TW201936569A - 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. Particular aspects of the invention relate to pharmaceutical compositions comprising the compounds and to the use of these compounds to treat disorders responsive to Kv7 potassium channel activation.

The voltage-dependent potassium (Kv) channel responds to changes in membrane potential to direct potassium ions (K ⁺ ) across the cell membrane and can thus modulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cells. Functional Kv channels exist as a multimeric structure formed by a combination of four alpha subunits and four beta subunits. The alpha subunit includes six transmembrane domains, a pore forming ring, and a voltage sensor, arranged symmetrically about the central aperture. The beta or auxiliary subunit interacts with the alpha subunit and can modify the properties of the channel complex to include, but is not limited to, changes in the electrophysiological or biophysical properties, performance levels, or performance patterns of the channel.

Nine Kv channel alpha subunit families have been identified and are referred to as Kv1-Kv9. Thus, there is a vast diversity of Kv channel functions due to the multiplicity of subfamilies, the formation of homologous and heteromeric subunits in subfamilies, and the additional effects associated with beta subunits (Christie, 25 Clinical and Experimental Pharmacology and Physiology, 1995, 22, 944-951).

The Kv7 channel family consists of at least five members, including one or more The following mammalian channels: Kv7.1, Kv7.2, Kv7.3, Kv7.4, Kv7.5, and any mammalian or non-mammalian equivalents or variants thereof (including splice variants). Alternatively, these members of the family are named 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 Kv7 potassium channel of neurons plays a role in controlling neuronal excitation. The Kv7 channel (especially the Kv7.2/Kv7.3 heterodimer) is the basis of the M current (Wang et al., Science. [Science] December 4, 1998; 282 (5395): 1890-3). The M current has a characteristic time and voltage dependence, resulting in stabilization of the membrane potential for multiple excitatory stimuli.

In this way, M current is involved in controlling neuronal excitability (Delmas and Brown, Nature, 2005, 6, 850-862). M current is a non-inactivation potassium current found in many neuronal cell types. In each cell type, it dominates membrane excitability by acting as the only continuous current in the initial range of action potentials (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 potassium channel of Kv7 (Wuttke et al., Molecular Pharmacology, 2005, 67, 1009-1017). Retigabine activates K ⁺ currents in neuronal cells, and this evoked current pharmacology is shown to be consistent with the published pharmacology of M-channels, the published pharmacology of the M-channel and Kv7.2 /3 K ⁺ channel heteromultimer correlation, suggesting that activation of the Kv7.2/3 channel is responsible for at least some of the anticonvulsant activity of the agent (Wickenden et al, Molecular Pharmacology 2000, 58, 591-600) ). Retigabine is effective in reducing the incidence of epileptic seizures (Bialer et al, Epilepsy Research 2002, 51, 31-71). Retigabine has a broad spectrum and effective anticonvulsant properties. In a series of anticonvulsant tests, retigabine was active after 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 performance patterns. The performance of Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle, whereas Kv7.2, Kv7.3, Kv7.4, and Kv7.5 appear to include hippocampus, cortex, ventral tegment, and dorsal root ganglion nerves. The dominant neuronal system (for review, see Greene and Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508).

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

Furthermore, in addition to the mRNA of Kv7.2, mRNAs of Kv7.3 and 5 are expressed in stellate cells and glial cells. Therefore, Kv7.2, Kv7.3, and Kv7.5 channels can 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 associated with the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease, and Huntington's disease.

Found in mRNA (eg, hippocampus, ventral hood, and amygdala) of Kv7.2 and Kv7.3 subunits in brain regions associated with anxiety and emotional behavior (eg, depression and bipolar disorder) (Saganich et al., Journal of Neuroscience 2001, 21, 4609-4624; Friedman et al, Nat Commun. [2016]; 7:11671), and it is reported that retigabine has an animal model of anxiety-like behavior. Activity (Korsgaard et al, J Pharmacol Exp Ther. [July 2005]; 314(1): 282-92. Epub April 6, 2005). Thus, Kv7 channels are associated with the treatment of emotion-related disorders such as, but not limited to, bipolar depression, major depression, anxiety, suicide, panic disorder, social phobia.

It has also been reported that the Kv7.2/3 channel is up-regulated in the neuropathic pain model (Wickenden et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators have been postulated in neuropathic pain. It is active in both epilepsy (Schroder et al., 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 means that the openers of these channels can also affect the sensory treatment of migraine (Goldstein et al., Society for Neuroscience Abstracts 2003, 53.8). Taken together, this evidence suggests a correlation between 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 opener regulates the function of the dopamine system (Friedman et al, Nat Commun. [2016]; Scotty et al, J Pharmacol Exp Ther. [Medical and Experimental Therapeutics] March 2009; 328(3) :951-62.doi:10.1124/jpet.108.146944.Epub December 19, 2008; Koyama et al, J Neurophysiol. [Journal of Neurophysiology] August 2006; 96(2): 535-43. Epub 2006 January 4th; Li et al., Br J Pharmacol. [UK Pharmacological Journal] December 2017; 174(23): 4277-4294.doi: 10.1111/bph.14026.Epub October 19, 2017; Hansen Et al., J Pharmacol Exp Ther. [Journal of Pharmacology and Experimental Therapy] September 2006; 318(3): 1006-19. Epub June 14, 2006), the opener will be associated with the treatment of mental disorders These mental disorders such as, but not limited to, mental illness, 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 disorders. WO 01/96540 discloses the use of M current regulators formed by the KCNQ2 and KCNQ3 genes for insomnia, while WO 01/092526 discloses A modulator of Kv7.5 is used to treat 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 accompanied by undesirable side effects. Therefore, the need for novel therapies for treating the disease has not been met.

To identify new therapies, the inventors have identified a series of novel compounds represented by Formula I as Kv7.2, Kv7.3, Kv7.4, and Kv7.5 channel openers. Accordingly, the present invention provides novel compounds as medicaments for the treatment of disorders modulated by KCNQ potassium channels.

The present invention relates to compounds having 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 _{The 8-} cycloalkyl group may be substituted by 1 or 2 F, CHF ₂ or CF ₃ and R 2 is H, C ₁ -C ₆ alkyl or CF ₃ ; or R 1 and R ₂ may be combined to form F, CHF ₂ as needed. Or a C ₃ -substituted C ₃ -C ₅ cycloalkyl group; R 3 is a C ₁ -C ₃ alkyl group or a CH ₂ OC _1-3 alkyl group optionally substituted by F; R 4 is selected from the group consisting of the following : OCF ₃ , OCH ₂ CF ₃ or OCHF ₂ ; The invention further relates to a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or excipient.

Furthermore, the present invention relates to a method of treating a patient as described in the scope and examples of the patent application, and to treating a patient suffering from epilepsy, bipolar disorder, migraine and schizophrenia, the method comprising administering a subject A therapeutically effective amount of a compound according to the invention is administered.

According to a specific example of the present invention, R4 is OCF ₃ or OCHF _2, and according to another specific example, R2 is H or CH _3.

In one specific example, R1 is optionally substituted with 1 or 2 F, CHF ₂ or CF ₃ substituted C ₃ -C ₄ cycloalkyl.

According to certain specific examples, three Rl is butyl, and R2 is H, and R4 is OCF _3, OCH ₂ CF _3, one or OCHF _2.

According to another specific embodiment, R1 and R2 are combined to form a cyclobutyl group which is optionally substituted with 1 or 2 F, and R4 is one of OCF ₃ , OCH ₂ CF ₃ or OCHF ₂ .

According to a particular embodiment of the invention, the compound according to the invention is selected from the group consisting of: ( S )-3-hydroxy-4,4-dimethyl- N -[( 1S ) -1-[3-(trifluoromethoxy)phenyl]ethyl]pentanylamine, ( R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[ 3-(Trifluoromethoxy)phenyl]ethyl]pentanamine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2, 2,2-Trifluoroethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2) , 2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl) -3-hydroxy-4,4-dimethylpentanamine, ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy- 4,4-Dimethylpentamidine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl Pentamidine, ( R )-3-hydroxy-4,4-dimethyl- N -((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanylamine, ( R )-3- Hydroxy-4,4-dimethyl-N-(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanylamine, ( S )-3-(3,3-difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide, ( R )-3-(3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide , ( S )-3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamine, ( R )-3-Hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( S ) -3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamide , ( R )-3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl) Propylamine, ( R )-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)) ring Propyl)propanamide, ( S )-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl) ()cyclopropyl)propanamine, ( S )-3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanthene Amine, ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, N -(( R ) -2-(difluoromethoxy)-1-(3-(trifluoro) Oxy) phenyl) ethyl) -3- (R) - hydroxy-4,4-dimethyl-pentyl Amides, N - ((R) -2- ( difluoromethoxy) -1- (3 -(Trifluoromethoxy)phenyl)ethyl)-3-( S )-hydroxy-4,4-dimethylpentanamine, ( S )-3-hydroxy- N -(( R )-2 -methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamine, ( R )-3-hydroxy- N -(( R )- 2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamine, ( S )-2-(3,3-difluoro- 1-hydroxy-cyclobutyl) - N - (1- (3- (trifluoromethoxy) phenyl) ethyl) amine acetyl, (S) -2- (1- hydroxy-cyclobutyl) - N - (1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamidamine, (3 R )-3-hydroxy-4-methyl- N -[(1 S ) 1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamine, (3 S )-3-hydroxy-4-methyl -N -[(1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamine, 4, 4 , 4-trifluoro-3-hydroxy- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamine, ( R )-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanthene Amine, ( S )-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl -N -(( S )-1-(3-(Trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-5,5,5-trifluoro-3-hydroxy-3- Methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamine, ( S )-5,5,5-trifluoro-3-hydroxy-3 -methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-3-(1-fluorocyclopropyl)-3- Hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamine, ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N - ((S) -1- ( 3- ( trifluoro - methoxy) phenyl) ethyl) butan Amides, (R) -2- (1- hydroxy-cyclopentyl) - N - (2- Methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, ( R )-3-cyclopropyl-3-hydroxy- N -(( S )-1-( 3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamine, ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3 -(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamine, ( S )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxyphenyl)ethyl)butanamine, and ( R )-4,4,4-trifluoro-3-hydroxy-3- Methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamine.

The compounds encompassed by the present invention include racemic mixtures of these compounds, optical isomers of related compounds, and polymorphic and amorphous forms of the compounds of the invention, as well as tautomerism of the compounds associated therewith. form. Furthermore, the compounds of the invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Both solvated and unsolvated forms of these compounds are contemplated by the present invention.

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

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

In another embodiment, the invention relates to a method of treating a subject suffering from epilepsy, bipolar disorder, migraine or schizophrenia, which method comprises administering to the subject a therapeutically effective amount according to the invention compound of.

In yet another embodiment, the invention relates to a method of treating a patient in need thereof, the patient having the following disorders: 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, autism disorder, Huntington's disease A choroid, sclerosis, multiple sclerosis, Alzheimer's disease, the method comprising administering to a subject a therapeutically effective amount of a compound according to the invention.

According to a specific example, 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 disorder, orientation Pain or schizophrenia, or in another specific example, for the treatment of 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, schizophrenia, aggressive behavior, chronic pain, neuropathy, autism, Huntington's disease, sclerosis, multiple sclerosis Disease, Alzheimer's disease.

In another embodiment, the compounds of the invention are 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, paralysis Madness, stress-related disorders, acute stress response, bipolar depression, major depression, anxiety, panic disorder, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizophrenia disorder, attack Behavior, chronic pain, neuropathy, autism, Huntington's disease, sclerosis, multiple sclerosis, Alzheimer's disease.

In the context of the present invention, "optionally substituted" means that the indicated moiety may be substituted or may be unsubstituted, and when substituted, is monosubstituted or disubstituted. It should be understood that this position is occupied by a hydrogen atom when the substituent is "indicated as needed".

Available "-" (hyphen), or "to" are used interchangeably to indicate that a given range, for example, the term "C _1-3 alkyl" is equivalent to "C ₁ to C ₃ alkyl."

The term "C _1- C ₃ alkyl" and "C _1- C ₆ alkyl" refers to an unbranched having from one up to six carbon atoms (inclusive) or a branched saturated hydrocarbon. 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 the formula -OR wherein R represents C ₁ -C ₃ alkyl 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. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Route of administration:

A pharmaceutical composition comprising a compound of the invention as defined above may be specifically formulated for administration by any suitable route, for example, orally, rectally, nasally, buccally, sublingually, transdermally and parenterally (e.g., subcutaneously, 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 to be treated, the nature of the condition being treated, and the active ingredient.

Pharmaceutical formulations and excipients:

Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutical excipient including, but not limited to, a filler, an anti-adhesive, a binder, a coating, a coloring agent, a disintegrating agent. , 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, such as one of the compounds disclosed in the experimental part herein. The invention also provides a process for the manufacture of a pharmaceutical composition comprising a compound according to the invention. The pharmaceutical compositions according to the present invention may be formulated according to conventional techniques using pharmaceutically acceptable excipients such as those disclosed in Remington, The Science and Practice of Pharmacy, 22nd edition (2012), edit Allen, LoydV., Jr.

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

The solid oral dosage forms can be presented in discrete unit forms (for example, lozenges or hard or soft capsules), each containing a predetermined amount of active ingredient, and preferably one or more suitable excipients. Where appropriate, these solid dosage forms may be prepared with a coating, such as an enteric coating, according to methods well known in the art, or they may be formulated to provide improved release of the active ingredient, for example Late or extended release. Where appropriate, the solid dosage form can be a dosage form that disintegrates in saliva, such as an oral amine dispersion tablet.

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, Lower alkyl ethers of gelatin, pectin, magnesium stearate, stearic acid and 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 may be prepared, for example, by mixing the active ingredient with a solid excipient, and then compressing the mixture in a conventional tablet machine; or for example, the formulation may be, for example, Powder, pills or minitablets 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 solutions or suspensions in aqueous or non-aqueous liquids. Examples of excipients suitable for liquid oral formulations include, but are not limited to, ethanol, propylene glycol, glycerin, polyethylene glycol, poloxamer, sorbitol, polysorbates, monoglycerides and diglycerides, rings 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 nonaqueous liquid, or by incorporating the active ingredient in an oil-in-water or water-in-oil liquid emulsion.

Additional excipients (e.g., coloring, flavoring, preservatives, and the like) can be employed in solid and liquid oral formulations.

Pharmaceutical compositions for parenteral administration include: sterile aqueous and nonaqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, and intended for use prior to use. A sterile powder that is reconstituted in a sterile solution or dispersion that is injected or infused. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin. liquid. The aqueous formulation should be suitably buffered if necessary and the aqueous formulation rendered isotonic with sufficient saline or glucose.

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

The excipients used in any pharmaceutical formulation must conform to the intended route of administration and be compatible with the active ingredient.

dose:

In one embodiment, the compound of the invention is administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day. In particular, the daily dose may range from 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The precise dose 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 accompanying disease to be treated, the desired therapeutic effect, and Other factors known to those of ordinary skill in the art.

Typical oral doses for adults are in the range of from 0.1 to 1000 mg per day of the compound of the invention, for example from 1 to 500 mg per day, for example from 1 to 100 mg per day or from 1 to 50 mg per day. Conveniently, the compounds of the invention are administered in unit dosage form containing the compound in an amount of from about 0.1 to 500 mg, such as 10 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg of the compound of the invention.

Isomeric forms and tautomeric forms:

When a compound of the invention contains one or more chiral centers, reference to any of these compounds will encompass enantiomerically pure or diastereomerically pure compounds and in any proportion unless otherwise stated. a mixture of enantiomers or diastereomers.

The MDL enhanced stereo representation is used to describe the unknown stereochemistry of the compounds of the invention. Therefore, the label "or1" on the chiral carbon atom is used to indicate that the absolute stereo configuration at the atom is unknown. For example, the stereo configuration of the carbon atom is (S) or (R).

Furthermore, the chiral bond from the carbon atom label "or1" using an upward wedge or a downward wedge is the same representation; for example, two graphs have the same meaning, which is absolute on the carbon atom labeled "or1" The stereo configuration is unknown and can be (S) or (R).

Thus, the use of an upward wedge key and a downward wedge key from an atom labeled "or1" is only intended to provide a visual cue, ie the figures represent different stereoisomers, wherein the configuration of the "or1" labeled carbon atom is Unknown.

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

Therape effective amount:

In the context of the present invention, the term "therapeutically effective amount" of a compound means a clinical condition sufficient to alleviate, arrest, partially block, remove or delay a given disease and its complications in a therapeutic intervention involving administration of the compound. The amount of performance. An amount sufficient to achieve the above is defined as a "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury as well as the weight and general condition of the subject. It will be appreciated that determining the appropriate dosage can be accomplished using conventional experiments by constructing a matrix of values and testing different points in the matrix, all within the ordinary skill of the 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, retarding, partially arresting, removing the clinical manifestations of the 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 in their entireties in the entireties in Explain here (to the maximum allowed by law degree).

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

Any and all examples or exemplary languages (including "for instance", "for example", "eg", and "as such" are used in this specification unless otherwise indicated. It is intended to clarify the invention and not to limit the scope of the invention.

The patent documents are hereby incorporated by reference in their entirety for all purposes in the extent of the disclosure of the disclosure of the disclosure.

The present invention includes all modifications and equivalents of the subject matter described in the appended claims.

Further specific examples of the invention

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 _{The 8-} cycloalkyl group may be substituted by 1 or 2 F, CHF ₂ or CF ₃ , and R 2 is H, C ₁ -C ₆ alkyl or CF ₃ ; or R 1 and R 2 may be combined to form 1 or 2 as needed. F, CHF ₂ or CF ₃ substituted C ₃ -C ₈ cycloalkyl; R ₃ 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 may be substituted with 1 or 2 F as required; R 4 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 of embodiment 1, wherein R4 is OCF ₃ or OCHF ₂ .

3. Specific examples of the compound according to any one of, wherein R2 is H or CH _3.

The compound according to any one of the preceding embodiments, wherein R3 is CH ₂ OC _1-3 alkyl.

5. A compound according to any of the foregoing specific examples, wherein R1 is optionally substituted with 1 or 2 F, CHF ₂ or CF ₃ substituted C ₃ -C ₄ cycloalkyl.

6. A compound according to any one of the preceding specific example, wherein R1 is a three-butyl, and R2 is H, and R4 is _{OCF 3, OCH 2 CF 3,} OCHF 2 or CF _3.

The compound according to any one of the preceding embodiments, wherein R1 and R2 are combined to form a cyclobutyl group optionally substituted by 1 or 2 F, and R4 is OCF ₃ , OCH ₂ CF ₃ , OCHF ₂ Or CF ₃ .

8. The compound according to the specific example 1, wherein the compound is selected from the group consisting of: ( S )-3-hydroxy-4,4-dimethyl- N -[(1 S ) 1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamine, R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[3 -(Trifluoromethoxy)phenyl]ethyl]pentanylamine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2 , 2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2, 2,2-Trifluoroethoxy)phenyl)ethyl)pentanylamine, ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)- 3-hydroxy-4,4-dimethylpentylamine, ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4 , 4-dimethylpentylamine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl) Pentamidine ( R )-3-hydroxy-4,4-dimethyl- N -((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanylamine, ( S ) -3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanylamine, ( R )-3-hydroxy- 4,4-dimethyl -N - ((S) -1- ( 3- ( trifluoromethoxy) phenyl) propyl) pentyl Amides, (S) -3- (3,3- Fluoro-cyclobutyl) -3-hydroxy - N - ((S) -1- (3- ( trifluoromethoxy) phenyl) ethyl) propan-acyl amine, (R) -3- (3,3- Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamine, ( S )-3-hydroxy-4- Methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4-methyl - N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( S )-3-(1-(difluoromethyl) Cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamine, ( R )-3-(1-( Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamine, ( R )-3-hydroxyl -N -(( S )-1-(3-(Trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamine, ( S )- 3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamine, ( S )-3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4 -Methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, N -(( R )-2-(difluoromethoxy)- 1-(3-(trifluoromethoxy)benzene ) Ethyl) -3- (R) - hydroxy-4,4-dimethyl-pentyl Amides, N - ((R) -2- ( difluoromethoxy) -1- (3- (trifluoromethyl Oxy)phenyl)ethyl)-3-( S )-hydroxy-4,4-dimethylpentanamine, ( S) -3-hydroxy- N -(( R )-2-methoxy- 1-(3-(Trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamine, ( R )-3-hydroxy- N -(( R )-2-methoxy 1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamine, ( S )-2-(3,3-difluoro-1-hydroxycyclobutane yl) - N - (1- (3- ( trifluoromethoxy) phenyl) ethyl) amine acetyl, (S) -2- (1- hydroxy-cyclobutyl) - N - (1- (3 -(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamidine, (3 R )-3-hydroxy-4-methyl- N -[(1 S )-1-[3 - (2,2,2-trifluoroethoxy) phenyl] ethyl] -3- (trifluoromethyl) pentyl Amides, (3 S) -3- hydroxy-4-methyl - N - [ (1 S )-1-[3-(2,2,2-Trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamine, 4,4,4-trifluoro 3-hydroxy- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamine, ( R )-4, 4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, ( S ) -4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamine, ( R )-5,5,5-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(Trifluoromethoxy)phenyl)ethyl)pentanylamine, ( S )-5,5,5-trifluoro-3-hydroxy-3-methyl- N- ( ( S )-1-(3-(Trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamine, ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )- l- (3- (trifluoromethoxy - methoxy) phenyl) ethyl) butan Amides, (R) -2- (1- hydroxy-cyclopentyl) - N - (2- methoxy-1- ( 3-(Trifluoromethoxy)phenyl)ethyl)acetamide, ( R )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2, 2-trifluoroethoxy)phenyl)ethyl)butanamine, ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2) -trifluoroethoxy)phenyl)ethyl)butanamine, ( R )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3 -(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamine, and ( R )-4,4,4-trifluoro-3-hydroxy-3-methyl- N- ( ( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamine

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 response, bipolar depression, major depression, anxiety, panic disorder, social phobia, sleep disorders, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizophrenia Obstacle, aggressive behavior, chronic pain, neuropathy, autism disorder, Huntington's disease, sclerosis, multiple sclerosis, Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount The 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 a compound as 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 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, schizophrenia, aggressive behavior, chronic pain, neuropathy, autism, Huntington's disease, sclerosis, multiple sclerosis Disease, Alzheimer's disease.

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

14. A compound as disclosed in specific examples 1 to 8 for use in the manufacture of a medicament for the treatment of 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, schizophrenia, aggressive behavior, chronic pain, neuropathy, autism, Huntington's disease, sclerosis, Multiple sclerosis, Alzheimer's disease.

Experimental part Biological assessment Cell culture

The synthetic cDNA fragment encoding human Kv7.3 and human Kv7.2 isolated from the P2A sequence was inserted into the pcDNA5/FRT/TO vector using BamHI and XhoI restriction sites. The construct was then transfected into HEK Flp-In 293 cells using Lipofectamine 2000. Transfected cells were grown for 48 hours in DMEM containing 10% (v/v) FBS and 1% PenStrep, followed by containing 10% (v/v) FBS, 1% PenStrep and 200 ug/mL hygromycin B in DMEM was maintained at 37 ° C in a humidified atmosphere of 5% CO ₂ under selection. The resulting stable hKv7.2/hKv7.3 cell line (HEK-hKv7.2/hKv7.3) was functionally tested with automated whole-cell patch clamp and showed a typical Kv7 current, which is sensitive to XE991. And enhanced by retigabine.

铊 flux measurement

Similar to the published procedure (CD Weaver et al, J Biomol Screen 2004, 9, 671-677), the FLIPR potassium assay kit (Molecular Device) was used to perform a sputum flux for potassium channel activation. Determination. HEK-hKv7.2/hKv7.3 cells at 80,000 cells/well (100 μl/well) (if these cells were measured on the next day) or 40,000 cells/well (100 μl/well) (if two days after inoculation) The density of these cells was measured on a 96-well, black-walled, clear bottom plate (Corning, Acton, Massachusetts, USA).

On the day of the assay, the medium was removed, after which 50 uL/well of test compound was diluted to a final concentration of 2x 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. A 5x final concentration (in both cases 5x concentration: 5 mM) of Tl ⁺ and K ⁺ -free chloride-free stimulation buffer and 1 x final concentration of test compound were prepared during the incubation. These cells were then assayed in a FDSS7000EX functional drug screening system (Hamamatsu). After a baseline fluorescence signal reading of 0.1 Hz for 60 sec and 1 Hz for 10 sec, 25 uL/well of stimulation buffer was added and the fluorescence was continuously measured at 1 Hz for 50 sec before continuing at 0.1 Hz for 4 min. The effect of the compound was quantified using AUC as a reading and normalized to the reference compound contained on each plate.

Compound action

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

Synthesis of the compounds of the 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 hydrazine or deuterated chloroform is used as a solvent. Tetramethyl decane was used as an internal reference standard. The chemical shift value relative to tetramethylnonane is expressed in ppm. The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintuple, h = sigmoid, dd = doublet, ddd = Double doublet, dt=double triplet, dq=double quartet, tt=triple triplet, m=multiple peak and brs=width single peak.

Chromatographic systems and methods for assessing chemical purity (LCMS method) and chiral purity (SFC and HPLC methods) 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

The general procedure for the synthesis of intermediates and compounds of formula I is described in Reaction Scheme 1 and is specifically illustrated in the Preparations and Examples. It is within the scope of the invention to be a variant of the procedure known to those skilled in the art.

The compounds of the invention were prepared as described in Scheme 1. Several of the compounds of formula I contain two chiral carbon atoms and form a mixture of diastereomers. When in this case, the diastereomers can be separated to yield the individual stereoisomers Ia and Ib.

Scheme I depicts the preparation of a compound of formula I by two general routes. The first route is by a method known in the art for converting an acid and an amine to a guanamine. The compound of formula I is synthesized by the reaction of an enantiomerically pure amine of formula II with an acid of formula III. This method comprises forming a reactive derivative of an acid of formula III, including but not limited to an active ester, and a reactive mixed anhydride, followed by condensation with an amine of formula II. One such method is in HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate The condensation is carried out in a solvent such as dichloromethane in the presence of a suitable base such as DIPEA (diisopropylethylamine).

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

A variant of this procedure is the direct coupling reaction between a chiral amine of the general formula II and a carboxylic acid ester of the 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), The reaction is heated to reflux to carry out the reaction.

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

The aldehyde having the formula VI and ( R )-2- can be present in a suitable solvent such as dichloroethane in the presence of a drying agent such as titanium isopropoxide (IV) or copper sulfate. Propane-2-sulfinamide condensation. The resulting sulfinylimine is treated with R ³ MgBr in a suitable inert solvent such as THF to yield the corresponding substituted ( R )-2-methyl- N -(( S )- 1-aryl-alkyl)propane-2-sulfinamide VII, which is converted to a compound of formula II by treatment with a suitable acid in a suitable solvent (eg HCl in MeOH) .

The aldehyde of formula VI used to prepare the compounds of the invention is commercially available or can be as described in the literature (see fx. Journal of Medicinal Chemistry, 45 (18), 3891-3904; 2002 ). The preparation is carried out as described.

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

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

Another variant of this procedure, as outlined in Scheme 4, particularly suitable for obtaining chiral amine having the formula II (wherein R ³ is hydroxymethylene derivative).

Option 4:

In this procedure, a suitable catalyst (eg bis(acetonitrile) (1,5-cyclooctadiene) ruthenium (I) tetrafluoroborate) is used in a suitable solvent (eg two Among them, glyoxylic acid formed in a condensation reaction between glyoxylate and (R)-2-methylpropane-2-sulfinamide can be described as described in JP 2017/095366 A The sulfinylimine is reacted with a suitably substituted boronic acid. The resulting intermediate VIII may be hydrolyzed and then protected, to yield an intermediate having the general formula IX, which can be further derivatized to obtain the desired substituent R ^3. In the compounds of the present invention, the carboxylate group of IX can be reduced to a hydroxymethylene group using LAH (lithium aluminum hydride), and a suitable reagent (for example, 2,2-difluoro-2-(fluorosulfonate) can be used. The base) acetic acid) is subjected to difluoromethylation in a suitable solvent such as acetonitrile under the following conditions, such as CuI catalysis.

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

A carboxylic acid of the general formula III can be prepared as outlined in Scheme 5:

The ketone having the general formula X is reacted with an alkyl ester of bromoacetic acid activated by, for example, Zn and iodine to yield the corresponding aldol adduct. In an alternative procedure, bromoacetate can be activated using Zn and TMSCl (trimethylsulfonium chloride). In the 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 an alcohol in water. The ester is hydrolyzed and subsequently acidified with a suitable acid to yield a compound of formula III.

Preparation of intermediates:

IIa: ( S )-1-(3-(Trifluoromethoxy)phenyl)ethaneamine hydrochloride

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

3-(Trifluoromethoxy)benzaldehyde (24.8 g, 130.4 mmol), ( R )-2-methylpropane-2-sulfinamide (19 g, 156.5 mmol) and CuSO ₄ at 55 °C (31.2 g, 195.7 mmol) A mixture of DCM (1,2-dichloroethane) (500 mL) was stirred for 24 hours. The mixture was filtered and the filter cake was washed with EtOAc EtOAc. The organic phases were combined and concentrated. The residue was purified by flash chromatography (yield: EtOAc: EtOAc (EtOAc)

_{^{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

To ( R )-2-methyl- N -[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamide (17.6 g, 59.8 mmol) at 0 °C MeMgBr (3 M in Et ₂ O, 40 mL) was added dropwise to a solution in DCM (250 mL). 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 NH ₄ Cl was added. The resulting mixture was extracted with DCM (100 mL×2). The organic phase was washed with brine (200mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash EtOAc (EtOAc:EtOAc:EtOAc

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

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

( R )-2-Methyl- N -[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]propane-2-sulfinamide in MeOH (75 mL) (10 g, 32.3 mmol) was taken in EtOAc / EtOAc (EtOAc) The mixture was concentrated to give ( S )-l-(3-(trifluoromethoxy)phenyl) ethaneamine hydrochloride (9 g, crude product) which was used directly without further purification.

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

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

3-hydroxybenzaldehyde (5 g, 40.9 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (10.5 g, 45 mmol) and Cs ₂ CO ₃ (26.7 g, 81.9) at 20 °C Methyl) mixture in DMF (60 mL) was stirred for 2 h. The mixture was filtered and the cake was washed with ethyl acetate (EtOAc). The filtrate was washed with water (100mL x 2) and brine (100mL x 2), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc

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

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

3-(2,2,2-Trifluoroethoxy)benzaldehyde (8.0 g, 39.2 mmol), ( R )-2-methylpropane-2-sulfinamide (5.2 g) at 55 °C , 43.1mmol) and CuSO ₄ (9.4g, 58.8mmol) was stirred in the mixture (70mL) DCE 20 hours. The mixture was filtered and the filter cake was washed with DCM (100 mL). The organic phases were concentrated and purified by column chromatography eluting with EtOAc (EtOAc:EtOAc

_{^{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 = 8.0 Hz, 2 H), 1.27 (s, 9 H).

Step 3: ( R )-2-Methyl-N-(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfinone Preparation of amine

To ( R )-2-methyl- N -[[3-(2,2,2-trifluoroethoxy)phenyl]methylene]propane-2-sulfinamide at 0 ° C ( 10 g, 32.5 mmol) MeMgBr (3M, 43 mL) was added dropwise to a solution in DCM (100 mL). 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 NH ₄ Cl was added. The resulting mixture was extracted with DCM (100 mL×2). The organic phase was washed with brine (200mL), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc)

¹ H NMR (CDCl ₃ 400 MHz): δ 7.27 (d, J = 8.4 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 8.4 Hz, J = 2.4 Hz, 1 H), 4.56 - 4.54 (m, 1 H), 4.34 (dd, J = 16.4 Hz, J = 8.4 Hz, 1 H), 3.30 (br s, 1 H), 1.51 (d, J = 8.4 Hz, 3 H), 1.20 (s, 9 H). No NH was observed.

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

To ( R )-2-methyl- N -[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]propane-2-sulfinamide ( 9 g, 27.8 mmol) HCl / MeOH (80 mL, 4M). The resulting mixture was stirred at 20 ° C for 4 h and concentrated to give a crude material (8 g).

IIc: ( S )-1-(3-(Difluoromethoxy)phenyl)ethane-1-amine hydrochloride

Step 1 :( R) - N - ( 3- ( difluoromethoxy) benzylidene) sulfinyl Preparation of 2-methyl-2-amine

To 3-(difluoromethoxy)benzaldehyde (2 g, 11.6 mmol) and 2-methylpropane-2-sulfinamide (1.7 g, 13.9 mmol) in DCE at 55 ° C. CuSO ₄ (9.3 g, 58.1 mmol) was added to the mixture in 60 mL). 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 (petroleum column eluted with petroleum ether / ethyl acetate = 20: 1-10:1) to give ( R ) -N- (3-(difluoromethoxy) Phenylmethyl)-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

At 0 ℃, the (R) - N - (3- ( difluoromethoxy) benzylidene) -2-methylpropane-2-sulfinyl amine (2g, 7.3mmol) in DCM (30mL Bromine (methyl) magnesium (3M in Et ₂ O, 4.8 mL) was added dropwise to the solution. 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) was quenched, and the aqueous phase was extracted with ethyl acetate (30mL × 3). The combined organic phases were washed with brine (40mL × 2), dried over anhydrous Na ₂ SO _4, filtered, concentrated and chromatographed through silica gel (petroleum ether / ethyl acetate = 5: 1: 1-1) to give 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)ethaneamine hydrochloride

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

IId: ( S )-1-(3-(Trifluoromethyl)phenyl)ethane-1-amine hydrochloride

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

3-(Trifluoromethyl)benzaldehyde (4.5 g, 25.8 mmol), ( R )-2-methylpropane-2-sulfinamide (3.8 g, 31 mmol) and CuSO ₄ (at 55 ° C) A mixture of 6.2 g, 38.8 mmol) in DCE (20 mL) was stirred for 24 h. 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 (SiO _2, petroleum ether / ethyl acetate) to afford the product yield 4.6g (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 = 7.6 Hz, 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)-2-sulfinamide (2 g, 7.2 mmol) in DCM (50 mL) MeMgBr (3M in Et ₂ O, 9.6 mL) was added dropwise to the solution. 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 a saturated aqueous solution of NH ₄ Cl was added. The mixture was extracted with DCM (50 mL×3). The combined organic phases were washed with brine (50mL × 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography (SiO _2, petroleum ether / ethyl acetate) to provide the desired product (1.3g, 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). No NH was observed.

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

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

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

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

3-(Trifluoromethoxy)benzaldehyde (10.0 g, 52.60 mmol), ( R )-2-methylpropane-2-sulfinamide (7.7 g, 63.1 mmol) and CuSO4 at 55 °C (12.6 g, 78.9 mmol) The mixture in DCE (200 mL) was stirred 16 hr. 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 eluting with 0-10% ethyl acetate / petroleum ether gradient to give yield (12.6 g (81.7%) of ( R )-2- Base- 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)-2-sulfinamide (2.0 g, 6.8 mmol) in DCM EtMgBr (3M in Et ₂ O, 9.1 mL) was added dropwise to the solution in 40 mL). The resulting mixture was stirred at 0 ° C for 1 hour and at 20 ° C for 3 hours. The mixture was cooled to 0 ℃ and adding saturated NH ₄ Cl solution (100mL). The mixture was extracted with DCM (100mL × 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 EtOAc (EtOAc:EtOAc:EtOAc

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

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

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

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

2-bromo-l- (3- (trifluoromethoxy) phenyl) ethanone (3.5g, 12.4mmol) in (60 mL) solution was added _{Ag 2 CO 3 (3.8g, 13.6mmol} ) in MeOH and _{BF 3 .Et 2 O (2.1g,} 14.8mmol). The mixture was stirred at 50 ° C for 16 hours under N ₂ . The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO ₂ eluted elute elute elute elute elut 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- (trifluoromethoxy - methoxy) phenyl) ethyl) -2-methylpropane-2-sulfinyl amine preparation

To a solution of 2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanone (500 mg, 2.1 mmol) in THF (15 mL), EtOAc (IV) 3.2 mmol) and ( R )-2-methylpropane-2-sulfinamide (336 mg, 2.8 mmol). The mixture was stirred at 50 ° C for 1 hour under N ₂ . The reaction mixture was quenched with brine (40 mL)EtOAc. The combined organic phases were dried over MgSO _4, filtered and concentrated. The residue was purified by column chromatography (SiO _2, elution solution is a 0-10% ethyl acetate / petroleum ether) to give (R) - N - (2- methoxy-1 (3 -(Trifluoromethoxy)phenyl)ethylidene-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 guanamine

At 0 ℃, the (R) - N - (2- methoxy-1- (3- (trifluoromethoxy) phenyl) ethyl) -2-methylpropane-2-sulfinyl A solution of the amine (160 mg, 0.5 mmol) in THF (5 mL). The mixture was stirred at 20 ° C for 16 hours. The reaction mixture was diluted with MeOH (20 mL) and then filtered and concentrated. The residue was purified product was purified by column chromatography (SiO _2, elution solution is a 0-10% ethyl acetate / petroleum ether) to give the desired (100mg, 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)ethaneamine

( R ) -N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)B in HCl/MeOH (10 mL, 4M) at 20 ° The benzyl-2-methylpropane-2-sulfinamide (280 mg, 0.8 mmol) was stirred for 14 hours. The reaction mixture was concentrated, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The combined organic extracts were dried over MgSO _4, filtered and concentrated to give the product as a yellow oil (170mg, 88% yield). This product was used directly without further purification.

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

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

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, washed with EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography (EtOAc EtOAcEtOAcEtOAcEtOAc

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

To ethyl-2-[( R )-tertiary butylsulfinyl]imidoacetate (7 g, 34.1 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (8.4 g , 40.9mmol) in two [Rh(COD)(MeCN) ₂ ]BF ₄ (1.3 g, 3.4 mmol) was added to a solution (100 mL), 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 ( 2R )-2-amino-2-[3-(trifluoro-methoxy)phenyl]acetate hydrochloride

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

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

Add Boc to a mixture of ethyl ( 2R )-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate hydrochloride (6 g, 20 mmol) in THF (150 mL) ₂ O (8.7 g, 40 mmol). NaHCO ₃ (1.7 g, 20 mmol) was then added to this solution and stirred at 25 ° C for 16 h. The mixture was concentrated and purified by EtOAc (EtOAc:EtOAc:EtOAc)

Step 5: Preparation of tert-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), ethyl ( 2R )-2-(tert-butoxycarbonylamino)-2-[ 3-(Trifluoro-methoxy)phenyl]acetate (4 g, 11 mmol) was cooled with ice. After the addition, the reaction was allowed to warm to 25 ° C and stirred for 2 hours. Anhydrous magnesium sulfate was added, and then a drop of water and ethyl acetate were sequentially added. The insoluble matter is filtered through a diatomaceous earth pad. The filtrate was concentrated and purified by chromatography on silica gel (SiO _2; petroleum ether: ethyl acetate = 5: 1) (2.1g, 59% yield) was purified.

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

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

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

To a tertiary butyl N -[(1 R )-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]aminocarboxylic acid at 25 ° C To a solution of EtOAc (5 mL, EtOAc) (EtOAc) Ammonium hydroxide (30%) to pH = 9, and the solution was concentrated and purified by chromatography (of SiO _2; petroleum ether: ethyl acetate = 2: 1) was purified on silica gel to provide (1 R & lt) 2-(Difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethaneamine (700 mg, 64% yield).

IIIa: 2-(1-hydroxycyclobutyl)acetic acid

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

TMSCl (1.9 g, 17.1 mmol) was added portionwise to Zn (14.9 g, 228.3 mmol) in THF (20 mL). 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 a rate that allowed the reaction to slowly boil. The resulting mixture was stirred at 70 ° C for 1 hour and then at 20 ° C for 1 hour, then 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 in ice _{NH 3 .H 2 O (150mL,} 25%) and extracted with ethyl acetate (100mL x 2). The organic layer was washed with water (200mL x 2) and brine (100ml x 2), dried over Na ₂ SO ₄ and concentrated to give the product (12g, crude).

¹ H NMR (CDCl ₃ 400 MHz): 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, 2 H), 1.78 (m, 1 H), 1.58 (m, 1H), 1.27 (t, J = 7.6 Hz, 3H).

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

The NaOH (6.3g, 158.05mmol) was dissolved in MeOH (150mL) and H ₂ O (50mL), and the addition of ethyl 2- (1-hydroxy-cyclobutyl) acetate (10g, 63.2mmol). The mixture was stirred at 20 <0>C for 16 h and then concentrated and the residue was crystallised from EtOAc EtOAc (EtOAc) The organic extracts were washed with water (100mL x 2) and brine (100mL x 2), dried over Na ₂ SO _4, and concentrated to give the crude product (6g, crude).

¹ H NMR (CDCl ₃ 400 MHz): 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

Under N _2, 3,3-difluoro-cyclobutanone (0.2g, 1.9mmol), Zn ( 198mg, 3mmol) and I ₂ (10mg, 0.04mmol) in (13 mL of) in THF was added dropwise acetyl 2-Bromoacetate (378 mg, 2.3 mmol). 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 (, 10mL saturated aqueous solution) was washed with ₃ NaHCO, 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

At 0 ℃, a solution of ethyl 2- (3,3-difluoro-1-hydroxy - cyclobutyl) acetate (0.26g, 1.3mmol) in MeOH (10mL) and H ₂ O (2mL) of 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 1 N HCl was added to the solution until the pH reached 1-2. The residue was diluted with brine (10 mL) and extracted with EtOAc EtOAc. The combined organic extracts were dried over Na ₂ SO _4, filtered and concentrated. The crude product (0.24 g) was used without further purification.

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

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

At _{15 ℃,, I 2 (7mg} , 0.03mmol) was added to Zn (560mg, 8.6mmol) in a mixture of THF (5mL) of ethyl 2-bromo-acetate (524mg, 3.1mmol) and 1,1 , 1-trifluoro-3-methyl-butan-2-one (0.4 g, 2.9 mmol). The mixture was stirred at 60 ° C for 6 hours. Add H ₂ SO ₄ (10% aq, 4mL), and the mixture was extracted with ethyl acetate (10mL 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 (1g , 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) and LiOH.H ₂ O (552 mg, 13.2 mmol) in THF at 15 °C (20mL) and the mixture H ₂ O (10mL) 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 (15mL), dried over Na ₂ SO _4, filtered, and concentrated to give a yellow solid of 3-hydroxy-4-methyl-3- (trifluoromethyl) pentanoic acid ( 1.1 g, crude product) was used 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-methylvalerate

To 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, at 20 ° C under N ₂ Ethyl 2-bromoacetate (2.4 g, 14.3 mmol) was added dropwise to a solution of EtOAc (20 mL). The mixture was stirred at 60 ° C for 6 hours. The reaction mixture was cooled to 0 ℃, and added carefully _{H 2 SO 4 (15ml, 10} % solution). The mixture (80mL × 3) and extracted with ethyl acetate 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, mp.

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

At 0 ℃, a solution of ethyl 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl - pentanoate (2.5g, 10.8mmol) in MeOH (80mL) and H ₂ O (25mL) NaOH (1.1 g, 26.9 mmol) was added to the solution. The mixture was stirred at 20 ° C for 8 hours and concentrated. The aqueous layer was acidified to pH = 1-2 with 1N aqueous HCl and extracted with methyl-tris-butyl ether (30mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated. The title compound (2.10 g, crude) 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-methylvalerate

4,4,4-Trifluorobutan-2-one (4.4 g) was added to a mixture of Zn (6.9 g, 104.7 mmol) and I ₂ (89 mg, 0.35 mmol) in THF (80 mL). , 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 ℃, and treated with _{H 2 SO 4 (100mL, 10} % aqueous solution) and quenched. The mixture was extracted with ethyl acetate (15 mL×3). The combined organic extracts were washed with brine (15mL), and 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) and NaOH (4.1 g, 102.7 mmol) in H ₂ O (150 mL) The mixture in the mixture was stirred for 16 hours. The pH was adjusted to about 2 with saturated KHSO ₄ at 0 ° C and mixture was extracted with ethyl acetate (200mL×3). The combined organic extracts were washed with brine (300mL), dried over Na ₂ SO _4, filtered and concentrated to afford the product (10g, crude).

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

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

To a solution of 1-(1-fluorocyclopropyl)ethanone (0.8 g, 7.8 mmol), Zn (1.5 g, 23.5 mmol) and I ₂ (20 mg, 0.8 mmol) in THF (15 mL) 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 ℃, and a solution of H ₂ SO ₄ (10% aq, 10mL). Water (30 mL) was added to the mixture and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (30mL), dried over Na ₂ SO _4, filtered and concentrated. The obtained product 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) and NaOH (670 mg, 16.8 mmol) in H ₂ O (30 mL) 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 (20mL × 4), and the combined organic extracts were washed to yield the crude product, which was used without further purification with brine (40 mL), dried over Na ₂ SO _4, filtered and concentrated And use it directly. (1.50 g, crude product).

IIIg: 3-cyclopropyl-3-hydroxybutyric acid

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

TMSCl (1.3 g, 11.9 mmol) was added to Zn (12.4 g, 190.2 mmol) in THF (150 mL), and the mixture was stirred at 20 ° C for 15 min and then heated to 70 ° C. Heating was stopped and methyl 2-bromoacetate (21.8 g, 142.7 mmol) was added dropwise at a rate such 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-cyclopropyl ethyl ketone (10 g, 118.9 mmol) in THF (50 mL). 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%) was extracted with ethyl acetate (150 mL). The organic extracts were washed with water (150 mL) and brine (150mL), dried over Na ₂ SO ₄ and concentrated to give the desired product (8.9g, crude).

Step 2: Preparation of 3-cyclopropyl-3-hydroxybutyric acid

The crude methyl 3-cyclopropyl-3-hydroxybutyrate (8.9 g, 56.3 mmol) and LiOH were obtained at 20 °C ^. H ₂ O (11.8g, 281.3mmol) was stirred for 16 hours THF (100mL) and a mixture of H ₂ O (50mL). H ₂ O (50 ml) was added and extracted with ethyl acetate (100 mL×2). Discard the organic extract. The pH of the aqueous layer was adjusted to about 5 with 2N HCl and extracted with ethyl acetate (100mL x 3), and the combined organic fractions were washed with brine (100mL 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 (400MHz, 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

Add Et ₃ N (2.34 g, 23.5 mmol) and MgCl ₂ (1.8 g, 18.4 mmol) to (3-ethoxy-3-oxo-propenyl)oxy potassium salt (2.6 g, 15.4 mmol) ) in a suspension in MeCN (30 mL) and stirred at 20 ° C for 2 hours. Pre-mixed 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) at 0 ° C And stirred at 20 ° C for 14 hours. The reaction was diluted with H ₂ O (30mL) mixture, and extracted with ethyl acetate (80mL × 2). The combined organic extracts were washed with brine (30mL), dried over Na ₂ SO _4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-10% ethyl acetate / petroleum ether gradient. A product of 0.98 g (65%) yield was obtained.

IVb: ethyl 3-oxooxy-3-[1-(trifluoromethyl)cyclopropyl]propionate

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

Add Et ₃ N (6.3 g, 62.3 mmol) and MgCl ₂ (4.6 g, 48.7 mmol) to potassium 3-ethoxy-3-oxo-propionate (6.9 g, 40.5 mmol) in CH ₃ CN The suspension in (25 mL) was stirred at 20 ° C for 2 hours. Was added carbonyl diimidazole (CDI) (3.8g, 23.3mmol) and 1- (trifluoromethyl) cyclopropanecarboxylic acid (3g, 19.5mmol) at 0 ℃ pre in CH ₃ CN (25mL) stirred mixture of 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 (40mL × 2), dried over anhydrous Na ₂ SO _4, filtered and concentrated. The residue was purified by column chromatography (peel ether / ethyl acetate = 30: 1-10: 1) on silica gel to afford 3.5 g (80%) of product.

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

(1 S )-1-[3-(Trifluoromethoxy)phenyl]ethaneamine hydrochloride ( IIa ) (5 g, 20.69 mmol), 4,4-dimethyl- at 25 °C 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) The resulting mixture was washed with water (500 mL) andEtOAc. The organic layer was washed with brine (350mL × 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by chromatography (SiO _2, petroleum ether / ethyl acetate = 1: 1: 0 to 3) to afford 4,4-dimethyl-3-oxo - N - [(1 S )-1-[3-(Trifluoromethoxy)phenyl]ethyl]pentanylamine (11.2 g, crude product).

Prepare the following intermediates using related intermediates by methods similar to Va

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

Prepared from IIb (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-oxo-pentyl Amides

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 of crude product

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

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)pentanamine

Prepared from IIb (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)pentanamine

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-pentamidine

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-penta Guanamine

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] Propylamine

The IIa (557mg, 2.30mmol), IVa (0.95g, 4.61mmol), DMAP (57mg, 0.46mmol) and Et ₃ N (2.33g, 23.04mmol) was degassed toluene (30mL) in, and treated with N ₂ purged three times, the mixture was stirred at 110 deg.] C under N ₂ 12 h. The mixture was concentrated and the residue was purified by flash chromatography eluting elut elut elut elut elut elut elut rate).

The following items were prepared using related intermediates by a method similar to that described for Vg

Vh: 3-sided oxy- N -[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-[1-(trifluoromethyl)cyclopropyl]propyl Guanamine

Yield was prepared from IVb (2 g, 8.9 mmol) and IIa (915.3 mg, 4.5 mmol): 1.7 g (97%).

Vl: ( S )-3-(3,3-Difluorocyclobutyl)-3-oxo- N- (1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

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 = 2.4 Hz, 2H), 2.86 - 2.71 (m, 5H), 1.51 (d, J = 7.2 Hz, 3H).

Example:

Example 1a:

( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamine

And Example 1b:

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

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

To 4,4-dimethyl-3-oxo- N -[( 1S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanylamine at 0 °C Va) (5.6g, 16.90mmol) was added portionwise NaBH ₄ (1.28g, 33.8mmol) in the mixture (50 mL) in MeOH. 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 the 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×3), dried over Na ₂ SO ₄ , filtered and concentrated to afford 3-hydroxy-4,4-dimethyl- N -[(1S)-1-[3 -(Trifluoromethoxy)phenyl]ethyl]pentanylamine (16.5 g, crude product).

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

Separation of 3-hydroxy-4,4-dimethyl- N -[( 1S )-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanylamine by chromatography (27 g, 83 mmol ).

Example 1a:

Yield: 10.5g

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

LCMS: t _R = 2.548min (LCMS Method 1), m / z = 334.0 [M + H] +.

SFC: t _R = 1.89min (SFC Method 4), de = 95%, [α] D 20 = -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 = 7.6 Hz, 1H), 5.13-5.06 (m, 1H), 3.62 (dd, J = 2.0 Hz, 8.4 Hz, 1H), 3.45-3.33 (m, 1H), 2.38-2.33 (m) , 1H), 2.23-2.17 (m, 1H), 1.44 (d, J = 7.2 Hz, 3H), 0.88 (s, 9H). LCMS: t _R = 2.553min (LCMS Method 1), m / z = 334.0 [M + H] +.

SFC: t _R = 1.87min (SFC Method 5), de = 100%, [α] D 20 = -42.3 (c = 0.61g / 100mL, MeOH).

The following examples were prepared using related intermediates by methods similar to those described for 1a and 1b :

Example 2a:

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

And Example 2b:

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

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

3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine at 84% The yield was prepared from Vb .

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

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

Example 2a:

Production: 0.25g

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

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

SFC: t _R = 1.78min (SFC Method 1), de = 98.3%, [α] D 20 = -68.0 (c = 0.25, MeOH).

Example 2b :

Yield: 0.37g

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.29 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 6.84 (dd, J = 8.0, 2.4 Hz, 1H), 6.04 (m, 1H), 5.13 (m, 1H), 4.36 (q, J = 16.0 Hz, 8.0 Hz, 2H), 3.70-3.67 (m, 1H), 3.15 (d, J = 2.8 Hz, 1H), 2.40 - 1.96 (m, 2H), 1.50 (d, J = 7.2 Hz, 3H), 0.93 (s, 9H) LC-MS: t _R = 2.543 min (LCMS Method 2), m/ z=348.0[M+H] ⁺ .

SFC: t _R = 1.87min (SFC Method 1), de = 92.0%, [α] D 20 = -53.3 (c = 0.21, MeOH).

Example 3a: N -(( S )-1-(3-(Difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamine

with

Example 3b: N -(( S )-1-(3-(Difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamine

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

Prepared from Vc , 84% yield.

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

Separation of N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamine (450 mg) 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 = 76 Hz, 1H), 6.14 (brs, 1H), 5.14 - 5.07 (m, 1H), 3.66 (d, J = 10.4 Hz, 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).

LCMS: t _R = 2.161min (LCMS Method 3), m / z = 316.1 [M + H] +.

SFC: t _R = 2.15min (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, 2 H), 6.31 (t, J = 76Hz, 1 H), 6.14 (brs, 1 H), 5.12-5.06 (m, 1 H), 3.67-3.62 (m, 1 H), 3.29 (s, 1 H), 2.37-2.31 (m, 1 H), 2.26-2.19 ( m, 1 H), 1.47-1.43 (m, 3 H), 0.98 (s, 9 H).

LCMS: t _R = 2.16min (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)pentanamine

with

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

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

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

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

3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamine was chromatographed on petroleum gel (petroleum ether) : Ethyl acetate = 3:1) Separation was carried out.

Example 4a : Yield: 220 mg

¹ H NMR (CDCl ₃ 400 MHz): 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 = 3.2 Hz, 1H), 2.40-2.36 (m, 1H), 2.26-2.20 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 0.91 (s, 9H) ).

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

SFC: t _R = 1.56min (SFC Method 3), de = 100%, [α] D 20 = -25.5 (c = 0.19g / 100mL, MeOH).

Example 4b : Yield: 270 mg

_{^{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 = 3.2 Hz, 1H), 2.39-2.35 (m, 1H), 2.27-2.21 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H).

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

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

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

with

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: 1.22g

Step 2: ( S )-3-Hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanylamine 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)pentanamine was passed on a silica gel by flash chromatography ( The eluent was separated by 0-30% ethyl acetate / petroleum ether gradient.

Example 8a : Yield: 0.51 g

¹ H NMR (CDCl ₃ 400 MHz): 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 = 7.6 Hz, 1H), 3.71-3.65 (m, 1H), 3.21 (d, J = 2.8 Hz, 1H), 2.40-2.23 (m, 2H), 1.82 (q, J = 7.2 Hz, 2H), 0.94-0.90 (m, 12H).

LCMS: t _R = 2.486min (LCMS Method 5), m / z = 348.0 [M + H] +.

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

Example 8b : Yield: 0.59 g

_{^{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 = 7.6 Hz, 1H), 3.69-3.63 (m, 1H), 3.15 (d, J = 3.2 Hz, 1H), 2.40-2.25 (m, 2H), 1.81 (q, J = 7.6 Hz) , 2H), 0.94-0.90 (m, 12H).

LCMS: t _R = 2.506min (LCMS Method 5), m / z = 348.0 [M + H] +.

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

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

with

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

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

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

Step 2: ( S )-3-(3,3-Difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl) Propane-decalamine and ( R )-3-(3,3-difluorocyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl) Separation of propylamine

Separation by chiral SFC.

Example 11a : Yield 90 mg

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

LCMS: t _R = 2.513min (LCMS method 2), m / z = 368.0 [M + H] +.

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

Example 11b : Yield 90 mg

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

LCMS: t _R = 2.235min (LCMS Method 3), m / z = 368.0 [M + H] +.

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

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

with

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

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

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 Separation of ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamine

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

Example 12a : Yield: 0.362 g

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

SFC: t _R = 2.864min (SFC Method 3), de = 99.2%, [α] D 20 = -74.0 (c = 0.20, MeOH).

Example 12b : Yield: 0.245 g

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

SFC: t _R = 3.071min (SFC Method 3), de = 99.7%, [α] D 20 = -47.0 (c = 0.20, MeOH).

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

with

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

Step 1: 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanoid Preparation of amine

Prepared from Vg .

Yield: 0.58g

Step 2: ( S )-3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)B Propionamide and ( R )-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)benzene Separation of ethyl)ethyl acrylamide

Passing 3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamine The separation was carried out by rapid gel chromatography (the eluent was 0-41% ethyl acetate / petroleum ether gradient).

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 = 58.4 Hz, 1H), 5.12 (quin, J = 7.2 Hz, 1H), 3.91 (d, J = 3.2 Hz, 1H), 3.81-3.75 (m, 1H), 2.62-2.48 (m) , 2H), 1.49 (d, J = 7.2 Hz, 3H), 0.87-0.76 (m, 2H), 0.76-0.62 (m, 2H).

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

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

Example 14b : Yield: 0.18 g

_{^{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 = 58.4 Hz, 1H), 5.12 (quin, J = 7.2 Hz, 1H), 3.86-3.79 (m, 2H), 2.55 (d, J = 5.6 Hz, 2H), 1.50 ( d, J = 6.8 Hz, 3H), 0.83-0.75 (m, 2H), 0.74-0.66 (m, 2H). LCMS: t _R = 2.467min (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)propyl Guanamine

with

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

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

Prepared from Vh and used directly in the next step.

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

The crude product from Step 1 was separated by chiral SFC to yield the desired product.

Example 16a: Yield: 556 mg

¹ H NMR (DMSO- d ⁶ 400 MHz): δ 8.37 (d, J = 7.6 Hz, 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 = 7.2 Hz, 3H), 0.85-0.77 (m, 4H).

LCMS: t _R = 2.626min (LCMS method 2), m / z = 386.0 [M + H] +.

SFC: t _R = 2.010min (SFC Method 3), de = 99.9%, [α] D 20 = -56.0 (c = 0.01g / 100mL, 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 = 5.2 Hz, 1H), 4.95-4.91 (m, 1H), 3.75-3.85 (m, 1H), 2.25-2.35 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H), 0.80-0.79 (m, 4H).

LCMS: t _R = 2.649min (LCMS method 2), m / z = 386.0 [M + H] +.

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

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

with

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

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

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

Step 2: ( S )-3-Hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine 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)pentanylamine by chromatography (SiO ₂ , petroleum ether / acetic acid Ethyl acetate = 0:1 to 1:1) was separated.

Example 20a : 250 mg

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

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

SFC: t _R = 2.404min (SFC method 13), de = 98.6%, [α] D 20 = -80.0 (c = 0.475g / 100mL, MeOH).

Example 20b: Yield 470 mg

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

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

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

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

with

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

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

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

Step 2: N -(( R )-2-(Difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-( R )-hydroxy-4,4 - dimethyl-pentamidine and N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-( S Separation of -hydroxy-4,4-dimethylpentylamine

N -(( R )-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanthene The amine is separated by chiral SFC.

Example 21a: Yield: 98 mg

_{^{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 = 7.6 Hz, 1H), 6.22 (t, J = 74.0 Hz, 1H), 5.34-5.30 (m, 1H), 4.18-4.09 (m, 2H), 3.69 (d, J = 10.8 Hz) , 1H), 2.91 (s, 1H), 2.45-2.43 (m, 1H), 2.34 - 2.27 (m, 1H), 0.93 (s, 9H).

LCMS: t _R = 2.471min (LCMS Method 5), m / z = 400.0 [M + H] +.

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

Example 21b: 160 mg

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

LCMS: t _R = 2.496min (LCMS Method 5), m / z = 400.0 [M + H] +.

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

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

with

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

Step 1: 3-Hydroxy- N -[(1 R )-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanion Preparation of amine

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

Step 2: ( S )-3-Hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl Pentamidine and ( R )-3-hydroxy- N -(( R )-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethyl Separation of pentamidine

Passing 3-hydroxy- N -[(1 R )-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentamethyleneamine Chiral SFC is separated.

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 = 7.2 Hz, 1H), 5.18-5.14 (m, 1H), 3.70-3.60 (m, 3H), 3.36 (s, 3H), 2.44 (d, J = 14.8 Hz, 1H), 2.25 -2.33 (m, 1H), 0.93 (s, 9H).

LCMS: t _R = 2.410min (LCMS Method 3), m / z = 364.0 [M + H] +.

SFC: t _R = 1.889min (SFC method 16), de = 100%, [α] D 20 = -0.4 (c = 1.0g / 100mL, 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 = 7.2 Hz, 1H), 5.20-5.15 (m, 1H), 3.69-3.60 (m, 3H), 3.40 (s, 1 H), 3.36 (s, 3H), 2.44 (d, J) =14.8 Hz, 1H), 2.25-2.33 (m, 1H), 0.93 (s, 9H).

LCMS: t _R = 2.523min (LCMS Method 1), m / z = 364.0 [M + H] +.

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

Example 5 :( S) -2- (3,3- difluoro-1-hydroxy-cyclobutyl) - N - (1- (3- ( trifluoromethoxy) phenyl) ethyl) amine acetyl

step 1:

(1 S )-1-[3-(Trifluoromethoxy)phenyl]ethaneamine hydrochloride ( IIa ) (291 mg, 1.20 mmol), 2-(3,3-di) at 20 °C A mixture of fluoro-1-hydroxy-cyclobutyl)acetic acid ( IIIb ) (0.22 g, 1.32 mmol), EtOAc (EtOAc) The mixture was washed with water (40 mL×2) andEtOAc. The organic layer was washed with brine (10mL × 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by flash chromatography eluting EtOAc EtOAc EtOAc

_{^{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 = 7.2 Hz, 1H), 5.01 (br s, 1H), 2.84 - 2.42 (m, 6H), 1.53 (d, J = 6.8 Hz, 3H).

LCMS: t _R = 2.53min (LCMS method 2), m / z = 354.0 [M + H] +.

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

The following examples were prepared by a method similar to that of Example 5 using the relevant starting materials:

Embodiment Example 6 :( S) -2- (1-hydroxy-cyclobutyl) - N - (1- (3- (2,2,2- trifluoroethoxy) phenyl) ethyl) amine acetyl

Step 1 :( S) -2- (1- hydroxy-cyclobutyl) - N - phenyl (1- (3- (2,2,2-trifluoroethoxy)) ethyl) amine acetyl

Prepared from IIb (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 = 8.4 Hz, J = 2.4 Hz, 1 H), 6.25 (d, J = 6.8 Hz, 1 H), 5.14 - 5.07 (m, 1 H), 4.35 (q, J = 8.0 Hz, 2 H), 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 = 6.8 Hz, 3H).

LCMS: t _R = 2.49min (LCMS method 2), m / z = 332.0 [M + H] +.

SFC: t _R = 2.67min (SFC Method 3), de = 96.9%, [α] D 20 = -69.0 (c = 0.1, MeOH).

Example 7a: 3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(three Fluoromethyl)pentamidine

with

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

Step 1: 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)-3-(trifluoromethyl) Preparation of pentamidine

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

Step 2: (3 R )-3-Hydroxy-4-methyl- N -[(1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]- 3- (trifluoromethyl) pent Amides and (3 S) -3- hydroxy-4-methyl - N - [(1 S) -1- [3- (2,2,2- trifluoro-ethoxy Separation of phenyl)ethyl]-3-(trifluoromethyl)pentanamide

The separation was carried out by rapid gel chromatography (the solution was 0-15% ethyl acetate / petroleum ether gradient).

Example 7a : Yield: 0.29 g

_{^{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, 2.4 Hz, 1 H), 6.32 (s, 1 H), 5.99 (d, J = 7.6 Hz, 1 H). 5.15-5.07 (m, 1 H), 4.36 (q, J = 8.0 Hz, 2 H), 2.45 (d, J = 15.2 Hz, 1 H), 2.34 (d, J = 15.2 Hz, 1 H), 2.13 - 2.06 (m, 1 H), 1.50 (d, J = 6.8 Hz, 3 H), 1.03 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H).

LCMS: t _R = 2.883min (LCMS Method 4), m / z = 402.0 [M + H] +.

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

Example 7b : Yield: 0.23 g

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

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

_{SFC:. T R = 2.262min (} SFC Method 7) de = 99.8%, [ α] D 20 = -37.1 (c = 0.0034g / mL, MeOH).

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

step 1:

Prepared from IIa and 4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butyric 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 = 8.4 Hz, 1H), 5.01-4.93 (m, 1H), 2.89 (s, 2H), 1.34 (d, J = 6.8 Hz, 3H) ).

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

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

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

with

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

Step 1: 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanthene Preparation of amine

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)B Ethyl pentadecylamine and ( S )-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)benzene Separation of ethyl)ethylamylamine

The diastereomers were separated by chiral SFC.

Example 10a : Yield = 0.268 g

_{^{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 = 6.0 Hz, 1H), 5.16 (quin, J = 6.8 Hz, 1H), 2.69 (d, J = 15.2 Hz, 1H), 2.37 (d, J = 15.2 Hz, 1H), 1.53 ( d, J = 6.8 Hz, 3H), 1.40 (s, 3H).

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

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

Example 10b: Yield = 0.448 g

_{^{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 = 6.8 Hz, 1H), 5.16 (quin, J = 6.8 Hz, 1H), 2.70 (d, J = 15.2 Hz, 1H), 2.35 (d, J = 15.2 Hz, 1H), 1.52 ( d, J = 6.8 Hz, 3H), 1.35 (s, 3H).

LCMS: t _R = 2.782min (LCMS method 2), m / z = 392.0 [M + H] +.

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

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

with

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)pentanamine preparation

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

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

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

Example 13a : Yield = 0.421 g

_{^{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 = 6.8 Hz, 1H), 5.00 (s, 1H), 2.54-2.44 (m, 2H), 2.44-2.31 (m, 2H), 1.51 (d, J = 7.2 Hz, 3H ), 1.38 (s, 3H).

LCMS: t _R = 2.666min (LCMS method 2), m / z = 374.0 [M + H] +.

SFC: t _R = 1.277min (SFC Method 8), de = 100%, [α] D 20 = -51.3 (c = 0.23g / 100mL, 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 = 6.8 Hz, 1H), 4.98 (s, 1H), 2.57-2.36 (m, 4H), 1.52 (d, J = 6.8 Hz, 3H), 1.36 (s, 3H).

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

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

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

with

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

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

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

Step 2: ( R )-3-(1-Fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamine And ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamine Separation

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

Example 15a: Yield = 1.05 g

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

LCMS: t _R = 2.359min (LCMS Method 3), m / z = 350.0 [M + H] +.

_{SFC:. T R = 2.027min (} SFC Method 9), de = 93.9%, [α] D 20 = -48.3 (c = 0.24g / 100mL, MeOH).

Example 15b: Yield: 0.80 g

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

LCMS: t _R = 2.655min (LCMS method 2), m / z = 350.0 [M + H] +.

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

Embodiment Example 17 :( R) -2- (1-hydroxy-cyclopentyl) - N - (2- methoxy-1- (3- (trifluoromethoxy) phenyl) ethyl) amine acetyl

Prepared from IIa and 2-(1-hydroxycyclopentyl)acetic acid. Yield: 30 mg, (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 = 7.2 Hz, 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).

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

_{SFC:. T R = 2.33min (} SFC method 10), de = 100%, [α] D 20 = -44.0, (c = 1mg / mL, MeOH).

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

with

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

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

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)butane Amine and ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamine Separation

Separation by chiral SFC.

Example 18a : Yield: 1.59 g

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

LCMS: t _R = 2.629min (LCMS method 2), m / z = 328.0 [M + H-18] +.

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

Example 18b: Yield: 1.44g

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

LCMS: t _R = 2.643min (LCMS method 2), m / z = 328.0 [M + H-18] +.

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

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

with

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

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

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)butanamine and ( S )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2-three) Separation of fluoroethoxy)phenyl)ethyl)butanamine

Example 19a : 2.3g

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

SFC: t _R = 1.721min (SFC Method 12), de = 99.6%, [α] D 20 = -51.0 (c = 0.20, MeOH).

Example 19b : 0.86g

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.33 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 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 = 7.2 Hz, 1H), 4.36 (q, J = 8.0 Hz, 2H), 2.50 (dd, J = 57.6) , 14.8 Hz, 2H), 1.51 (d, J = 6.8 Hz, 3H), 1.39 (s, 3H); LC-MS: t _R = 2.737 min (LCMS Method 2), m/z = 374.0 [M+H ] ⁺ .

SFC: t _R = 1.904min (SFC Method 12), de = 100%, [α] D 20 = -57.1 (c = 0.21, MeOH).

Claims (16)

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 _{The 8-} cycloalkyl group may be substituted by 1 or 2 F, CHF ₂ or CF ₃ , and R 2 is H, C ₁ -C ₆ alkyl or CF ₃ ; or R 1 and R 2 may be combined to form 1 or 2 as needed. F, CHF ₂ or CF ₃ substituted C ₃ -C ₅ cycloalkyl; R ₃ is C ₁ -C ₃ alkyl or CH ₂ OC _1-3 alkyl, said C ₁ -C ₃ alkyl or CH ₂ The OC _1-3 alkyl group may be substituted with 1 or 2 F as needed; R4 is selected from the group consisting of OCF ₃ , OCH ₂ CF ₃ or OCHF ₂ . The compound according to claim 1, wherein R4 is OCF ₃ or OCHF ₂ . Compound according to any one of the preceding claims, the terms according to, wherein R2 is H or CH _3. The compound of any one of the preceding claims, wherein R3 is CH ₂ OC _1-3 alkyl. The compound according to any one of the preceding request, wherein R1 is optionally substituted with 1 or 2 F, CHF ₂ or CF ₃ substituted C ₃ -C ₄ cycloalkyl. The compound according to any one of the preceding request, wherein R1 is a three-butyl, and R2 is H, and R4 is _{OCF 3, OCH 2 CF 3,} OCHF 2 or CF _3. The compound according to any one of the preceding claims, wherein R1 and R2 are combined to form a cyclobutyl group which is optionally substituted by 1 or 2 F, and R4 is OCF ₃ , OCH ₂ CF ₃ , OCHF ₂ or CF ₃ . The compound according to claim 1, wherein the compound is selected from the group consisting of: ( S )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1 -[3-(Trifluoromethoxy)phenyl]ethyl]pentanylamine, R )-3-hydroxy-4,4-dimethyl- N -[(1 S )-1-[3-( Trifluoromethoxy)phenyl]ethyl]pentanylamine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2,2 -trifluoroethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(2,2, 2-Trifluoroethoxy)phenyl)ethyl)pentanylamine, ( S ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3- Hydroxy-4,4-dimethylpentylamine, ( R ) -N -(( S )-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4 - dimethyl amenoguanamine, ( S )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)pentanthene Amine ( R )-3-hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamine, ( S )-3 -hydroxy-4,4-dimethyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)propyl)pentanylamine, ( R )-3-hydroxy-4, 4-dimethyl -N - ((S) -1- ( 3- ( trifluoromethoxy) phenyl) propyl) pentyl Amides, (S) -3- (3,3- difluoro Butyl) -3-hydroxy - N - ((S) -1- (3- ( trifluoromethoxy) phenyl) ethyl) propan-acyl amine, (R) -3- (3,3- difluoro Cyclobutyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamine, ( S )-3-hydroxy-4-methyl - N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4-methyl- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanylamine, ( S )-3-(1-(difluoromethyl) ring Propyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro-methoxy)phenyl)ethyl)propanamine, ( R )-3-(1-(difluoro) Methyl)cyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamine, ( R )-3-hydroxy- N -(( S )-1-(3-(Trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamine, ( S )-3- Hydroxy- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamine, ( S ) -3-hydroxy-4-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-3-hydroxy-4-methyl -N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanylamine, N -(( R )-2-(difluoromethoxy)-1- (3-(trifluoromethoxy)phenyl)B ) -3- (R) - hydroxy-4,4-dimethyl-pentyl Amides, N - ((R) -2- ( difluoromethoxy) -1- (3- (trifluoromethoxy) Phenyl)ethyl)-3-( S )-hydroxy-4,4-dimethylpentanamine, ( S )-3-hydroxy- N -(( R )-2-methoxy-1-( 3-(Trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamine, ( R )-3-hydroxy- N -(( R )-2-methoxy-1- (3-(Trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamine, ( S )-2-(3,3-difluoro-1-hydroxycyclobutyl)- N - (1- (3- (trifluoromethoxy) phenyl) ethyl) amine acetyl, (S) -2- (1- hydroxy-cyclobutyl) - N - (1- (3- (2 , 2,2-trifluoroethoxy)phenyl)ethyl)acetamidamine, (3 R )-3-hydroxy-4-methyl- N -[(1 S )-1-[3-(2 , 2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanylamine, (3 S )-3-hydroxy-4-methyl- N -[(1 S )-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamine, 4,4,4-trifluoro-3- Hydroxy- N -[(1 S )-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamine, ( R )-4,4,5 ,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamine, ( S )-4, 4,5,5-tetrafluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-( Trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-5,5,5-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3- (trifluoromethoxy)phenyl)ethyl)pentanylamine, ( S )-5,5,5-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3 -(Trifluoromethoxy)phenyl)ethyl)pentanylamine, ( R )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-( Trifluoromethoxy)phenyl)ethyl)butanamine, ( S )-3-(1-fluorocyclopropyl)-3-hydroxy- N -(( S )-1-(3-(trifluoro) - methoxy) phenyl) ethyl) butan Amides, (R) -2- (1- hydroxy-cyclopentyl) - N - (2- methoxy-1- (3- (trifluoromethoxy Phenyl)ethyl)acetamidine, ( R )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy) Phenyl)ethyl)butanamine, ( S )-3-cyclopropyl-3-hydroxy- N -(( S )-1-(3-(2,2,2-trifluoroethoxy)benzene Ethyl)butanamine, ( R )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3-(2,2,2- Trifluoroethoxy)phenyl)ethyl)butanamine, and ( S )-4,4,4-trifluoro-3-hydroxy-3-methyl- N -(( S )-1-(3 -(2,2,2-Trifluoroethoxy)phenyl)ethyl)butanamine. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 and a pharmaceutically acceptable excipient. A method of treating a patient in need thereof with epilepsy, bipolar disorder, migraine or schizophrenia, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 8 . A method of treating a patient in need thereof: psychosis, mania, stress related disorder, acute stress response, bipolar depression, major depression, anxiety, panic disorder, social phobia, sleep disturbance, ADHD, PTSD, OCD, impulsive disorder, personality disorder, schizophrenic disorder, aggressive behavior, chronic pain, neuropathy, autism disorder, Huntington's disease, sclerosis, multiple sclerosis, Az In the case of the disease, the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 8. A use according to the compounds of claims 1 to 8 for use in therapy. A use according to any one of claims 1 to 8 for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. Use of a compound according to claims 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, division Disease disorders, aggressive behavior, chronic pain, neuropathy, autism disorders, Huntington's disease, sclerosis, multiple sclerosis, Alzheimer's disease. A compound according to any one of claims 1 to 8 for use in the manufacture of a medicament for the treatment of epilepsy, bipolar disorder, migraine or schizophrenia. A compound according to any one of claims 1 to 8 for use in the manufacture of a medicament for the treatment of 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, schizophrenia, aggressive behavior, chronic pain, neuropathy, autism, Huntington's disease, sclerosis, Multiple sclerosis, Alzheimer's disease.