unless otherwise stated. A mixture of enantiomers or diastereomers.

MDL enhanced stereo representations are used to describe unknown stereochemistry of compounds of the invention. Therefore, the label "or1" on a chiral carbon atom is used to indicate that the absolute stereoconfiguration at that atom is unknown ; for example, the stereo configuration of the carbon atom is (S) or (R).

Also, the chiral bond from the carbon atom labeled "or1" using an up-wedge or a down-wedge is the same representation; for example, both diagrams have the same meaning, which is absolute on the carbon atom labeled "or1" Stereoconfiguration is unknown and may be (S) or (R).

Therefore, the use of up-wedge and down-wedge bonds from atoms labeled "or1" is intended only to provide a visual cue that the figures represent different stereoisomers, where the configuration of the carbon atom labeled "or1" is Unknown.

Furthermore, some of the compounds of the present invention can exist in different tautomeric forms, and it is intended that any tautomeric forms these compounds are capable of forming are included within the scope of the present invention.

Therapeutically effective dose:

In the context of the present invention, the term "therapeutically effective amount" of a compound means sufficient to alleviate, arrest, partially arrest, remove or delay the clinical course of a given disease and its complications during a therapeutic intervention involving administration of said compound. amount of performance. An amount sufficient to achieve the above is defined as "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 state of the subject. It will be appreciated that determining the appropriate dosage can be accomplished using routine experimentation, by constructing a matrix of values and testing various points in the matrix, all within the ordinary skill of a trained physician.

Treatment (Treatment and treating):

In the context of the present invention, "treatment" or "treating" is intended to indicate the management and care of a patient for the purpose of relieving, arresting, partial arresting, removing the clinical manifestations of a disease or delaying its progression. The patient to be treated is preferably a mammal, especially a human.

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

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

Unless otherwise indicated, any and all examples, or exemplary language (including "for instance", "for example", e.g.) and "as such" used in this specification mean only It is intended to better illustrate the invention and not to limit the scope of the invention.

Patent documents are cited and incorporated herein for convenience only and do not reflect any view on the validity, patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subject matter described in the claims appended hereto as permitted by applicable law.

Additional Specific Examples of the Invention

其中R1選自下組，該組由以下組成：C₁-C₆烷基、CF₃、CH₂CF₃、CF₂CHF₂、C₃-C₈環烷基，其中所述C₃-C₈環烷基可以被1個或2個F、CHF₂或CF₃取代，並且R2是H、C₁-C₆烷基或CF₃；或者R1和R2組合以形成視需要被1個或2個F、CHF₂或CF₃取代的C₃-C₈環烷基；R3是C₁-C₃烷基或CH₂O-C_1-3烷基，所述C₁-C₃烷基或CH₂O-C_1-3烷基可以視需要被1個或2個F取代； R4選自下組，該組由以下組成：C₁-C₆烷氧基、OCF₃、OCH₂CF₃、OCHF₂、CF₃。 1. A compound of formula I

Wherein R1 is selected from the group consisting of: C ₁ -C ₆ alkyl, CF ₃ , CH ₂ CF ₃ , CF ₂ CHF ₂ , C ₃ -C ₈ cycloalkyl, wherein said C ₃ -C ₈ Cycloalkyl can be substituted by 1 or 2 F, CHF ₂ or CF ₃ , and R2 is H, C ₁ -C ₆ alkyl or CF ₃ ; or R1 and R2 are combined to form optionally substituted by 1 or 2 C ₃ -C ₈ cycloalkyl substituted by F, CHF ₂ or CF ₃ ; R3 is C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl, said C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl can be optionally substituted by 1 or 2 F; R4 is selected from the group consisting of C ₁ -C ₆ alkoxy, OCF ₃ , OCH ₂ CF ₃ , OCHF ₂ , CF ₃ .

2. The compound according to embodiment 1, wherein R4 is _OCF3 or _OCHF2 .

3. The compound according to any one of the preceding embodiments, wherein R2 is H or _CH3 .

4. The compound according to any one of the preceding _embodiments , wherein R3 is _{CH2OC1-3alkyl} .

5. The compound according to any one of the preceding embodiments, wherein R1 is C3- _C4cycloalkyl optionally substituted with 1 _or 2 F, _CHF2 or _CF3 .

6. The compound according to any one of the preceding embodiments, wherein R1 is tert-butyl, and R2 is H, and R4 is _OCF3 , _{OCH2CF3 , OCHF2} or _CF3 .

7. The _compound according to any one of the preceding embodiments, wherein R1 and R2 combine to form cyclobutyl optionally substituted by 1 or 2 F, and R4 is _OCF3 , _OCH2CF3 , _OCHF2 or CF ₃ .

8. The compound according to embodiment 1, wherein the compound is selected from the group consisting of ( S )-3-hydroxyl-4,4-dimethyl- N -[( 1S ) -1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide, R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[3 -(trifluoromethoxy)phenyl]ethyl]pentanamide, ( 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, ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)- 3-Hydroxy-4,4-dimethylpentanamide, ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4 ,4-Dimethylpentanamide, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl) Pentamide ( R )-3-Hydroxy-4,4-dimethyl- N -((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide, ( S ) -3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, ( R )-3-hydroxy- 4,4-Dimethyl-N-(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, ( S )-3-(3,3-difluoro Cyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( R )-3-(3,3-di Fluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( S )-3-hydroxy-4-methan Base- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, ( S )-3-(1-(difluoromethyl) Cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)propionamide, ( R )-3-(1-(di Fluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( R )-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, ( S )-3 -Hydroxy- N -(( S )-1-(3-(three Fluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, ( S )-3-hydroxy-4-methyl- N -(( S ) -1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(tri Fluoromethoxy)phenyl)ethyl)pentamide, N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl) -3-( R )-hydroxy-4,4-dimethylpentanamide, N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)benzene Base) ethyl) -3-( S )-hydroxy-4,4-dimethylpentanamide, ( S ) -3-hydroxy- N -(( R )-2-methoxy-1-(3 -(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, ( R )-3-hydroxy- N -(( R )-2-methoxy-1-( 3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, ( S )-2-(3,3-difluoro-1-hydroxycyclobutyl) -N -(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, ( S )-2-(1-hydroxycyclobutyl) -N- (1-(3-(2, 2,2-trifluoroethoxy)phenyl)ethyl)acetamide, (3 R )-3-hydroxy-4-methyl- N -[(1 S )-1-[3-(2, 2,2-Trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide, ( 3S )-3-hydroxy-4-methyl- N -[( 1S ) -1-[3-(2,2,2-Trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide, 4,4,4-trifluoro-3-hydroxy -N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide, ( R )-4,4,5, 5-Tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( S )-4,4 ,5,5-Tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )- 5,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( S ) -5,5,5-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide, ( S )- 3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)benzene Base) ethyl) butyramide, ( R )-2-(1-hydroxycyclopentyl) -N- (2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl ) Acetamide, ( R )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl) Butyramide, ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyl Amide, ( R )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy) Phenyl)ethyl)butanamide, and ( R )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2, 2-Trifluoroethoxy)phenyl)ethyl)butanamide

9. A method of treating a subject suffering from a disease or disorder selected from the group consisting of epilepsy, bipolar disorder, migraine and schizophrenia, Psychosis, Mania, Stress-Related Disorders, Acute Stress Reaction, Bipolar Depression, Major Depression, Anxiety, Panic Disorder, Social Phobia, Sleep Disorder, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizophrenia disorder, aggressive behavior, chronic pain, neuropathy, autism-like disorders, Huntington's disease, sclerosis, multiple sclerosis, Alzheimer's disease, the method comprising administering to a subject a therapeutically effective amount of Compounds as described in specific examples 1-8.

10. Use of the compounds disclosed in specific examples 1 to 8 in therapy.

11. Use of the compounds disclosed in specific examples 1 to 8 for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia.

12. Use of the compounds disclosed in specific examples 1 to 8 for the treatment of the following diseases: psychosis, mania, stress-related disorders, acute stress response, bipolar depression, major depression, anxiety, panic disorder, social phobia , Sleep Disorders, ADHD, PTSD, OCD, Impulsive Disorder, Personality Disorder, Schizophrenic Disorder, Aggressive Behavior, Chronic Pain, Neuropathy, Autistic Disorders, Huntington's Disease, Sclerosis, Multiple Sclerosis Syndrome, Alzheimer's disease.

13. A compound as disclosed in Embodiments 1 to 8 for use in the manufacture of a medicament for treating epilepsy, bipolar disorder, migraine or schizophrenia.

14. A compound disclosed in specific examples 1 to 8 for the manufacture of a medicament for the treatment of the following diseases: psychosis, mania, stress-related disorders, acute stress response, bipolar depression, major depression, anxiety, panic disorder, Social phobia, sleep disorder, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizoid disorder, aggressive behavior, chronic pain, neuropathy, autistic disorder, Huntington's chorea, sclerosis, Multiple sclerosis, Alzheimer's disease.

Experimental part biological assessment cell culture

Synthetic cDNA fragments encoding human Kv7.3 and human Kv7.2 isolated from the P2A sequence were inserted into the pcDNA5/FRT/TO vector using BamHI and XhoI restriction sites. The constructs were then transfected into HEK Flp-In 293 cells using Lipofectamine2000. The transfected cells were grown in DMEM containing 10% (v/v) FBS and 1% PenStrep for 48 hours, and then in DMEM containing 10% (v/v) FBS, 1% PenStrep and 200ug/mL hygromycin B was maintained under selection in DMEM at 37 °C in a humidified atmosphere of 5% _CO . The generated stable hKv7.2/hKv7.3 cell line (HEK-hKv7.2/hKv7.3) was functionally tested with automated whole-cell patch clamp and showed typical Kv7 currents that were sensitive to XE991 And enhanced by retigabine.

Thallium flux assay

Thallium flux for potassium channel activation was performed using the FLIPR Potassium Assay Kit (Molecular Device) similar to published procedures (C.D. Weaver et al., J Biomol Screen 2004, 9, 671-677) Determination. HEK-hKv7.2/hKv7.3 cells were plated at 80,000 cells/well (100 μl/well) (if assaying these cells the next day) or 40,000 cells/well (100 μl/well) (if two days after seeding) The density of these cells) was determined by plating in 96-well, black-walled, clear-bottom culture dishes (Corning, Acton, MA, USA).

On assay day, medium was removed, after which 50 uL/well of test compound was diluted to 2x final concentration in HBSS containing 20 mM HEPES, and 50 uL/well of 2x dye loading buffer was added. These cells were then incubated for 60 min at room temperature in the dark. Chloride-free stimulation buffer containing Tl ⁺ and K ⁺ and test compounds at 1x final concentration were prepared during incubation at 5x final concentration (5x concentration in both cases: 5 mM). These cells were then assayed in the FDSS7000EX Functional Drug Screening System (Hamamatsu). After baseline fluorescence signal readings at 0.1 Hz for 60 sec and 1 Hz for 10 sec, 25 uL/well of stimulation buffer was added and fluorescence was continuously measured for 50 sec at 1 Hz followed by 4 min at 0.1 Hz. Compound effects were quantified using AUC as readout and normalized to the reference compound contained on each plate.

Compound effect

In the assays described above, the compounds of the invention have the following biological activities:

Synthesis of compounds of the present invention: General method:

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

Chromatographic systems and methods to assess chemical purity (LCMS method) and chiral purity (SFC and HPLC method) are described below.

LCMS Method 1 : Instrument: Agilent 1200 LCMS system with ELS detector.

LCMS method 2 : Instrument: Agilent 1200 LCMS system with ELS detector

LCMS method 3 : Instrument: Agilent 1200 LCMS system with ELS detector

LCMS method 4 : Instrument: Agilent 1200 LCMS system with ELS detector

LCMS Method 5 : Instrument: Agilent 1200 LCMS system with ELS detector

LCMS method 6 : Instrument: Agilent 1200 LCMS system with ELS detector

SFC method 1 : Instrument: Agilent 1260 with DAD detector

SFC Method 2 : Instrument: Waters UPC2

SFC Method 3 : Instrument: Waters UPC2

SFC Method 4 : Instrument: Agilent 1260

SFC Method 5 : Instrument: Agilent 1260

SFC Method 6 : Instrument: Waters UPC2

SFC Method 7 : Instrument: Waters UPC2

SFC Method 8 : Instrument: Agilent 1260

SFC Method 9 : Instrument: Agilent 1260

SFC Method 10 : Instrument: Agilent 1260

SFC Method 11 : Instrument: Waters UPC2

SFC Method 12 : Instrument: Agilent 1260

SFC Method 13 : Instrument: Agilent 1260

SFC Method 14 : Instrument: Agilent 1260

SFC Method 15 : Instrument: Agilent 1260

SFC Method 16 : Instrument: Agilent 1260

Chiral HPLC method 1 : Instrument: Shimadzu (SHIMADZU) LC-20AB

Chiral HPLC method 2 : Instrument: Shimadzu LC-20AB

General procedures for the synthesis of intermediates and compounds of general formula I are described in Reaction Scheme 1 and specified in the Preparations and Examples. Within the scope of the invention are variations of the described procedures known to those skilled in the art.

Compounds of the invention were prepared as described in Scheme 1 . Several of the compounds of general formula I contain two chiral carbon atoms and are formed as mixtures of diastereomers. When this is the case, the diastereoisomers can be separated to yield single stereoisomers Ia and Ib.

Scheme I depicts the preparation of compounds of general formula I by two general routes. The first route is by methods known in the art for the conversion of acids and amines into amides, by combining Compounds of formula I are synthesized by the reaction of enantiomerically pure amines of formula II and acids of general formula III. This process involves the formation of reactive derivatives of acids of formula III (including but not limited to active esters) and reactive mixed anhydrides, followed by condensation with amines of general formula II. One such method is based on HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphoric acid ester) and a suitable base such as DIPEA (diisopropylethylamine) in a solvent such as dichloromethane.

Alternatively, when R ² is H, compounds of general formula I can be prepared via a second general route, wherein an intermediate of general formula V is treated with a suitable reducing agent (eg NaBH ₄ ) in a suitable solvent ( such as methanol). Intermediates of formula V can be obtained from enantiomerically pure amines of general formula II and carboxylic acids of general formula IV (R=H). This transformation can be performed using similar reaction conditions as described above for the condensation of II and III to form I.

A variation of this procedure is a direct coupling reaction between a chiral amine of general formula II and a carboxylate of general formula IV (R=Me, Et). 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 DMAP (4-dimethylaminopyridine)), can be obtained by adding The reaction was carried out by heating the reactants to reflux.

Optional active amines of general formula II can be prepared as outlined in Scheme 2:

Aldehydes of general formula VI can be combined with ( R )-2-formaldehyde in a suitable solvent (such as dichloroethane) in the presence of a desiccant (such as titanium(IV) isopropoxide, or copper sulfate). Propane-2-sulfinamide condensation. Treatment of the formed sulfinylimine with R ³ MgBr in a suitable inert solvent (such as THF) yields the corresponding substituted ( R )-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 .

The aldehydes of formula VI used in the preparation of the compounds of the present invention are commercially available, or can be obtained as described in the literature (see fx . Prepared as described.

In a variation of this procedure, as shown in Scheme 3, by hydride reduction of the intermediate sulfinylimine with a reagent such as lithium tri-sec-butylborohydride (L-selectride), the compound of formula II Chiral amines can be obtained from aryl ketones.

Ketones useful in the preparation of compounds of the invention are commercially available or can be prepared by methods known to those skilled in the art.

Another variation of this procedure, as outlined in Scheme 4, is particularly suitable for obtaining chiral amines of general formula II (wherein ^R3 is a hydroxymethylene derivative).

Option 4:

)中，如在JP 2017/095366 A中所描述的，可以將在乙醛酸酯和(R)-2-甲基丙烷-2-亞磺醯胺之間的縮合反應中形成的乙醛酸亞磺醯基亞胺與合適取代的硼酸反應。可以將所得中間體VIII水解並再保護，以產出具有通式IX的中間體，可以將其進一步衍生以獲得所希望的R³取代基。在本發明的化合物中，可以將IX的羧酸酯基團使用LAH(氫化鋁鋰)還原為羥基亞甲基，並且使用適合的試劑(例如2,2-二氟-2-(氟磺醯基)乙酸)，在以下條件下，如CuI催化，在適合的溶劑(例如乙腈)中進行二氟甲基化。 In this procedure, a suitable catalyst such as bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate is used in a suitable solvent such as di

), as described in JP 2017/095366 A, glyoxylic acid formed in the condensation reaction between glyoxylate and (R)-2-methylpropane-2-sulfinamide can be The sulfinyl imine is reacted with an appropriately substituted boronic acid. The resulting intermediate VIII can be hydrolyzed and reprotected to yield an intermediate of general formula IX which can be further derivatized to obtain the desired ^R3 substituent. In compounds of the invention, the carboxylate group of IX can be reduced to the hydroxymethylene group using LAH (lithium aluminum hydride) and a suitable reagent such as 2,2-difluoro-2-(fluorosulfonyl base) acetic acid), difluoromethylation is carried out in a suitable solvent (eg acetonitrile) under the following conditions, as catalyzed by CuI.

Those skilled in the art will recognize that other transformations from intermediates of general formula IX are possible; the present invention is intended to cover such alternative transformations.

Carboxylic acids of general formula III can be prepared as outlined in Scheme 5:

Reaction of ketones of general formula X with alkyl esters of bromoacetic acid activated by eg Zn and iodine yields the corresponding aldol adducts. In an alternative procedure, bromoacetate can be activated using Zn and TMSCl (trimethylsilyl chloride). In a final step, the alkyl group is completed by treatment with a suitable base (such as NaOH or LiOH) in a suitable solvent (such as water, or alcohol in water) Hydrolysis of the ester, followed by acidification with a suitable acid, yields compounds of formula III.

Preparation of intermediates:

IIa: ( S )-1-(3-(trifluoromethoxy)phenyl)ethanamine hydrochloride

Step 1: Preparation of ( R )-2-methyl- N- (3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide

At 55°C, 3-(trifluoromethoxy)benzaldehyde (24.8g, 130.4mmol), ( R )-2-methylpropane-2-sulfinamide (19g, 156.5mmol) and CuSO ₄ (31.2 g, 195.7 mmol) in DCE (1,2-dichloroethane) (500 mL) was stirred for 24 hours. The mixture was filtered and the filter cake was washed with DCM (dichloromethane) (200 mL). The organic phases were combined and concentrated. The residue was purified by flash chromatography on silica gel (0-15% ethyl acetate/petroleum ether (gradient)) to yield the product (33 g, 86% yield).

¹ H NMR (CDCl ₃ 400MHz): δ 8.59(s,1 H),7.79-7.71(m,2H),7.53(t, J =8.0Hz,1H),7.38(d, J =8.0Hz,1H) ,1.28(s,9H).

Step 2: Preparation of (R )-2-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfinamide

At 0°C, to ( R )-2-methyl- N -[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamide (17.6g, 59.8mmol) To a solution in DCM (250 mL) was added MeMgBr (3M in _Et2O , 40 mL) dropwise. The resulting mixture was stirred at 0°C for 1 hour and at 15°C for 16 hours. The mixture was cooled to 0 °C, and a saturated solution of _NH4Cl was added. The resulting mixture was extracted with DCM (100 mL x 2). The organic phase was washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on silica gel with 0-50% ethyl acetate/petroleum ether (gradient) to give the product (10.3 g, 56% yield).

¹ H NMR (CDCl ₃ 400MHz): δ 7.37(t, J =8.0Hz, 1 H), 7.27-7.24(m, 1 H), 7.21(s, 1 H), 7.13(br d, J =8.0Hz ,1H), 4.65-7.59(m,1H), 3.32(br d, J =2.4Hz,1H), 1.54(d, J =6.4Hz,3H), 1.22(s,9H).

Step 3: Preparation of (S )-1-(3-(trifluoromethoxy)phenyl)ethanamine hydrochloride

( R )-2-Methyl- N -[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]propane-2-sulfinamide in MeOH (75 mL) (10 g, 32.3 mmol) was treated with HCl/MeOH (75 mL) and stirred at 15 °C for 16 h. The mixture was concentrated to give ( S )-1-(3-(trifluoromethoxy)phenyl)ethanamine hydrochloride (9 g, crude product), which was used without further purification.

IIb: (1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethanamine hydrochloride

Step 1: Preparation of 3-(2,2,2-trifluoroethoxy)benzaldehyde

At 20°C, 3-hydroxybenzaldehyde (5g, 40.9mmol), 2,2,2-trifluoroethyl triflate (10.5g, 45mmol) and Cs ₂ CO ₃ (26.7g, 81.9 mmol) in DMF (60 mL) was stirred for 2 hours. The mixture was filtered and the filter cake was washed with ethyl acetate (200ml). The filtrate was washed with water (100 mL x 2) and brine (100 mL x 2), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give the product (8.0 g, 95% yield).

¹ HNMR (CDCl ₃ 400MHz): δ 7.58-7.51(m,2 H),7.42(s,1 H),7.27-7.25(m,1 H), 4.42(q, J =12.0Hz, J =8.0Hz ,2 H).

Step 2: Preparation of ( R )-2-methyl- N -[[3-(2,2,2-trifluoro-ethoxy)phenyl]methylene]propane-2-sulfinamide

At 55°C, 3-(2,2,2-trifluoroethoxy)benzaldehyde (8.0g, 39.2mmol), ( R )-2-methylpropane-2-sulfinamide (5.2g , 43.1 mmol) and CuSO ₄ (9.4 g, 58.8 mmol) in DCE (70 mL) was stirred for 20 hours. The mixture was filtered and the filter cake was washed with DCM (100 mL). These organic phases were concentrated and purified by column chromatography on silica gel (11% ethyl acetate in petroleum ether) to yield the product (10.0 g, 83% yield).

¹ H NMR (CDCl ₃ 400MHz): δ 8.55(s, 1 H), 7.50-7.42(m, 3 H), 7.13(d, J =5.2Hz, 1 H), 4.41(q, J =12.0Hz, J =8.0Hz,2H), 1.27(s,9H).

Step 3: (R )-2-Methyl-N-(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinyl Amine preparation

At 0°C, to ( R )-2-methyl- N -[[3-(2,2,2-trifluoroethoxy)phenyl]methylene]propane-2-sulfinamide ( 10 g, 32.5 mmol) in DCM (100 mL) was added MeMgBr (3M, 43 mL) dropwise. The resulting mixture was stirred at 0°C for 1 hour and at 20°C for 3 hours. The mixture was cooled to 0 °C, and a saturated solution of _NH4Cl was added. The resulting mixture was extracted with DCM (100 mL x 2). The organic phase was washed with brine (200 mL), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=1:1) to give the product (9 g, 79% yield).

¹ H NMR (CDCl ₃ 400MHz): δ 7.27 (d, J =8.4Hz, 1 H), 7.01 (d, J =8.4Hz, 1 H), 6.93 (d, J =2.4Hz, 1 H), 6.83 (dd, J =8.4Hz, J =2.4Hz,1H),4.56-4.54(m,1H), 4.34(dd, J =16.4Hz, J =8.4Hz,1H),3.30(br s, 1H), 1.51(d, J =8.4Hz, 3H), 1.20(s, 9H). NH was not observed.

Step 4: Preparation of (1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethanamine hydrochloride

To ( R )-2-methyl- N -[(1S)-1-[3-(2,2,2-trifluoroethoxy) phenyl] ethyl] propane-2-sulfinamide ( 9 g, 27.8 mmol) in MeOH (100 mL) was added HCl/MeOH (80 mL, 4M). The resulting mixture was stirred at 20°C for 4 hours, and concentrated to give the crude product (8 g), which was used without further purification.

IIc: ( S )-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

Step 1: Preparation of ( R ) -N- (3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide

3-(Difluoromethoxy)benzaldehyde (2 g, 11.6 mmol) and 2-methylpropane-2-sulfinamide (1.7 g, 13.9 mmol) were dissolved in DCE ( 60 mL) was added CuSO ₄ (9.3 g, 58.1 mmol). The mixture was stirred at 55°C for 12 hours, filtered and the filtrate was concentrated. The crude product was purified by a silica gel column (the silica gel column was eluted with petroleum ether/ethyl acetate=20:1-10:1) to give ( R ) -N- (3-(difluoromethoxy )benzylidene)-2-methylpropane-2-sulfinamide (2.5 g, 70% yield).

Step 2: Preparation of (R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To ( R ) -N- (3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2g, 7.3mmol) in DCM (30mL) at 0°C ) was added dropwise (methyl)magnesium bromide (3M in _Et2O , 4.8 mL). The resulting mixture was stirred at 0°C for 1 hour and at 20°C for 16 hours. The reaction was quenched with NH ₄ Cl (saturated aqueous solution, 10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (40 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1-1:1) , to provide ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl))-2-methylpropane-2-sulfinamide (960 mg, 45.4% yield ).

Step 3: Preparation of (S )-1-(3-(difluoromethoxy)phenyl)ethanamine hydrochloride

To ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.8g, 2.8mmol) To a solution in MeOH (4 mL) was added HCl/MeOH (4M, 2 mL). The resulting mixture was stirred at 25 °C for 3 hours, and the reaction was concentrated to afford ( S )-1-(3-(difluoromethoxy)phenyl)ethanamine in a crude yield of 1.6 g, which It was used directly without further purification.

IId: ( S )-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride

Step 1: Preparation of (R )-2-methyl- N- (3-(trifluoromethyl)benzylidene)propane-2-sulfinamide

At 55 °C, 3-(trifluoromethyl)benzaldehyde (4.5 g, 25.8 mmol), ( R )-2-methylpropane-2-sulfinamide (3.8 g, 31 mmol) and CuSO ₄ ( 6.2 g, 38.8 mmol) in DCE (20 mL) was stirred for 24 hours. The mixture was filtered and the filter cake was washed with DCM (100 mL). The filtrate was concentrated and the residue was purified by column chromatography ( _Si02 , petroleum ether/ethyl acetate) to afford the product in 4.6 g yield (58%).

¹ H NMR (CDCl _3, 400MHz): δ 8.60(s,1H),8.09(s,1H),7.98(d, J =7.6Hz,1H),7.73(d, J =7.6Hz,1H),7.59 (t, J =7.6Hz, 1H), 1.25(s, 9H).

Step 2: Preparation of (R)-2-methyl-N-((S)-1-(3-trifluoro-methyl)phenyl)ethyl)propane-2-sulfinamide

To ( R )-2-methyl- N- (3-(trifluoromethyl)benzylidene)propane-2-sulfinamide (2 g, 7.2 mmol) in DCM (50 mL) at 0 °C To the solution in , MeMgBr (3M in _Et2O , 9.6 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1 hour and at 25°C for 3 hours. The reaction mixture was cooled to 0° C., and saturated aqueous NH ₄ Cl was added. The mixture was extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate) to afford the desired product (1.3 g, 61% yield).

¹ H NMR (CDCl _{3 ,} 400MHz): δ 7.40-7.65 (4H), 4.11-4.06 (m, 1H), 1.51 (d, J = 6.8Hz, 3H), 1.17 (s, 9H). NH was not observed.

Step 3: Preparation of ( S )-1-[3-(trifluoromethyl)phenyl]ethanamine hydrochloride

To ( R )-2-methyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfonamide (1.3g, 4.4mmol) in MeOH (20 mL) was added HCl/MeOH (4M, 20 mL). The resulting mixture was stirred at 25°C for 20 hours, and then concentrated to provide a yield of 850 mg of product. The crude product was used directly without further purification.

IIe: ( S )-1-(3-(trifluoromethoxy)phenyl)propane-1-amine hydrochloride

Step 1: Preparation of (R )-2-methyl- N- (3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide:

At 55°C, 3-(trifluoromethoxy)benzaldehyde (10.0g, 52.60mmol), ( R )-2-methylpropane-2-sulfinamide (7.7g, 63.1mmol) and CuSO4 (12.6 g, 78.9 mmol) in DCE (200 mL) was stirred for 16 hours. The mixture was filtered and the filter cake was washed with DCM (200 mL). The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (0-10% ethyl acetate/petroleum ether gradient) to give a yield of 12.6 g (81.7%) of ( R )-2-formazan -N -[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamide.

Step 2: Preparation of (R )-2-methyl- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)propyl)propane-2-sulfinamide

To ( R )-2-methyl- N- (3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (2.0 g, 6.8 mmol) in DCM ( 40 mL) was added EtMgBr (3M in _Et2O , 9.1 mL) dropwise. The resulting mixture was stirred at 0°C for 1 hour and at 20°C for 3 hours. The mixture was cooled to 0 °C and saturated aqueous _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 Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on silica gel (0-50% ethyl acetate/petroleum ether gradient) to yield the product (1.4 g, 62% yield).

Step 3: Preparation of ( S )-1-[3-(trifluoromethoxy)phenyl]propane-1-amine hydrochloride

To ( R )-2-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide (1.4g, 4.2mmol) To a solution in MeOH (40 mL) was added HCl/MeOH (4M, 20 mL). The resulting mixture was stirred at 30 °C for 12 hours, and then concentrated to give crude ( S )-1-[3-(trifluoromethoxy)phenyl]propan-1-amine hydrochloride, which was (1 g) was used without further purification.

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

Step 1: Preparation of 2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanone

To a solution of 2-bromo-1-(3-(trifluoromethoxy)phenyl)ethanone (3.5 g, 12.4 mmol) in MeOH (60 mL) was added Ag ₂ CO ₃ (3.8 g, 13.6 mmol) and _BF3.Et2O (2.1 _g , 14.8 mmol). The mixture was stirred at 50 °C under _N2 for 16 h. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , eluent: 0-5% ethyl acetate/petroleum ether) to give 2-methoxy-1-(3-(trifluoro-methoxy yl)phenyl)ethanone (2.1 g, 64% yield).

¹ H NMR (400MHz, CDCl ₃ )δ 7.87(d, J =8.0Hz, 1H), 7.80(s, 1H), 7.52(t, J =8.4Hz, 1H), 7.46-7.42(m, 1H), 4.68(s,2H), 3.51(s,3H).

Step 2: ( R ) -N- (2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethylene)-2-methylpropane-2-sulfinamide preparation

To a solution of 2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanone (500 mg, 2.1 mmol) in THF (15 mL) was added titanium(IV) isopropoxide (910 mg, 3.2mmol) and ( R )-2-methylpropane-2-sulfinamide (336mg, 2.8mmol). The mixture was stirred at 50 °C under _N2 for 1 h. The reaction mixture was quenched with brine (40 mL), and extracted with ethyl acetate (30 mL×2). The combined organic phases were dried over _MgSO4 , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , eluent: 0-10% ethyl acetate/petroleum ether) to give ( R ) -N- (2-methoxy-1-(3 -(trifluoromethoxy)phenyl)ethylene)-2-methylpropane-2-sulfinamide (160 mg, 20% yield).

Step 3: ( R ) -N -(( R )-2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethyl)-2-methylpropane-2-sulfin Preparation of amides

At 0°C, to ( R ) -N- (2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethylene)-2-methylpropane-2-sulfinyl To a solution of the amine (160 mg, 0.5 mmol) in THF (5 mL) was added lithium tri-sec-butylborohydride (1M in THF, 1.42 mmol, 1.42 mL). The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with methanol (20 mL), and then filtered and concentrated. The residue was purified by column chromatography ( _Si02 , eluent: 0-10% ethyl acetate/petroleum ether) to give the desired product (100 mg, 59% yield).

¹ H NMR (400MHz,DMSO- d ⁶ )δ 7.46-7.40(m,3H),7.27-7.25(m,1H),5.86(d, J =8.8Hz,1H),5.25(d, J =5.6Hz ,2H), 4.84-4.72(m,1H), 3.25(s,3H), 1.09(s,9H).

Step 4: Preparation of (R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanamine

( R ) -N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethane in HCl/MeOH (10 mL, 4M) at 20 °C (280 mg, 0.8 mmol) was stirred for 14 hours. The reaction mixture was concentrated, and the residue was diluted with water (30 mL), ammonium hydroxide was added to pH=8-9, and extracted with ethyl acetate (30 mL×2). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated to give the product as a yellow oil (170 mg, 88% yield). The product was used directly without further purification.

IIg: (1 R )-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine

Step 1: Preparation of ethyl 2-[( R )-tertiary butylsulfinyl]iminoacetate

To a solution of ethyl 2-oxoacetate (7.5 g, 36.7 mmol) and ( R )-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol) in DCM (150 mL) CuSO ₄ (12.9 g, 80.8 mmol) was added, and the reaction mixture was stirred at 25° C. for 24 hours. The solid was filtered off, 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 yield the desired product (5.1 g, 67.6% yield).

Step 2: Ethyl (2 R )-2-[[( R )-tertiary butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate preparation

(100mL)中的溶液裡添加[Rh(COD)(MeCN)₂]BF₄(1.3g，3.4mmol)，並將此混合物在80℃下攪拌16小時。將該產物通過矽膠層析法(石油醚：乙酸乙酯=5：1)進行純化，以產出9.8g(78%)。 Ethyl-2-[( R )-tertiary butylsulfinyl]iminoacetate (7g, 34.1 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (8.4g , 40.9mmol) in two

To a solution in (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 hours. The product was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to yield 9.8 g (78%).

Step 3: Preparation of ethyl (2 R )-2-amino-2-[3-(trifluoro-methoxy)phenyl] acetate hydrochloride

Ethyl (2 R )-2-[[( R )-tertiary butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate (9.8g , 26.7 mmol) in MeOH (100 mL) was added HCl/MeOH (4M, 100 mL) and the mixture was stirred at 25 °C for 2 h and then concentrated to afford ethyl(2 R )-2-amine 2-[3-(trifluoromethoxy)phenyl]acetate (7.8 g, crude product).

Step 4: Preparation of ethyl (2 R )-2-(tertiary butoxycarbonylamino)-2-[3-(trifluoromethoxy)phenyl]acetate

To a mixture of ethyl( 2R )-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate hydrochloride (6 g, 20 mmol) in THF (150 mL) was added Boc ₂ O (8.7 g, 40 mmol). Then NaHCO ₃ (1.7 g, 20 mmol) was added to this solution and stirred at 25° C. for 16 hours. This mixture was concentrated and purified by chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to afford the product (7.2 g, 99% yield).

Step 5: Preparation of tertiary butyl N -[(1 R )-2-hydroxy-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate

To a suspension of LiAlH ₄ (1.7 g, 44 mmol) in THF (200 mL) was added ethyl(2 R )-2-(tertiary butoxycarbonylamino)-2-[ 3-(Trifluoro-methoxy)phenyl]acetate (4 g, 11 mmol) while ice cooling. After the addition, the reaction was allowed to warm to 25°C and stir for 2 hours. Anhydrous magnesium sulfate was added, and then a drop of water and ethyl acetate were added sequentially. Insoluble material was filtered off through a pad of celite. The filtrate was concentrated and purified by chromatography on silica gel (SiO ₂ ; petroleum ether:ethyl acetate=5:1 ) (2.1 g, 59% yield).

Step 6: Preparation of tertiary butyl N -[(1 R )-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate

To tertiary butyl N -[( 1R )-2-hydroxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]carbamate (1.5g, 4.7mmol) in MeCN (20 mL) was added CuI (360 mg, 1.9 mmol) and stirred at 25 °C under _N2 atmosphere for 30 min. Subsequently, a solution of 2,2-difluoro-2-fluorosulfonyl-acetic acid (1.7 g, 9.3 mmol) in MeCN (5 mL) was added over 30 minutes at 45 °C, and the reaction was heated at 45 °C Stir for 1 hour. This mixture was concentrated and then diluted with ethyl acetate (100 mL), filtered and concentrated to afford the desired product (1.5 g, crude).

Step 7: Preparation of (1 R )-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine

At 25°C, to tertiary butyl N -[(1 R )-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate To a solution of the ester (1.5 g, 4 mmol) in MeOH (15 mL) was added HCl/MeOH (4M in MeOH, 30 mL), and the reaction was stirred at 25 °C for 30 min. Ammonium hydroxide (30%) was added to pH = 9, and this solution was concentrated and purified by chromatography on silica gel (SiO ₂ ; petroleum ether: ethyl acetate = 2:1) to provide (1 R ) - 2-(Difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine (700 mg, 64% yield).

IIIa: 2-(1-Hydroxycyclobutyl)acetic acid

Step 1: Preparation of ethyl 2-(1-hydroxycyclobutyl) acetate

To Zn (14.9 g, 228.3 mmol) in THF (20 mL) was added TMSCl (1.9 g, 17.1 mmol) in portions. The resulting mixture was stirred at 20°C for 15 min and then refluxed. The reaction mixture was cooled to room temperature, and ethyl 2-bromoacetate (28.6 g, 171.2 mmol) was added dropwise at such a rate that the reaction boiled slowly. The resulting mixture was stirred at 70°C for 1 hour and then at 20°C for 1 hour before adding a solution of cyclobutanone (10 g, 142.7 mmol) in THF (5 mL). The mixture was stirred for a further 2 hours at 20°C. The mixture was poured into NH ₃ .H ₂ O (150 mL, 25%) on ice and extracted with ethyl acetate (100 mL x 2). The organic layer was washed with water (200 mL x 2) and brine (100 ml x 2), dried over Na ₂ SO ₄ and concentrated to give the product (12 g, crude).

¹ H NMR (CDCl ₃ 400MHz): δ 4.20-4.14 (m, 2 H), 3.69 (s, 1 H), 2.65 (s, 2 H), 2.17- 2.12 (m, 2 H), 2.03-2.00 ( m,2H), 1.78(m,1H), 1.58(m,1H), 1.27(t, J =7.6Hz,3H).

Step 2: Preparation of 2-(1-hydroxycyclobutyl)acetic acid

NaOH (6.3 g, 158.05 mmol) was dissolved in MeOH (150 mL) and H ₂ O (50 mL), and ethyl 2-(1-hydroxycyclobutyl)acetate (10 g, 63.2 mmol) was added. The mixture was stirred at 20°C for 16 hours, and then concentrated, and the residue was acidified to pH=2-3 by 2N HCl solution, and extracted with ethyl acetate (200ml x 2). The organic extract was washed with water (100 mL x 2) and brine (100 mL x 2), dried over Na ₂ SO ₄ , and concentrated to give the crude product (6 g, crude).

¹ H NMR (CDCl ₃ 400MHz): δ 2.74 (s, 2 H), 2.23-2.05 (m, 4 H), 1.81 (m, 1 H), 1.63-1.58 (m, 1 H).

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

Step 1: Preparation of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate

To a solution of 3,3-difluorocyclobutanone (0.2 g, 1.9 mmol), Zn (198 mg, 3 mmol) and I ₂ (10 mg, 0.04 mmol) in THF (13 mL) was added dropwise under N ₂ 2-Bromoacetate (378mg, 2.3mmol). The mixture was stirred at 55°C for 6 hours. 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×3). The organic extracts were washed with NaHCO ₃ (sat. aq., 10 mL), dried over Na ₂ SO ₄ and concentrated. The crude product (0.26 g) was used without further purification.

Step 2: Preparation of 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetic acid

To ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate (0.26 g, 1.3 mmol) in MeOH (10 mL) and H ₂ O (2 mL) at 0° C. NaOH (107 mg, 2.7 mmol) was added to the solution. The mixture was stirred at 20°C for 8 hours. The reaction solution was cooled to 0°C, and 1N HCl was added to the solution until the pH reached 1-2. The residue was diluted with brine (10 mL) and extracted with methyl-tert-butyl ether (30 mL×5). _The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The crude product (0.24 g) was used without further purification.

IIIc: 3-Hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid

Step 1: Preparation of ethyl 3-hydroxy-4-methyl-3-(trifluoro-methyl)valerate

To a mixture of Zn (560 mg, 8.6 mmol), _I2 (7 mg, 0.03 mmol) in THF (5 mL) was added ethyl 2-bromoacetate (524 mg, 3.1 mmol) and 1,1 at 15 °C , 1-Trifluoro-3-methyl-butan-2-one (0.4 g, 2.9 mmol). The mixture was stirred at 60°C for 6 hours. H ₂ SO ₄ (10% aq., 4 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 4). The combined organic phases were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give ethyl 3-hydroxy-4-methyl-3-(trifluoromethyl)pentanoate (1 g , crude product).

Step 2: Preparation of 3-hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid

Ethyl 3-hydroxy-4-methyl-3-(trifluoro-methyl)pentanoate (1.5 g, crude product) and LiOH.H ₂ O (552 mg, 13.2 mmol) were dissolved in THF at 15 °C (20 mL) and _H2O (10 mL) was stirred for 16 h. The pH was adjusted to about 3 with 2M HCl, and the mixture was extracted with ethyl acetate (5 mL x 4). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 3-hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid ( 1.1 g, crude product), which was used directly in the next step without further purification.

IIId: 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoic acid

Step 1: Preparation of ethyl 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoate

3,3,4,4-Tetrafluorobutan-2 _- one (2.00 g, 13.88 mmol), Zn (1.0 g, 15.7 mmol) and I ₂ (35.2 mg, 0.14 mmol) in THF (20 mL) was added ethyl 2-bromoacetate (2.4 g, 14.3 mmol) dropwise. The mixture was stirred at 60°C for 6 hours. The reaction mixture was cooled to 0°C, and H ₂ SO ₄ (15 ml, 10% aq.) was added carefully. The mixture was extracted with ethyl acetate (80 mL x 3), and the combined organic extracts were washed with saturated aqueous NaHCO ₃ (30 mL), dried over Na ₂ SO ₄ and concentrated. The title compound (2.5 g, crude product) was obtained and used in the next step without further purification.

Step 2: Preparation of 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoic acid

Ethyl 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-pentanoate (2.5 g, 10.8 mmol) in MeOH (80 mL) and H ₂ O (25 mL) was dissolved at 0°C NaOH (1.1 g, 26.9 mmol) was added to the solution in . The mixture was stirred at 20°C for 8 hours and concentrated. The aqueous layer was acidified with 1N aqueous HCl to pH=1-2, and extracted with methyl-tert-butyl ether (30 mL×5). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated. The title compound (2.10 g, crude product) was obtained and used without further purification.

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

Step 1: Preparation of ethyl 5,5,5-trifluoro-3-hydroxy-3-methylpentanoate

To a mixture of Zn (6.9 g, 104.7 mmol) and I ₂ (89 mg, 0.35 mmol) in THF (80 mL) was added 4,4,4-trifluorobutan-2-one (4.4 g , 34.9 mmol) and ethyl 2-bromoacetate (6.4 g, 38.4 mmol). The mixture was stirred at 60°C for 6 hours. The reaction mixture was cooled to 0 °C and quenched with _H2SO4 (100 _mL , 10% in water). The mixture was extracted with ethyl acetate (15 mL×3). The combined organic extracts were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The product (11.00 g, crude) was obtained and used without further purification.

Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

Ethyl 5,5,5-trifluoro-3-hydroxy-3-methyl-pentanoate (11 g, crude product) and NaOH (4.1 g, 102.7 mmol) were dissolved in H ₂ O (150 mL ) was stirred for 16 hours. The pH was adjusted to about 2 with saturated KHSO ₄ at 0° C., and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated to afford the product (10 g, crude).

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

Step 1: Preparation of ethyl 3-(1-fluorocyclopropyl)-3-hydroxybutyrate

To 1-(1-fluorocyclopropyl)ethanone (0.8g, 7.8mmol), Zn (1.5g, 23.5mmol) and I ₂ (20mg, 0.8mmol) in THF (15mL) at 15°C Ethyl 2-bromoacetate (1.4 g, 8.6 mmol) was added dropwise to the mixture. The mixture was stirred at 65°C for 6 hours. The reaction mixture was cooled _to 0 °C, and _H2SO4 (10% aqueous solution, 10 mL) was added dropwise. Water (30 mL) was added to the mixture and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The product obtained was used without further purification. Yield: 1.6 g, crude product.

Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxybutyric acid

Ethyl 3-(1-fluorocyclopropyl)-3-hydroxy-butyrate (1.6 g, crude product) and NaOH (670 mg, 16.8 mmol) were dissolved in H ₂ O (30 mL) at 15 °C The mixture was stirred for 16 hours. The pH was adjusted to about 2 with 10% HCl(aq). The mixture was extracted with ethyl acetate (20 mL x 4) and the combined organic extracts were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product which was used without further purification And use it directly. (1.50 g, crude product).

IIIg: 3-Cyclopropyl-3-hydroxybutanoic acid

Step 1: Preparation of methyl 3-cyclopropyl-3-hydroxybutyrate

To Zn (12.4 g, 190.2 mmol) in THF (150 mL) was added TMSCl (1.3 g, 11.9 mmol) and the resulting mixture was stirred at 20°C for 15 minutes and then heated to 70°C. Heating was stopped and methyl 2-bromoacetate (21.8 g, 142.7 mmol) was added dropwise at such a rate that the ether slowly boiled. The resulting mixture was stirred at 70°C for 1 hour and at 20°C for 1 hour, and then a solution of 1-cyclopropylethanone (10 g, 118.9 mmol) in THF (50 mL) was added. The reaction was stirred at 20°C for 16 hours. The mixture was poured into NH ₃ on ice ^. H ₂ O (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: Preparation of 3-cyclopropyl-3-hydroxybutyric acid

At 20 ° C, the crude product methyl 3-cyclopropyl-3-hydroxybutyrate (8.9g, 56.3mmol) and LiOH ^. A mixture of _H2O (11.8 g, 281.3 mmol) in THF (100 mL) and _H2O (50 mL) was stirred for 16 hours. H ₂ O (50 ml) was added and extracted with ethyl acetate (100 mL x 2). Organic extracts were discarded. The pH of the aqueous layer was adjusted to about 5 with 2N HCl, extracted with ethyl acetate (100 mL x 3), and the combined organic fractions were washed with brine (100 mL x 10), dried over Na ₂ SO ₄ , filtered and concentrated To give the desired product in 30% overall yield (5.1 g).

¹ H 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).

IVa: Ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propionate

Step 1: Preparation of ethyl 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propionate

Et ₃ N (2.34 g, 23.5 mmol) and MgCl ₂ (1.8 g, 18.4 mmol) were added to (3-ethoxy-3-oxo-propionyl)oxy potassium salt (2.6 g, 15.4 mmol) ) in MeCN (30 mL) and stirred at 20 °C for 2 hours. A pre-stirred mixture of CDI (carbonyl-diimidazole) (1.4 g, 8.8 mmol) and 1-(difluoromethyl)cyclopropanecarboxylic acid (1 g, 7.4 mmol) in MeCN (20 mL) was added at 0 °C , and stirred at 20 °C for 14 hours. The reaction mixture was diluted with H ₂ O (30 mL), and extracted with ethyl acetate (80 mL×2). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10% ethyl acetate/petroleum ether gradient). The product was obtained in a yield of 0.98 g (65%).

IVb: Ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propionate

Step 1: Preparation of ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propionate

Et ₃ N (6.3 g, 62.3 mmol) and MgCl ₂ (4.6 g, 48.7 mmol) were added to potassium 3-ethoxy-3-oxo-propionate (6.9 g, 40.5 mmol) in CH ₃ CN (25 mL) and stirred at 20°C for 2 hours. A pre-stirred mixture of carbonyldiimidazole (CDI) (3.8 g, 23.3 mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid (3 g, 19.5 mmol) in CH ₃ CN (25 mL) was added at 0 °C , and stirred at 20 °C for 14 hours. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (40 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=30:1-10:1) to afford the product in 3.5 g (80%) yield.

Va: 4,4-dimethyl-3-oxo- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

At 25°C, (1 S )-1-[3-(trifluoromethoxy)phenyl]ethanamine hydrochloride ( IIa ) (5g, 20.69mmol), 4,4-dimethyl- A solution of 3-oxo-pentanoic acid (3.28 g, 22.76 mmol), HATU (9.44 g, 24.83 mmol) and DIPEA (8 g, 62.1 mmol) in DCM (250 mL) was stirred for 16 hours. The resulting mixture was washed with water (500 mL), and extracted with DCM (500 mL×2). The organic layer was washed with brine (350 mL×2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography (SiO ₂ , petroleum ether/ethyl acetate=1:0 to 3:1) to afford 4,4-dimethyl-3-oxo- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (11.2 g, crude product).

The following intermediates were prepared by a similar method to Va , using the related intermediates

Vb: 4,4-dimethyl-3-oxo- N -[(1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]pentyl amine

Prepared from lib (2.6 g, 10.1 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (1.6 g, 11.1 mmol).

Yield: 2.6 g (75%).

Vc: ( S ) -N- (1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentanamide

Prepared from IIc (0.8 g, 4.3 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (616 mg, 4.3 mmol).

Yield: 1.3 g crude product

Vd: ( S )-4,4-dimethyl-3-oxo- N- (1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

Prepared from IId (850 mg, 3.77 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (597 mg, 4.14 mmol).

Yield: 1.12g (94%)

Ve: ( S )-4,4-dimethyl-3-oxo- N- (1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

Prepared from IIe (1.04 g, 4.07 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (645 mg, 4.47 mmol).

Yield: 1.28 g (91%).

Vf: (S)-4-methyl-3-oxo-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

Prepared from lib (2.89 g, 11.32 mmol) and 4-methyl-3-oxo-pentanoic acid (1.62 g).

Yield: 2.6 g (69%).

Vi: ( S )-4-methyl-3-oxo- N- (1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Prepared from IIa (2.7 g, 13.16 mmol) and 4-methyl-3-oxo-pentanoic acid (1.60 g).

Yield: 2.00 g (47%).

Vj: N -[(1 R )-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-3-side Oxy-pentanamide

Prepared from IIg (600 mg, 2.21 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (382 mg, 2.66 mmol)

Yield: 520 mg (51%).

Vk: N -[(1 R )-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-3-oxo-pentyl Amide

Prepared from IIf (40 mg, 0.15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (25 mg, 0.17 mmol)

Yield: 100 mg, (94%).

Vg: 3-[1-(difluoromethyl)cyclopropyl]-3-oxo- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl] Acrylamide

A mixture of IIa (557 mg, 2.30 mmol), IVa (0.95 g, 4.61 mmol), DMAP (57 mg, 0.46 mmol) and _Et3N (2.33 g, 23.04 mmol) in toluene (30 mL) was degassed and washed with _N2 After purging 3 times, the mixture was stirred at 110 °C for 12 h under _N2 . The mixture was concentrated and the residue was purified by flash chromatography on silica gel (0-35% ethyl acetate/petroleum ether gradient) to yield the desired product (0.61 g, 72% yield Rate).

The following items were prepared by methods similar to those described for Vg using the relevant intermediates

Vh: 3-oxo- N -[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-[1-(trifluoromethyl)cyclopropyl]propyl Amide

Preparation from IVb (2 g, 8.9 mmol) and Ha (915.3 mg, 4.5 mmol) Yield: 1.7 g (97%).

Vl: ( S )-3-(3,3-difluorocyclobutyl)-3-oxo- N- (1-(3-(trifluoromethoxy)phenyl)ethyl)acrylamide

Prepared from methyl 3-(3,3-difluorocyclobutyl)-3-oxopropionate (600 mg, 3.12 mmol) and IIa (377 mg, 1.56 mmol).

Yield: 470 mg, (82%).

¹ H NMR (CDCl _3, 400MHz)δ 7.39-7.35(m,1H),7.26-7.23(m,1H),7.15-7.11(m,2H),5.16-5.08(m,1H),3.44(d, J =2.4Hz, 2H), 2.86-2.71(m, 5H), 1.51(d, J =7.2Hz, 3H).

Example:

Example 1a:

( S )-3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

and Example 1b:

( R )-3-Hydroxy-4,4-dimethyl- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

Step 1: Preparation of 3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

At 0°C, to 4,4-dimethyl-3-oxo- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide ( To a mixture of Va ) (5.6 g, 16.90 mmol) in MeOH (50 mL) was added NaBH ₄ (1.28 g, 33.8 mmol) in portions. The mixture was stirred at 0°C for 1 hour. Water (50 mL) was added portionwise at 0°C. This reaction was repeated twice on the same scale, and the crude products from three separate reactions were combined and processed as follows:

The mixture was concentrated to remove MeOH, and then extracted with ethyl acetate (100 mL×4). The combined organic extracts were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated to afford 3-hydroxy-4,4-dimethyl- N -[(1S)-1-[3 -(trifluoromethoxy)phenyl]ethyl]pentanamide (16.5 g, crude product).

Step 2: ( S )-3-Hydroxy-4,4-dimethyl- N -[( 1S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide and ( Separation of R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

3-Hydroxy-4,4-dimethyl- N -[( 1S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (27g, 83mmol ).

Example 1a:

Yield: 10.5g

¹ H NMR (CDCl ₃ 400MHz): δ 7.33(t, J =8.0Hz, 1H), 7.22(d, J =8.0Hz, 1H), 7.05-7.20(2H), 6.40(br, 1H), 5.15( m,1H),3.64(dd, J =2.0Hz,8.4Hz,1H),3.05(br,1H),2.15-2.40(m,2H),1.45(d, J =7.2Hz,3H),0.88( s, 9H).

LC-MS: _tR = 2.548 min (LCMS method 1), m/z = 334.0 [M+H] ⁺ .

SFC: tR = _1.89min (SFC method 4), de = 95%, ^{[α] D20} ₌ -71.7 (c = 0.72g/100mL, MeOH).

Example 1b:

Yield: 10.5g

¹ H NMR (CDCl ₃ 400MHz): δ 7.32(t, J =8.0Hz, 1H), 7.22(d, J =7.6Hz, 1H), 7.13(s, 1H), 7.10-7.07(m, 1H), 6.52(d, J =7.6Hz,1H),5.13-5.06(m,1H),3.62(dd, J =2.0Hz,8.4Hz,1H),3.45-3.33(m,1H),2.38-2.33(m ,1H), 2.23-2.17(m,1H), 1.44(d, J =7.2Hz,3H), 0.88(s,9H). LC-MS: _tR = 2.553 min (LCMS method 1), m/z = 334.0 [M+H] ⁺ .

SFC: tR = 1.87 _min (SFC method 5), de = 100%, [α] _D ²⁰ = -42.3 (c = 0.61 g/100 mL, MeOH).

The following examples were prepared using the relevant intermediates by methods analogous to those described for 1a and 1b :

Example 2a:

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

and Example 2b:

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

Step 1: 3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide preparation

3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentamide was added to 84% Yield prepared from Vb .

Step 2: ( S )-3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl) Pentamide and ( R )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl ) Separation of pentamide

3-Hydroxy-4,4-dimethyl- N -[(1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]pentanamide (0.84 g, 2.52 mmol) were separated by chiral SFC.

Example 2a:

Yield: 0.25g

¹ H NMR(CDCl ₃ ,400MHz)δ 7.30(t, J =7.6Hz,1H),7.01(d, J =7.6Hz,1H),6.93(s,1H),6.85(dd, J =8.4Hz, 2.8Hz, 1H), 6.08(br d, J =5.2Hz, 1H), 5.13(m, 1H), 4.36(q, J =16.0Hz, 8.0Hz, 2H), 3.68(dd, J =10.4Hz, 3.0Hz, 1H), 3.24(d, J =3.2Hz, 1H), 2.39-2.23(m, 2H), 1.49(d, J =6.8Hz, 3H), 0.93(s, 9H).

LC-MS: t _R =2.68 min (LCMS method 2), m/z = 348.0 [M+H] ⁺ .

^SFC : tR = 1.78 _min (SFC method 1), de = 98.3%, [α] _D20 = -68.0 (c = 0.25, MeOH).

Embodiment 2b :

Yield: 0.37g

¹ H NMR(CDCl ₃ ,400MHz)δ7.29(t, J =8.0Hz,1H),7.01(d, J =8.0Hz,1H),6.94(s,1H),6.84(dd, J =8.0, 2.4Hz,1H),6.04(m,1H),5.13(m,1H),4.36(q, J =16.0Hz,8.0Hz,2H),3.70-3.67(m,1H),3.15(d, J = 2.8Hz, 1H), 2.40-1.96(m, 2H), 1.50(d, J =7.2Hz, 3H), 0.93(s, 9H) LC-MS: t _R =2.543min (LCMS method 2), m/ z=348.0[M+H] ⁺ .

SFC: tR = _1.87min (SFC method ^{1), de = 92.0%, [α] D20} ₌ -53.3 (c = 0.21, MeOH).

Example 3a: N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

and

Example 3b: N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Step 1: Preparation of N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

Prepared from Vc in 84% yield.

Step 2: ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide and ( R Separation of ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxyl-4,4-dimethylpentanamide

N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide (450 mg) was separated by chiral SFC .

Example 3a:

Yield: 168mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.31-7.29(m,1H),7.26-7.24(m,1H),7.16-7.14(m,1H),7.10-6.98(m,1H),6.49(t, J =76Hz,1H),6.14(brs,1H),5.14-5.07(m,1H),3.66(d, J =10.4Hz,1H),3.17(s,1H),2.38-2.34(m,1H) ,2.28-2.18(m,1H),1.47-1.40(m,3H),0.98(s,9H).

LC-MS: _tR = 2.161 min (LCMS method 3), m/z = 316.1 [M+H] ⁺ .

SFC: t _R =2.15 min (SFC method 2), de=96.6%, [α] _D ²⁰ =-16 (c=0.25, MeOH).

Example 3b:

Yield: 126mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.34-7.30(m,1H),7.16-7.12(m,1H),7.04-6.97(m,2H),6.31(t, J =76Hz,1H), 6.14(brs,1H),5.12-5.06(m,1H),3.67-3.62(m,1H), 3.29(s,1H),2.37-2.31(m,1H),2.26-2.19( m,1H), 1.47-1.43(m,3H), 0.98(s,9H).

LC-MS: _tR = 2.16 min (LCMS method 3), m/z = 316.1 [M+H] ⁺ .

SFC: t _R =2.42 min (SFC method 2), de=100%, [α] _D ²⁰ =-57.6 (c=0.5, MeOH).

Example 4a: 3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoro-methyl)phenyl)ethyl)pentanamide

and

Example 4b: 3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoro-methyl)phenyl)ethyl)pentanamide

Step 1: Preparation of 3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

Prepared from Vd (980 mg, 87% yield).

Step 2: ( S )-3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide and ( R ) Separation of -3-Hydroxy-4,4-dimethyl- N -((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide was purified by chromatography on silica gel (petroleum ether : ethyl acetate=3:1) for separation.

Example 4a : Yield: 220mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.56(s,1H),7.52-7.43(m,3H),6.22-6.21(m,1H),5.21-5.14(m,1H),3.68-3.64(m, 1H), 3.14(d, J =3.2Hz, 1H), 2.40-2.36(m, 1H), 2.26-2.20(m, 1H), 1.50(d, J =7.2Hz, 3H), 0.91(s, 9H ).

LC-MS: t _R =2.48 min (LCMS method 1), m/z = 318.0 [M+H] ⁺ .

SFC: tR = 1.56 _min (SFC method 3), de = 100%, [α] _D ²⁰ = -25.5 (c = 0.19 g/100 mL, MeOH).

Example 4b : Yield: 270mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.54-7.45(m,4H),6.25-6.23(m,1H),5.20-5.13(m,1H),3.69-3.65(m,1H),3.24(d, J =3.2Hz, 1H), 2.39-2.35(m, 1H), 2.27-2.21(m, 1H), 1.49(d, J =6.8Hz, 3H), 0.91(s, 9H).

LC-MS: t _R =2.48 min (LCMS method 1), m/z = 318.0 [M+H] ⁺ .

SFC: t _R = 1.93 min (SFC method 3), de = 100%, [α] _D ²⁰ = -61.4 (c = 0.57 g/100 mL, MeOH).

Example 8a: 3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)propyl)pentanamide

and

Example 8b : 3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)propyl)pentanamide

Step 1: Preparation of 3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

Prepared from Ve , yield: 1.22 g

Step 2: ( S )-3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide and ( R Separation of )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide was passed through flash chromatography on silica gel ( The eluent is 0-30% ethyl acetate/petroleum ether gradient) for separation.

Example 8a : Yield: 0.51g

¹ H NMR (CDCl ₃ 400MHz): δ 7.40-7.34(m,1H),7.25-7.21(m,1H),7.14-7.10(m,2H),6.22-6.15(m,1H),4.92(q, J =7.6Hz,1H),3.71-3.65(m,1H),3.21(d, J =2.8Hz,1H),2.40-2.23(m,2H),1.82(q, J =7.2Hz,2H), 0.94-0.90 (m,12H).

LC-MS: _tR = 2.486 min (LCMS method 5), m/z = 348.0 [M+H] ⁺ .

SFC: t _R =1.775 min. (SFC method 3), de=98.7%, [α] _D ²⁰ =-80.0 (c=0.31 g/100 mL, MeOH).

Example 8b : Yield: 0.59g

¹ H NMR (CDCl ₃ 400MHz): δ 7.39-7.33(m,1H),7.25-7.20(m,1H),7.14-7.09(m,2H),6.24(br d, J =8.0Hz,1H), 4.92(q, J =7.6Hz,1H),3.69-3.63(m,1H),3.15(d, J =3.2Hz,1H),2.40-2.25(m,2H),1.81(q, J =7.6Hz ,2H),0.94-0.90(m,12H).

LC-MS: _tR = 2.506 min (LCMS method 5), m/z = 348.0 [M+H] ⁺ .

SFC: t _R = 1.609 min. (SFC method 3) de = 98.7%, [α] _D ²⁰ = -40.0 (c = 0.27 g/100 mL, MeOH).

Example 11a : 3-(3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide

and

Example 11b: 3-(3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide

Step 1: 3-(3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide preparation

Prepared from Vl . Yield: 300mg, (60.7%).

Step 2: (S )-3-(3,3-difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl) Propane-amide and ( R )-3-(3,3-difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl base) separation of acrylamide

Separation was performed by chiral SFC.

Embodiment 11a : Yield 90mg

¹ H NMR (400MHz, CDCl ₃ )δ 7.42-7.35(m,1H),7.25(d, J =7.6Hz,1H),7.17-7.11(m,2H),5.93(d, J =7.2Hz,1H ),5.19-5.09(m,1H),4.01-3.93(m,1H),3.86(d, J =3.6Hz,1H),2.62-2.48(m,3H),2.46-2.13(m,4H), 1.50(d, J =6.8Hz, 3H).

LC-MS: tR = 2.513 _min (LCMS method 2), m/z = 368.0 [M+H] ⁺ .

SFC: t _R =2.169 min. (SFC method 3), de=97.4%, [α] _D ²⁰ =-42.0 (c=2.0 mg/mL, MeOH).

Embodiment 11b : Yield 90mg

¹ H NMR (400MHz, CDCl ₃ )δ 7.40-7.36(m,1H),7.25(d, J =7.6Hz,1H),7.16-7.11(m,2H),5.99(d, J =7.2Hz,1H ),5.18-5.09(m,1H),3.98(t, J =7.2Hz,1H),3.83(br s,1H),2.61-2.49(m,3H),2.45-2.12(m,4H),1.50 (d, J =6.8Hz, 3H).

LC-MS: tR = 2.235 _min (LCMS method 3), m/z = 368.0 [M+H] ⁺ .

SFC: t _R =2.013 min. (SFC method 3), de=99.6%, [α] _D ²⁰ =-17.0 (c=2.0 mg/mL, MeOH).

Example 12a: 3-Hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)pentanamide

and

Example 12b: 3-Hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)pentanamide

Step 1: Preparation of 3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

Prepared from Vf .

Yield: 0.88g (87%)

Step 2: ( S )-3-Hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide and ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

Separation of 3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide by chiral SFC .

Example 12a : Yield: 0.362g

¹ H NMR (CDCl ₃ ,400MHz)δ 7.31(t, J =8.0Hz,1H),7.01(d, J =7.2Hz,1H),6.92(t, J =2.0Hz,1H),6.83(dd, J =8.0,2.4Hz,1H),6.08(br d, J =7.2Hz,1H),5.12(m,1H),4.36(q, J =8.0Hz,2H),3.80-3.74(m,1H) ,3.36(d, J =3.2Hz,1H),2.37-2.27(m,2H),1.73-1.70(m,1H),1.49(d, J =6.8Hz,3H),0.94(dd, J =10.4 , 6.8Hz, 6H); LC-MS: t _R =2.531min (LCMS method 2), m/z=334.0[M+H] ⁺ .

SFC: tR = _2.864min (SFC method 3 ^{), de = 99.2%, [α] D20} ₌ -74.0 (c = 0.20, MeOH).

Example 12b : Yield: 0.245g

¹ H NMR (CDCl ₃ ,400MHz)δ 7.30(t, J =8.0Hz,1H),7.00(d, J =8.0Hz,1H),6.92(t, J =2.0Hz,1H),6.83(dd, J =8.0,2.4Hz,1H),6.14(br d, J =6.8Hz,1H),5.11(m,1H),4.36(q, J =16.4,8.0Hz,2H),3.79-3.75(m, 1H), 3.34(d, J =3.2Hz, 1H), 2.38-2.25(m, 2H), 1.73-1.62(m, 1H), 1.49(d, J =7.2Hz, 3H), 0.94(dd, J =10.0, 6.8Hz, 6H); LC-MS: t _R =2.543min (LCMS method 2), m/z=334.0[M+H] ⁺ .

^SFC : tR = 3.071 _min (SFC method 3), de = 99.7%, [α] _D20 = -47.0 (c = 0.20, MeOH).

Example 14a: 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propane Amide

and

Example 14b: 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propane Amide

Step 1: 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionyl Amine preparation

Prepared from Vg .

Yield: 0.58g

Step 2: ( S )-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl base) propionamide and ( R )-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)benzene Base) Separation of Ethyl) Acrylamide

Pass 3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)acrylamide through Fast silica gel chromatography (eluent: 0-41% ethyl acetate/petroleum ether gradient) for separation.

Example 14a : 0.2g

¹ H NMR (CDCl ₃ 400MHz): δ 7.40-7.34(m,1H),7.26-7.22(m,1H),7.16-7.11(m,2H),6.11(br d, J =7.2Hz,1H), 5.88(t, J =58.4Hz, 1H), 5.12(quin, J =7.2Hz, 1H), 3.91(d, J =3.2Hz, 1H), 3.81-3.75(m, 1H), 2.62-2.48(m ,2H), 1.49(d, J =7.2Hz,3H),0.87-0.76(m,2H),0.76-0.62(m,2H).

LC-MS: t _R =2.448 min (LCMS method 1), m/z = 368.0 [M+H] ⁺ .

SFC: t _R = 2.282 min. (SFC method 3), de = 97.9%, [α] _D ²⁰ = -62.0 (c = 0.27 g/100 mL, MeOH).

Example 14b : Yield: 0.18g

¹ H NMR (CDCl ₃ 400MHz): δ 7.40-7.34(m,1H),7.24(d, J =7.6Hz,1H),7.17-7.10(m,2H),6.06(br d, J =7.6Hz, 1H),5.84(t, J =58.4Hz,1H),5.12(quin, J =7.2Hz,1H),3.86-3.79(m,2H),2.55(d, J =5.6Hz,2H),1.50( d, J =6.8Hz, 3H), 0.83-0.75(m, 2H), 0.74-0.66(m, 2H). LC-MS: t _R =2.467 min (LCMS method 1), m/z = 368.0 [M+H] ⁺ .

SFC t _R = 1.960 min. (SFC method 3), de = 96.3%, [α] _D ²⁰ = -54.4 (c = 0.25 g/100 mL, MeOH).

Example 16a: 3-Hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propane Amide

and

Example 16b: 3-Hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propane Amide

Step 1: 3-Hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propane Preparation of amides

Prepared from Vh and used directly in next step.

Step 2: ( R )-3-Hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclo Propyl)acrylamide and ( S )-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl Separation of base) cyclopropyl) propionamide

The crude product from step 1 was isolated by chiral SFC to yield the desired product.

Example 16a: Yield: 556mg

¹ H NMR (DMSO- d ⁶ 400MHz): δ 8.37(d, J =7.6Hz,1H),7.43-7.39(m,1H),7.31-7.29(m,1H),7.23(s,1H),7.18 -7.16(m,1H),5.21(d, J =5.2Hz,1H),4.96-4.88(m,1H),3.85-3.75(m,1H),2.35-2.25(m,2H),1.30(d , J =7.2Hz,3H),0.85-0.77(m,4H).

LC-MS: _tR = 2.626 min (LCMS method 2), m/z = 386.0 [M+H] ⁺ .

SFC: t _R =2.010 min. (SFC method 3), de=99.9%, [α] _D ²⁰ =-56.0 (c=0.01 g/100 mL, MeOH).

Example 16b: Yield: 692 mg

¹ H NMR (DMSO- d ⁶ 400MHz): δ 8.36(d, J =8.0Hz,1H),7.42-7.38(m,1H),7.32(d, J =8.0Hz,1H),7.25(s,1H ),7.17-7.15(m,1H),5.20(d, J =5.2Hz,1H),4.95-4.91(m,1H),3.75-3.85(m,1H),2.25-2.35(m,2H), 1.30(d, J =6.8Hz, 3H), 0.80-0.79(m, 4H).

LC-MS: _tR = 2.649 min (LCMS method 2), m/z = 386.0 [M+H] ⁺ .

SFC: t _R =1.615 min. (SFC method 3), de=95.7%, [α] _D ²⁰ =-46.0 (c=0.01 g/100 mL, MeOH).

Example 20a: 3-Hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

and

Example 20b: 3-Hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Step 1: Preparation of 3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Prepared from Vi . Yield: 1.80g (72%)

Step 2: ( S )-3-Hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide and ( R )-3 Separation of -Hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

3-Hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide was purified by chromatography (SiO ₂ , petroleum ether/acetic acid Ethyl ester = 0:1 to 1:1) for separation.

Example 20a : 250mg

¹ H NMR (CDCl ₃ , 400MHz) δ 7.37(t, J =8.0Hz, 1 H), 7.27-7.21(m, 1H), 7.16-7.11(m, 2H), 6.15(d, J = 6.8Hz ,1 H),5.16(quin, J =6.8Hz,1 H),3.83-3.74(m,1 H),3.26(d, J =3.2Hz,1 H),2.37(dd, J =15.2,3.2 Hz,1H),2.31(dd, J =15.2,8.8Hz,1H),1.74-1.68(m,1H),1.50(d, J =6.8Hz,3H),0.95(d, J = 6.8Hz, 3H), 0.93(d, J =6.8Hz, 3H).

LC-MS: t _R =2.629 min (LCMS method 2), m/z = 320.0 [M+H] ⁺ .

SFC: tR = _2.404min (SFC method 13), de = 98.6%, [α] _D20 = -80.0 (c = 0.475g/100mL ^, MeOH).

Example 20b: Yield 470mg

¹ H NMR (CDCl ₃ , 400MHz)δ 7.37(t, J =7.6Hz, 1H), 7.28-7.23(m, 1H), 7.16(s, 1H), 7.14-7.11(m, 1H), 6.19(d, J =6.8Hz,1H),5.15(quin, J =7.2Hz,1H),3.80-3.74(m,1H),3.20(d, J =3.6Hz,1H),2.38 (dd, J =14.8,2.4Hz,1H),2.30(dd, J =14.8,9.2Hz,1H),1.73-1.66(m,1H),1.49(d, J =6.8Hz,3H ),0.95(d, J =6.8Hz,3H),0.93(d, J =6.8Hz,3H).

LC-MS: t _R =2.654 min (LCMS method 2), m/z = 320.0 [M+H] ⁺ .

SFC: t _R = 1.979 min (SFC method 13), de = 100%, [α] _D ²⁰ = -52.0 (c = 0.53 g/100 mL, MeOH).

Example 21a: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-hydroxy-4,4-di Methylpentamide

and

Example 21b: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-hydroxy-4,4-di Methylpentamide

Step 1: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethyl Preparation of pentamide

Prepared from Vj . Yield = 350mg, (96%)

Step 2: N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-( R )-hydroxy-4,4 -Dimethyl-pentanamide and N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-( S Separation of )-Hydroxy-4,4-Dimethylpentanamide

N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanoyl Amines were separated by chiral SFC.

Example 21a: Yield: 98mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.39(t, J =8.0Hz,1H),7.29-7.26(m,1H),7.20(s,1H),7.16(d, J =8.0Hz,1H), 6.65(d, J =7.6Hz,1H),6.22(t, J =74.0Hz,1H),5.34-5.30(m,1H),4.18-4.09(m,2H),3.69(d, J =10.8Hz ,1H), 2.91(s,1H), 2.45-2.43(m,1H), 2.34-2.27(m,1H), 0.93(s,9H).

LC-MS: tR = 2.471 _min (LCMS method 5), m/z = 400.0 [M+H] ⁺ .

SFC: t _R = 1.935 min (SFC method 14), de = 98.2%, [α] _D ²⁰ = -2.4 (c = 1.0 g/100 mL, MeCN).

Example 21b: 160mg

¹ H NMR (DMSO- d ⁶ 400MHz): δ 8.54(d, J =8.4Hz, 1H), 7.49(d, J =8.0Hz, 1H), 7.41(d, J =8.0Hz, 1H), 7.39( s,1H),7.28(d, J =8.0Hz,1H),6.67(t, J =76.0Hz,1H),5.21-5.18(m,1H),4.67(s,1H),4.04-3.98(m , 2H), 3.53(d, J =10.2Hz, 1H), 2.31-2.26(m, 1H), 2.19-2.12(m, 1H), 0.82(s, 9H).

LC-MS: tR = 2.496 _min (LCMS method 5), m/z = 400.0 [M+H] ⁺ .

SFC: t _R = 2.461 min (SFC method 14), de = 97.1%, [α] _D ²⁰ = -11.2 (c = 1.0 g/100 mL, MeCN).

Example 22a: 3-Hydroxy- N -[(1 R )-2-methoxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]-4,4-dimethyl- Pentamide

and

Example 22b: 3-Hydroxy- N -[(1 R )-2-methoxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]-4,4-dimethyl- Pentamide

Step 1: 3-Hydroxy- N -[( 1R )-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanoyl Amine preparation

Prepared from Vk . Yield: 84 mg, (60%).

Step 2: ( S )-3-Hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl Pentamide and ( R )-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl Isolation of pentylamide

Pass 3-hydroxy- N -[(1 R )-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide through Chiral SFC for separation.

Example 22a : Yield: 40 mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.35(t, J =8.0Hz,1H),7.27-7.26(m,1H),7.20(s,1H),7.12(d, J =7.6Hz,1H), 6.66(d, J =7.2Hz,1H),5.18-5.14(m,1H),3.70-3.60(m,3H),3.36(s,3H),2.44(d, J =14.8Hz,1H),2.25 -2.33(m,1H),0.93(s,9H).

LC-MS: tR = 2.410 _min (LCMS method 3), m/z = 364.0 [M+H] ⁺ .

SFC: tR = 1.889 _min (SFC method 16), de = 100%, ^[ α] _D20 = -0.4 (c = 1.0 g/100 mL, MeCN).

Example 22b : Yield: 38 mg

¹ H NMR (CDCl ₃ 400MHz): δ 7.36(t, J =8.0Hz,1H),7.27-7.25(m,1H),7.18(s,1H),7.12(d, J =7.6Hz,1H), 6.56(d, J =7.2Hz,1H),5.20-5.15(m,1H),3.69-3.60(m,3H),3.40(s,1H),3.36(s,3H),2.44(d, J =14.8Hz,1H),2.25-2.33(m,1H),0.93(s,9H).

LC-MS: tR = 2.523 _min (LCMS method 1), m/z = 364.0 [M+H] ⁺ .

SFC: t _R = 2.106 min (SFC method 16), de = 98.2%, [α] _D ²⁰ = -2.7 (c = 1.0 g/100 mL, MeCN).

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

step 1:

At 20°C, (1 S )-1-[3-(trifluoromethoxy)phenyl]ethanamine hydrochloride ( IIa ) (291 mg, 1.20 mmol), 2-(3,3-di A mixture of fluoro-1-hydroxy-cyclobutyl)acetic acid ( IIIb ) (0.22 g, 1.32 mmol), HATU (549 mg, 1.44 mmol) and DIPEA (467 mg, 3.6 mmol) in DCM (15 mL) was stirred for 16 hours. The mixture was washed with water (40 mL x 2) and extracted with DCM (40 mL). The organic layer was washed with brine (10 mL×2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography on silica gel (0-35% ethyl acetate/petroleum ether gradient) to give the product (0.2 g, 47% yield).

¹ H NMR (CDCl _3, 400MHz): δ 7.41-7.37(m,1H),7.26-7.23(m,1H),7.18-7.13(m,2H),5.93(br d, J =6.8Hz,1H) ,5.15(quin, J =7.2Hz,1H),5.01(br s,1H),2.84-2.42(m,6H),1.53(d, J =6.8Hz,3H).

LC-MS: _tR = 2.53 min (LCMS method 2), m/z = 354.0 [M+H] ⁺ .

HPLC: t _R =13.3 min. (chiral HPLC method 1), de = 100%. [α] ²⁰ _D = -51.1 (c = 0.23g/100mL, MeOH).

The following examples were prepared by a method analogous to Example 5, using the relevant starting materials:

Example 6: ( S )-2-(1-hydroxycyclobutyl) -N- (1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide

Step 1: Preparation of (S )-2-(1-hydroxycyclobutyl) -N- (1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide

Prepared from lib (5.0 g, 22.81 mmol) and IIIa (3.3 g, 25.09 mmol).

Yield: 5.2 g, (45%).

¹ H NMR (CDCl _3, 400MHz): δ 7.29(t, J =8.0Hz, 1 H), 6.99(d, J =7.6Hz, 1 H), 6.90(s, 1 H), 6.83(dd, J =8.4Hz, J =2.4Hz, 1H), 6.25(d, J =6.8Hz, 1H), 5.14-5.07(m, 1H), 4.35(q, J =8.0Hz, 2H), 4.14 (s,2 H),2.53(s,2 H),2.15-1.99(m,4 H),1.76(m,1 H),1.55(m,1 H),1.48(d, J =6.8Hz, 3H).

LC-MS: _tR = 2.49 min (LCMS method 2), m/z = 332.0 [M+H] ⁺ .

^SFC : tR = _2.67min (SFC method 3), de = 96.9%, [α] _D20 = -69.0 (c = 0.1, MeOH).

Example 7a: 3-Hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(tri Fluoromethyl) pentamide

and

Example 7b: 3-Hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(tri Fluoromethyl) pentamide

Step 1: 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)-3-(trifluoromethyl base) preparation of pentamide

Prepared from IIb and IIIc . Yield: 0.65 g, (crude product). The crude product was used directly without purification.

Step 2: ( 3R )-3-Hydroxy-4-methyl- N -[( 1S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]- 3-(Trifluoromethyl)pentanamide and (3 S )-3-hydroxy-4-methyl- N -[(1 S )-1-[3-(2,2,2-trifluoroethoxy Separation of base) phenyl] ethyl] -3- (trifluoromethyl) pentamide

Separation was carried out by flash silica gel chromatography (eluent: 0-15% ethyl acetate/petroleum ether gradient).

Example 7a : Yield: 0.29g

¹ H NMR (CDCl ₃ , 400MHz): δ 7.32(t, J =8.0Hz, 1 H), 7.00(d, J =7.6Hz, 1 H), 6.91(d, J =2.0Hz, 1 H), 6.85(dd, J =8.0,2.4Hz,1H),6.32(s,1H),5.99(d, J =7.6Hz,1H).5.15-5.07(m,1H),4.36(q, J =8.0Hz,2H),2.45(d, J =15.2Hz,1H),2.34(d, J =15.2Hz,1H),2.13-2.06(m,1H),1.50(d, J =6.8Hz, 3H), 1.03(d, J =6.8Hz, 3H), 0.97(d, J =6.8Hz, 3H).

LC-MS: _tR = 2.883 min (LCMS method 4), m/z = 402.0 [M+H] ⁺ .

SFC: t _R =2.454 min. (SFC method 6), de=100%, [α] _D ²⁰ =-43.5 (c=0.0058 g/mL, MeOH).

Example 7b : Yield: 0.23g

¹ H NMR (CDCl ₃ , 400MHz): δ 7.32(t, J =8.0Hz, 1 H), 7.00(d, J =7.6Hz, 1 H), 6.91-6.84(m, 2 H), 6.33(s ,1 H),5.90(d, J =7.6Hz,1 H),5.19-5.10(m,1 H),4.35(q, J =8.4Hz,2 H),2.51(d, J =14.8Hz, 1H), 2.35(d, J =14.8Hz, 1H), 2.15-2.06(m, 1H), 1.52(d, J =7.2Hz, 3H), 1.05(d, J =6.8Hz, 3 H), 0.98(d, J =6.8Hz, 3H).

LC-MS: t _R =2.834 min (LCMS method 6), m/z = 402.0 [M+H] ⁺ .

SFC: t _R =2.262 min. (SFC method 7) de = 99.8%, [α] _D ²⁰ =-37.1 (c = 0.0034 g/mL, MeOH).

Example 9: 4,4,4-Trifluoro-3-hydroxy- N -[(1 S )-1-[3-(trifluoro-methoxy)phenyl]ethyl]-3-(trifluoro Methyl)butyramide

step 1:

Prepared from IIa and 4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoic acid. Yield: 650mg, (63%)

¹ H NMR (DMSO- d ⁶ 400MHz): δ 9.14(d, J =7.2Hz, 1H), 8.45(s, 1H), 7.44(t, J =8.0Hz, 1H), 7.32(d, J = 7.6 Hz,1H),7.24(s,1H),7.21(d, J =8.4Hz,1H),5.01-4.93(m,1H),2.89(s,2H),1.34(d, J =6.8Hz,3H ).

LC-MS: t _R =2.850 min (LCMS method 4), m/z = 413.9 [M+H] ⁺ .

Chiral HPLC: t _R = 15.61 min, (HPLC method 2), de = 98.4%, [α] _D ²⁰ = -41.1 (c = 0.185 g/100 mL, MeOH).

Example 10a: 4,4,5,5-Tetrafluoro-3-hydroxy-3-methyl- N -((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentane Amide

and

Example 10b: 4,4,5,5-Tetrafluoro-3-hydroxy-3-methyl- N -((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentane Amide

Step 1: 4,4,5,5-Tetrafluoro-3-hydroxy-3-methyl- N -((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanoyl Amine preparation

Prepared from IIa and IIId . Yield: 1g (53%)

Step 2: ( R )-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl base) pentamide and ( S )-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)benzene Separation of base) ethyl) pentamide

The diastereoisomers were separated by chiral SFC.

Example 10a : Yield=0.268g

¹ H NMR (CDCl ₃ 400MHz): δ 7.42-7.36(m,1H),7.24(d, J =7.6Hz,1H),7.17-7.12(m,2H),6.28-5.97(m,2H),5.93 (br d, J =6.0Hz,1H),5.16(quin, J =6.8Hz,1H),2.69(d, J =15.2Hz,1H),2.37(d, J =15.2Hz,1H),1.53( d, J =6.8Hz,3H), 1.40(s,3H).

LC-MS: t _R =2.759 min (LCMS method 2), m/z = 392.0 [M+H] ⁺ .

SFC: t _R = 1.550 min. (SFC method 15), de = 100%, [α] _D ²⁰ = -50.5 (c = 0.19 g/100 mL, MeOH).

Example 10b: Yield=0.148g

¹ H NMR (CDCl ₃ 400MHz): δ 7.44-7.36(m,1H),7.26(d, J =8.0Hz,1H),7.19-7.12(m,2H),6.33-6.01(m,2H),5.91 (br d, J =6.8Hz,1H),5.16(quin, J =6.8Hz,1H),2.70(d, J =15.2Hz,1H),2.35(d, J =15.2Hz,1H),1.52( d, J =6.8Hz,3H),1.35(s,3H).

LC-MS: _tR = 2.782 min (LCMS method 2), m/z = 392.0 [M+H] ⁺ .

SFC: t _R = 1.329 min. (SFC method 15), de = 100%, [α] _D ²⁰ = -48.6 (c = 0.21 g/100 mL, MeOH).

Example 13a: 5,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxyphenyl)ethyl)pentanamide

and

Example 13b: 5,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

Step 1: 5,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide preparation

Prepared from IIa and IIIe . Yield: 1g, (43%)

Step 2: ( R )-5,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl) Pentamide and ( S )-5,5,5-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl ) Separation of pentamide

Separation was carried out by flash chromatography on silica gel (0-31% ethyl acetate/petroleum ether gradient).

Example 13a : Yield=0.421g

¹ H NMR (CDCl ₃ 400MHz): δ 7.42-7.36(m,1H),7.24(d, J =8.0Hz,1H),7.17-7.12(m,2H),5.98(br d, J =6.8Hz, 1H), 5.15(quin, J =6.8Hz, 1H), 5.00(s, 1H), 2.54-2.44(m, 2H), 2.44-2.31(m, 2H), 1.51(d, J =7.2Hz, 3H ), 1.38(s,3H).

LC-MS: _tR = 2.666 min (LCMS method 2), m/z = 374.0 [M+H] ⁺ .

SFC: t _R = 1.277 min. (SFC method 8), de = 100%, [α] _D ²⁰ = -51.3 (c = 0.23 g/100 mL, MeOH).

Example 13b : 0.261g

¹ H NMR (CDCl ₃ 400MHz): δ 7.42-7.36(m,1H),7.25(d, J =8.0Hz,1H),7.17-7.12(m,2H),5.96(br d, J =7.2Hz, 1H), 5.16(quin, J =6.8Hz, 1H), 4.98(s, 1H), 2.57-2.36(m, 4H), 1.52(d, J =6.8Hz, 3H), 1.36(s, 3H).

LC-MS: t _R =2.674 min (LCMS method 2), m/z = 374.0 [M+H] ⁺ .

SFC: t _R = 1.197 min. (SFC method 8), de = 93.4%, [α] _D ²⁰ = -43.2 (c = 0.19 g/100 mL, MeOH).

Example 15a: 3-(1-Fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide

and

Example 15b: 3-(1-Fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide

Step 1: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide

Prepared from IIa and IIIf . The crude product was used directly in the next step

Step 2: ( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide and ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)butyramide separate

Separation was carried out by flash chromatography on silica gel (0-30% ethyl acetate/petroleum ether gradient).

Example 15a: Yield=1.05g

¹ H NMR (CDCl ₃ 400MHz): δ 7.37(t, J =8.0Hz, 1 H), 7.27-7.24(m, 1 H), 7.17-7.12(m, 2 H), 6.11(br s, 1 H ),5.18-5.10(m,1H),5.02(s,1H),2.61(dd, J =14.4,2.4Hz,1H),2.46(dd, J =14.4,1.6Hz,1H), 1.51(d, J =7.2Hz, 3H), 1.33(s, 3H), 0.78-0.68(m, 3H), 0.52-0.50(m, 1H).

LC-MS: _tR = 2.359 min (LCMS method 3), m/z = 350.0 [M+H] ⁺ .

SFC: t _R = 2.027 min. (SFC method 9), de = 93.9%, [α] _D ²⁰ = -48.3 (c = 0.24 g/100 mL, MeOH).

Example 15b: Yield: 0.80 g

¹ H NMR (CDCl ₃ 400MHz): δ 7.38(t, J =8.0Hz, 1 H), 7.27-7.23(m, 1 H), 7.15-7.12(m, 2 H), 6.06(d, J =7.2 Hz,1H),5.19-5.11(m,1H),4.99(s,1H),2.62(dd, J =14.4,2.0Hz,1H),2.47(d, J =1.6Hz,1H ),2.43(d, J =1.6Hz,1H),1.51(d, J =7.2Hz,3H),1.33(s,3H),0.97-0.87(m,1H),0.85-0.81( m,3 H).

LC-MS: _tR = 2.655 min (LCMS method 2), m/z = 350.0 [M+H] ⁺ .

SFC: t _R = 1.937 min. (SFC method 9), de = 98.7%, [α] _D ²⁰ = -64.4 (c = 0.27 g/100 mL, MeOH).

Example 17: ( R )-2-(1-hydroxycyclopentyl) -N- (2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide

Prepared from IIa and 2-(1-hydroxycyclopentyl)acetic acid. Yield: 30mg, (12.8%).

¹ H NMR (400MHz, CDCl ₃ )δ 7.37(t, J =8.0Hz, 1H), 7.26-7.25(m, 1H), 7.19(s, 1H), 7.16-7.11(m, 1H), 6.66(br d, J =7.2Hz,1H),5.21-5.15(m,1H),3.82(s,1H),3.70-3.60(m,2H),3.37(s,3H),2.59-2.49(m,2H) ,1.86-1.81(m,4H),1.59-1.56(m,4H).

LC-MS: t _R =2.481min (LCMS method 2), m/z=362.0[M+H] ⁺ ,

SFC: t _R =2.33 min. (SFC method 10), de=100%, [α] _D ²⁰ =-44.0, (c=1 mg/mL, MeOH).

Example 18a : 3-Cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyramide

and

Example 18b : 3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyramide

Step 1: Preparation of 3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

Prepared from IIb and IIIg . Yield: 3.7g, (30.9%)

Step 2: ( R )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyryl Amine and ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyramide separation

Separation was performed by chiral SFC.

Example 18a : Yield: 1.59 g

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.32(d, J =8.0Hz, 1H), 7.28(t, J =8.0Hz, 1H), 7.04-6.98(m, 2H), 6.93-6.90(m ,1H),4.97-4.91(m,1H),4.73(q, J =8.8Hz,2H),4.61(s,1H),2.37-2.25(m,2H),1.34(d, J =7.2Hz, 3H), 1.10(s, 3H), 0.87-0.84(m, 1H), 0.30-0.09(m, 4H).

LC-MS: tR = 2.629 _min (LCMS method 2), m/z = 328.0 [M+H-18] ⁺ .

SFC: t _R =3.154min (SFC method 11), de=99.7%, [α] _D ²⁰ =-62.0 (c=2mg/mL, MeOH)

Example 18b: Yield: 1.44g

¹ H NMR (400MHz,DMSO-d ₆ )δ 8.19(br d, J =8.0Hz,1H),7.12(t, J =8.0Hz,1H),6.87-6.79(m,2H),6.77-6.74( m,1H),4.81-4.73(m,1H),4.57(q, J =8.8Hz,2H),4.42(s,1H),2.19-2.08(m,2H),1.17(d, J =6.8Hz ,3H), 0.94(s,3H), 0.73-0.64(m,1H), 0.19-0.00(m,4H).

LC-MS: tR = 2.643 _min (LCMS method 2), m/z = 328.0 [M+H-18] ⁺ .

SFC: t _R =2.570min. (SFC method 11), de=97.0%, [α] _D ²⁰ =-58.0 (c=2mg/mL, MeOH)

Example 19a: 4,4,4-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl) Ethyl) butyramide

and

Example 19b : 4,4,4-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl) Ethyl) butyramide

Step 1: 4,4,4-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl base) preparation of butyramide

Prepared from IIb and 4,4,4-trifluoro-3-hydroxy-3-methyl-butyric acid. Yield: 6.67g, (73%)

Step 2: ( R )-4,4,4-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy) ) ethyl) butyramide and ( S )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-tri Separation of fluoroethoxy)phenyl)ethyl)butyramide

Example 19a : 2.3g

¹ H NMR (CDCl ₃ ,400MHz)δ 7.32(t, J =8.0Hz,1H),6.99(d, J =7.8Hz,1H),6.92-6.88(m,1H),6.88-6.83(m,1H ),5.99(br d, J =6.8Hz,1H),5.84(s,1H),5.12(quin, J =7.2Hz,1H),4.35(q, J =8.0Hz,2H),2.51(dd, J =53.2, 15.2Hz, 2H), 1.51(d, J =7.2Hz, 3H), 1.41(s, 3H); LC-MS: t _R =2.732min (LCMS method 2), m/z=374.0[ M+H] ⁺ .

SFC: tR = 1.721 _min (SFC method 12), de = 99.6%, ^{[α] D20} ₌ -51.0 (c = 0.20, MeOH).

Example 19b : 0.86g

¹ H NMR (CDCl ₃ ,400MHz)δ7.33(t, J =8.0Hz,1H),7.00(d, J =7.2Hz,1H),6.93-6.90(m,1H),6.88-6.83(m, 1H),5.98-5.91(m,1H),5.91(s,1H),5.12(quin, J =7.2Hz,1H),4.36(q, J =8.0Hz,2H),2.50(dd, J =57.6 , 14.8Hz, 2H), 1.51(d, J =6.8Hz, 3H), 1.39(s, 3H); LC-MS: t _R =2.737min (LCMS method 2), m/z=374.0[M+H ] ⁺ .

^SFC : tR = 1.904 _min (SFC method 12), de = 100%, [α] _D20 = -57.1 (c = 0.21, MeOH).

Claims (12)

A compound of formula I,

Wherein R1 is selected from the group consisting of C ₁ -C ₆ alkyl, CF ₃ , CH ₂ CF ₃ , CF ₂ CHF ₂ , C ₃ -C ₈ cycloalkyl, wherein the C ₃ -C ₈ Cycloalkyl can be substituted by 1 or 2 F, CHF ₂ or CF ₃ , and R2 is H, C ₁ -C ₆ alkyl or CF ₃ ; or R1 and R2 are combined to form optionally 1 or 2 F, CHF ₂ or CF ₃ substituted C ₃ -C ₅ cycloalkyl; R3 is C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl, the C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl groups may be optionally substituted by 1 or 2 Fs; R4 is selected from the group consisting of OCF ₃ or OCHF ₂ . The compound according to claim 1, wherein R2 is H or _CH3 . The compound according to claim 1, wherein R3 is CH ₂ OC _1-3 alkyl. The compound according to claim 1, wherein R1 is a C ₃ -C ₄ cycloalkyl group optionally substituted by 1 or 2 F, CHF ₂ or CF ₃ . The compound according to claim 1, wherein R1 is tertiary butyl, R2 is H, and R4 is OCF ₃ or OCHF ₂ . The compound according to claim 1, wherein R1 and R2 combine to form a cyclobutyl group optionally substituted by 1 or 2 Fs, and R4 is OCF ₃ or OCHF ₂ . The compound as claimed in item 1, wherein the compound is selected from the group consisting of: ( S )-3-hydroxyl-4,4-dimethyl- N -[( 1S )-1-[3 -(trifluoromethoxy)phenyl]ethyl]pentanamide, (R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[3-(trifluoro Methoxy)phenyl]ethyl]pentanamide, ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4, 4-Dimethylpentanamide, ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethyl Pentamide, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, ( R )-3-Hydroxy-4,4-dimethyl-N-(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, ( S )-3- (3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( R )-3 -(3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, ( S )- 3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)propionamide, ( R )-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propane Amide, ( R )-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropane Base) propionamide, ( S )-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl )cyclopropyl)acrylamide, ( S )-3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide , ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, N -(( R )- 2-(Difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-( R )-hydroxy-4,4-dimethylpentanamide, N - (( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-( S )-hydroxy-4,4-dimethylpentane Amide, ( S )-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl Pentamide, ( R )-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, ( S )-2-(3,3- Difluoro-1-hydroxycyclobutyl) -N- (1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, 4,4,4-trifluoro-3-hydroxy- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide, ( R )-4,4,5,5- Tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( S )-4,4,5 ,5-Tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )-5, 5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( S )-5 ,5,5-Trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, ( R )- 3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide, ( S )-3- (1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)butyramide, and ( R )-2- (1-hydroxycyclopentyl) -N- (2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide. The compound as described in claim 1, wherein the compound is selected from the group consisting of: (S)-3-hydroxyl-4,4-dimethyl-N-[(1S)-1-[3- (Trifluoromethoxy)phenyl]ethyl]pentanamide, (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoro Methoxy)phenyl)ethyl)acetamide, (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)benzene base) propyl) pentamide, and N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R )-hydroxy-4,4-dimethylpentanamide. A compound selected from the group consisting of (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)benzene Base] ethyl] pentamide, (R)-3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide, (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, (S) -N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide, (R)-N-(( S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide, (S)-3-hydroxy-4,4-di Methyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentamide, (R)-3-hydroxy-4,4-dimethyl-N-( (S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide, (S)-3-hydroxy-4,4-dimethyl-N-((S)-1- (3-(Trifluoromethoxy)phenyl)propyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(tri Fluoromethoxy)phenyl)propyl)pentamide, (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-( Trifluoromethoxy)phenyl)ethyl)propionamide, (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3- (Trifluoromethoxy)phenyl)ethyl)propionamide, (S)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-tri Fluoroethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethyl Oxy)phenyl)ethyl)pentamide, (S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-( Trifluoromethoxy)phenyl)ethyl)propionamide, (R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-( 3-(trifluoromethoxy)phenyl)ethyl)propionamide, (R)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl Base)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, (S)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)benzene Base) ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, (S)-3-hydroxy-4-methyl-N-((S)-1-(3- (Trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)benzene Base) ethyl) pentamide, N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethyl N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(S)-hydroxy-4 ,4-Dimethylpentanamide, (S)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)- 4,4-Dimethylpentanamide, (R)-3-Hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl) -4,4-Dimethylpentanamide, (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)benzene Base) ethyl) acetamide, (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl ) Acetamide, (3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]- 3-(Trifluoromethyl)pentanamide, (3S)-3-Hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy) Phenyl]ethyl]-3-(trifluoromethyl)pentanamide, 4,4,4-trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy )phenyl]ethyl]-3-(trifluoromethyl)butanamide, (R)-4,4,5,5-tetrafluoro-3-hydroxyl-3-methyl-N-((S) -1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-( (S)-1-(3-(Trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N- ((S)-1-(3-(Trifluoromethoxy)phenyl)ethyl)pentanamide, (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N -((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentamide, (R)-3-(1-fluorocyclopropyl)-3-hydroxyl-N-( (S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide, (S)-3-(1-fluorocyclopropyl)-3-hydroxyl-N-((S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide, (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1- (3-(Trifluoromethoxy)phenyl)ethyl)acetamide, (R)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2 ,2-trifluoroethoxy)phenyl)ethyl)butyramide, (S)-3-cyclopropyl-3-hydroxyl-N-((S)-1-(3-(2,2, 2-trifluoroethoxy)phenyl)ethyl)butyramide, (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-( 3-(2,2,2-Trifluoroethoxy)phenyl)ethyl)butanamide, with and (S)-4,4,4-Trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl) Ethyl) butyramide. A pharmaceutical composition comprising the compound as described in any one of claims 1 to 9 and a pharmaceutically acceptable excipient. A use of the compound according to claim 1 or 9, which is used to manufacture medicines for treating epilepsy, bipolar disorder, migraine or schizophrenia. A use of the compound according to claim 1 or 9, which is used for the manufacture of drugs for the treatment of the following diseases: psychosis, mania, stress-related disorders, acute stress response, bipolar depression, severe depression, anxiety, panic social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizoid disorder, aggressive behavior, chronic pain, neuropathy, autism spectrum disorders, Huntington Huntingtons chorea, sclerosis, multiple sclerosis, Alzheimer's disease.