Alcohol derivatives as kv7 potassium channel openers for use in epilepsy or seizures

Abstract

The present invention provides alcohol derivatives as Kv7 potassium channel openers for use in epilepsy or seizures. The present invention provides novel compounds that activate the Kv7 potassium channel. Separate aspects of the invention relate to pharmaceutical compositions comprising said compounds and the use of these compounds to treat disorders responsive to Kv7 potassium channel activation.

Description

[0001] This application is a divisional application of an application with a filing date of July 30, 2020, an application number of 202080054003.7, and an invention name of “Alcohol derivatives as Kv7 potassium channel openers for use in epilepsy or epileptic seizures”. Technical Field

[0002] The present invention relates to the use of novel compounds that activate Kv7 potassium channels in the treatment of epilepsy or epileptic seizures. Background Art

[0003] Voltage-dependent potassium (Kv) channels direct potassium ions (K + ) across the cell membrane, and can therefore regulate the excitability of the cell by regulating (increasing or decreasing) the electrical activity of the cell. Functional Kv channels exist as a multimeric structure formed by the association of four α subunits and four β subunits. The α subunit contains six transmembrane domains, a pore-forming ring and a voltage receptor, and is symmetrically arranged around the central hole. β subunits or auxiliary subunits interact with the α subunits, and can modify the properties of the channel complex to include but not limited to changes in the electrophysiological or biophysical properties, expression levels or expression patterns of the channel.

[0004] Nine Kv channel α subunit families have been identified and are referred to as Kv1-Kv9. Thus, there is a great diversity in Kv channel function, which arises from the multiplicity of subfamilies, the formation of both homomeric and heteromeric subunits within subfamilies, and the additive effects of association with β subunits (Christie, 25 Clinical and Experimental Pharmacology and Physiology, 1995, 22, 944-951).

[0005] The Kv7 channel family consists of at least five members, including one or more of the following mammalian channels: Kv7.1, Kv7.2, Kv7.3, Kv7.4, Kv7.5, and any mammalian or non-mammalian equivalents or variants 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).

[0006] As mentioned above, the Kv7 potassium channel of neurons plays a role in controlling neuronal excitation. Kv7 channels (particularly Kv7.2 / Kv7.3 heterodimers) are the basis of M currents (Wang et al. Science. [Science] December 4, 1998; 282(5395): 1890-3). M currents have characteristic time and voltage dependence, resulting in stabilization of membrane potential in response to multiple excitatory stimuli.

[0007] In this way, the M current participates in controlling neuronal excitability (Delmas and Brown, Nature [Nature], 2005, 6, 850-862). The M current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, the M current dominates in controlling membrane excitability by being the only persistent current within the action potential initiation range (Marrion, Annual Review Physiology [Physiology Annual Review] 1997, 59, 483-504).

[0008] Retigabine (ethyl N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamate) is a compound that binds to the Kv7 potassium channel (Wuttke et al., Molecular Pharmacology, 2005, 67, 1009-1017). Retigabine activates K in neuronal cells. + The pharmacology of the evoked currents was shown to be consistent with the published pharmacology of M-channels that are associated with Kv7.2 / 3K + Channel heteromultimers are associated, suggesting that activation of Kv7.2 / 3 channels is responsible for at least some of the anticonvulsant activity of the agent (Wickenden et al., Molecular Pharmacology 2000, 58, 591-600); Gunthorpe et al. Epilepsia. 2012 Mar; 53(3): 412-24). Retigabine is effective in reducing the incidence of seizures in patients with epilepsy (Bialer et al., Epilepsy Research 2002, 51, 31-71). Retigabine has broad-spectrum and potent anticonvulsant properties. In a series of anticonvulsant tests, retigabine was active in rats and mice after oral and intraperitoneal administration (Rostock et al., Epilepsy Research 1996, 23, 211-223).

[0009] The five members of this family differ in their expression patterns. Expression of Kv7.1 is restricted to the heart, peripheral epithelium, and smooth muscle, whereas expression of Kv7.2, Kv7.3, Kv7.4, and Kv7.5 appears to be predominant in the nervous system including the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion neurons (for review, see Greene and Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508).

[0010] The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal seizures (Rogawski, Trends in Neurosciences 2000, 23, 393-398). The proteins encoded by the KCNQ2 and KCNQ3 genes are localized to pyramidal neurons of the human cortex and hippocampus, brain regions associated with the generation and propagation of epileptic seizures (Cooper et al., Proceedings National Academy of Science USA 2000, 97, 4914-4919).

[0011] Furthermore, in addition to the mRNA for Kv7.2, the mRNAs for Kv7.3 and 5 are expressed in astrocytes 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), which would be relevant to the treatment of neurodegenerative disorders such as, but not limited to, Alzheimer's disease, Parkinson's disease and Huntington's disease.

[0012] mRNA for Kv7.2 and Kv7.3 subunits is found in brain regions associated with anxiety and affective behaviors such as depression and bipolar disorder, such as the hippocampus, ventral tegmental area, and amygdala (Saganich et al. Journal of Neuroscience 2001, 21, 4609-4624; Friedman et al. Nat Commun. 2016; 7: 11671.), and retigabine is reported to be active in animal models of anxiety-like behaviors (Korsgaard et al. J Pharmacol Exp Ther. 2005 Jul; 314(1): 282-92. Epub 2005 Apr 6.). Therefore, Kv7 channels are relevant to the treatment of affect-related disorders such as, but not limited to, bipolar depression, major depression, anxiety, suicide, panic disorder, and social phobia.

[0013] Kv7.2 / 3 channels have also been reported to be upregulated in neuropathic pain models (Wickenden et al., Society for Neuroscience Abstracts 2002, 454.7), and potassium channel modulators have been postulated to be active in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001, 40, 888-898). In addition to a role in neuropathic pain, mRNA expression of Kv7.2-5 in the trigeminal nerve and dorsal root ganglia and in the caudate nucleus of the trigeminal nerve suggests that openers of these channels may also affect sensory processing in migraine (Goldstein et al., Society for Neuroscience Abstracts 2003, 53.8). Taken together, this evidence suggests the relevance of KCNQ channel openers for the treatment of chronic pain and neuropathy-related disorders.

[0014] WO 07 / 90409 relates to the use of Kv7 channel openers for the treatment of schizophrenia. Kv7 channel openers modulate the function of the dopaminergic system (Friedman et al. Nat Commun. 2016; Scotty et al. J Pharmacol Exp Ther. 2009 Mar;328(3):951-62. doi:10.1124 / jpet.108.146944. Epub 2008 Dec 19; Koyama et al. J Neurophysiol. 2006 Aug;96(2):535-43. Epub 2006 Jan 4; Li et al. Br J Pharmacol. 2017 Dec;174(23):4277-4294. doi:10.1111 / bph.14026. Epub 2017 Oct 19; Hansen et al. J Neurophysiol. 2006 Aug;96(2):535-43. Epub 2006 Jan 4; Li et al. Br J Pharmacol. 2017 Dec;174(23):4277-4294. doi:10.1111 / bph.14026. Epub 2017 Oct 19; Hansen et al. J Neurophysiol. 2006 Aug;96(2):535-43. Epub 2006 Jan 4; Hansen et al. J Neurophysiol. 2006 Aug;96(2):535-43. Epub 2006 Jan 4; Li et al. Br J Pharmacol. 2017 Dec;174(23):4277-4294. doi:10.1111 / bph.14026. Epub 2017 Oct 19; Hansen et al. Pharmacol Exp Ther. 2006 Sep; 318(3): 1006-19. Epub 2006 Jun 14), which is relevant to the treatment of mental disorders (such as but not limited to psychosis, mania, stress-related disorders, acute stress response, attention deficit / hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsive disorder, personality disorder, schizotypal disorder, aggressive behavior, autism spectrum disorder). WO 01 / 96540 discloses the use of M current modulators formed by expressing KCNQ2 and KCNQ3 genes for insomnia, while WO 01 / 092526 discloses that modulators of Kv7.5 can be used to treat sleep disorders. WO 09 / 015667 discloses the use of Kv7 openers in the treatment of sexual dysfunction.

[0015] While patients suffering from the above-mentioned disorders may have available treatment options, many of these options lack the desired efficacy and are accompanied by undesirable side effects. Thus, there is an unmet need for novel therapies for the treatment of epilepsy and epileptic seizures.

[0016] In order to identify new therapeutics, the inventors have identified a series of novel compounds represented by Formula I that act as Kv7.2, Kv7.3, Kv7.4 and Kv7.5 channel openers for use as drugs in the treatment of epilepsy, epileptic syndromes and symptoms, and epileptic seizures. Summary of the invention

[0017] The present invention relates to compounds having formula I

[0018]

[0019] in

[0020] R1 is selected from the group consisting of: C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R2 is H, C1-C6 alkyl or CF3;

[0021] or

[0022] R1 and R2 combine to form a C3-C5 cycloalkyl group optionally substituted with F, CHF2 or CF3;

[0023] R3 is C1-C3 alkyl or CH2O-C 1-3 alkyl;

[0024] R4 is selected from the group consisting of OCF3, OCH2CF3 or OCHF2, or a pharmaceutically acceptable salt thereof, and the compound is used for use in treating epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy or epileptic seizures.

[0025] The present invention also relates to a pharmaceutical composition comprising a compound according to the present invention and a pharmaceutically acceptable carrier or excipient.

[0026] Furthermore, the present invention relates to a method of treating a patient as described in the claims and examples, and including treating a patient suffering from epilepsy, an epileptic syndrome, an epileptic symptom, treatment-resistant or refractory epilepsy or epileptic seizures, the method comprising administering to the subject a therapeutically effective amount of a compound according to the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Acute administration of (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide demonstrated anticonvulsant efficacy in the rat MEST assay.

[0028] Oral administration of (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide to rats 30 min prior to testing significantly increased the seizure threshold CC50 (i.e., the current (measured in mA) applied to the animal that produces a tonic hindlimb extensor seizure in 50% of the animals) relative to vehicle. **<0.01, ***: p<0.001. DETAILED DESCRIPTION

[0029] According to an embodiment of the present invention, R4 is OCF3 or OCHF2, and according to another embodiment, R2 is H or CH3.

[0030] In one embodiment, R1 is C3-C4 cycloalkyl optionally substituted with 1 or 2 F, CHF2 or CF3.

[0031] According to a specific embodiment, R1 is tert-butyl, and R2 is H, and R4 is one of OCF3, OCH2CF3 or OCHF2.

[0032] According to another specific embodiment, R1 and R2 are combined to form a cyclobutyl group optionally substituted with 1 or 2 F, and R4 is one of OCF3, OCH2CF3 or OCHF2.

[0033] According to a specific embodiment of the present invention, the compound according to the present invention is selected from the group consisting of:

[0034] (S)-3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,

[0035] (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide,

[0036] (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

[0037] (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

[0038] (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,

[0039] (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide,

[0040] (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,

[0041] (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide,

[0042] (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,

[0043] (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide,

[0044] (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide,

[0045] (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide,

[0046] (S)-3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

[0047] (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide,

[0048] (S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)propionamide,

[0049] (R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide,

[0050] (R)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,

[0051] (S)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide,

[0052] (S)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

[0053] (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

[0054] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethylpentanamide,

[0055] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide,

[0056] (S)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, (R)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide,

[0057] (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,

[0058] (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide,

[0059] (3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,

[0060] (3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide,

[0061] 4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide,

[0062] (R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

[0063] (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

[0064] (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

[0065] (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide,

[0066] (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide,

[0067] (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide,

[0068] (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide,

[0069] (R)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,

[0070] (S)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide,

[0071] (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxyphenyl)ethyl)butanamide, and

[0072] (R)-4,4,4-Trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyramide

[0073] or a pharmaceutically acceptable salt of any of these compounds.

[0074] References to compounds encompassed by the present invention include racemic mixtures of these compounds, optical isomers of compounds related thereto, and polymorphic and amorphous forms of compounds of the present invention, as well as tautomeric forms of compounds related thereto. In addition, the compounds of the present invention may exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The present invention encompasses both solvated and unsolvated forms of these compounds.

[0075] The compounds according to the present invention may be in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier.

[0076] In another embodiment, the invention relates to a method of treating a patient in need thereof suffering from epilepsy, an epileptic syndrome, an epileptic symptom, treatment-resistant or refractory epilepsy, or an epileptic seizure, the method comprising administering to the subject a therapeutically effective amount of a compound according to the invention.

[0077] In yet another embodiment, the present invention relates to a method of treating a patient in need thereof or for use in treating epilepsy symptoms as part of a neurodegenerative disorder (e.g., Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration), wherein the patient suffers from focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures and other epilepsy syndromes (e.g., severe myoclonic epilepsy of infancy, epilepsy with sustained spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy Ohtahara syndrome), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection or metabolic disorders (e.g., hyponatremia), the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0078] The use of the compounds according to the invention is for the treatment of epilepsy, including in the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures and other epilepsy syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with sustained spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy Ohtahara syndrome), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorder or metabolic disorders (such as hyponatremia), or for use in epileptic symptoms that are part of neurodegenerative disorders (such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration).

[0079] The compounds for use according to the present invention are useful for the treatment of epilepsy, including in the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures and other epilepsy syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with sustained spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy Ohtahara syndrome), or in epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorder or metabolic disorders (such as hyponatremia), or for use in epileptic symptoms that are part of a neurodegenerative disorder (such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration).

[0080] In another embodiment, the compounds of the invention are used in the manufacture of a medicament for use in the treatment of epilepsy, epileptic syndromes, epileptic symptoms, treatment-resistant or refractory epilepsy, or epileptic seizures (including focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures and other epilepsy syndromes (such as severe myoclonic epilepsy of infancy, epilepsy with sustained spikes during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome, and early myoclonic encephalopathy Ohtahara syndrome), or seizures associated with stress, hormonal changes, medications, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorder, or metabolic disorders (such as hyponatremia), or for manufacture for use in the treatment of epilepsy symptoms as part of a neurodegenerative disorder (such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration).

[0081] In the context of the present invention, "optionally substituted" means that the indicated part may or may not be substituted, and when substituted, it is monosubstituted or disubstituted. It should be understood that when no substituents are indicated for an "optionally substituted" part, the position is occupied by a hydrogen atom.

[0082] A given range may be indicated interchangeably with "-" (dash) or "to", for example, the term "C 1-3 "C1 to C3 alkyl" is equivalent to "C1 to C3 alkyl".

[0083] The term "C 1- C3 alkyl" and "C 1-"C6 alkyl" refers to an unbranched or branched saturated hydrocarbon having from one to six carbon atoms (inclusive). Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl and tert-butyl.

[0084] The term "C 1- "C3 alkoxy" refers to a moiety of formula -OR, wherein R represents a C1-C3 alkyl group as defined above.

[0085] The term "C 3- C6 cycloalkyl", "C 3- C5 cycloalkyl" or "C 3- "C8 cycloalkyl" refers to a saturated monocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0086] Route of Administration:

[0087] The pharmaceutical compositions comprising the compounds of the invention defined above may be specifically formulated for administration by any suitable route, such as oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (eg subcutaneous, intramuscular and intravenous) routes; the oral route being preferred.

[0088] 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 to be treated and the active ingredient.

[0089] Pharmaceutical preparations and excipients:

[0090] Hereinafter, the term "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients, including but not limited to fillers, anti-adhesives, binders, coatings, colorants, disintegrants, flavoring agents, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

[0091] The present invention also provides a pharmaceutical composition comprising a compound according to the present invention (such as one of the compounds disclosed in the experimental section herein). The present invention also provides a method for manufacturing a pharmaceutical composition comprising a compound according to the present invention. The pharmaceutical composition according to the present invention can be formulated with a pharmaceutically acceptable excipient according to conventional techniques, such as those disclosed in: Remington, "The Science and Practice of Pharmacy", 22nd edition (2012), edited by Allen, Loyd V., Jr.

[0092] Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in suitable liquids.

[0093] Solid oral dosage forms may be presented in discrete unit form (e.g. tablets 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, or they may be formulated to provide a modified release of the active ingredient, such as delayed or extended release, according to methods well known in the art. Where appropriate, the solid dosage form may be a dosage form that disintegrates in saliva, such as, for example, an orodispersible tablet.

[0094] Examples of excipients suitable for solid oral formulations include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, cross-linked sodium carboxymethylcellulose, sucrose, cyclodextrin, talc, gelatin, pectin, magnesium stearate, stearic acid, and lower alkyl ethers of cellulose. Similarly, solid formulations may include excipients known in the art for delayed or extended 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 press; or the formulation may be placed in a hard capsule, for example, in the form of a powder, pill, or mini tablet. The amount of solid excipient will vary widely, but will typically range from about 25 mg to about 1 g per dosage unit.

[0095] Liquid oral dosage forms can be presented, for example, in 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, glycerol, polyethylene glycol, poloxamer, sorbitol, polysorbate, monoglycerides and diglycerides, cyclodextrins, coconut oil, palm oil and water. Liquid oral dosage forms can be prepared, for example, by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

[0096] Additional excipients such as coloring agents, flavoring agents, preservatives, and the like may be used in both solid and liquid oral preparations.

[0097] Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion, and sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion prior to use. Examples of excipients suitable for parenteral formulations include, but are not limited to, water, coconut oil, palm oil, and cyclodextrin solutions. Aqueous formulations should be appropriately buffered, if necessary, and rendered isotonic with sufficient saline or glucose.

[0098] Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, skin patches, implants and formulations for buccal or sublingual administration.

[0099] Excipients used in any pharmaceutical formulation must be suitable for the intended route of administration and be compatible with the active ingredient.

[0100] dose:

[0101] In one embodiment, the compound of the present invention is administered in an amount from about 0.001 mg / kg body weight to about 100 mg / kg body weight per day. Specifically, the daily dose may be in the range of 0.01 mg / kg body weight to about 50 mg / kg body weight per day. The exact dosage will depend on the frequency and mode of administration, the sex, age, weight and general condition of the subject to be treated, the nature and severity of the condition to be treated, any concomitant disease to be treated, the desired therapeutic effect, and other factors known to those skilled in the art.

[0102] Typical oral dosage for adults will be in the following range: 0.1-1000 mg / day of the compound of the present invention, such as 1-500 mg / day, such as 1-100 mg / day or 1-50 mg / day. Conveniently, the compound of the present invention is administered in a unit dosage form containing the compound in an amount of 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 present invention.

[0103] Isomers and tautomeric forms:

[0104] When the compounds of the invention contain one or more chiral centers, reference to any of these compounds will encompass the enantiomerically or diastereomerically pure compound as well as mixtures of enantiomers or diastereomers in any ratio, unless otherwise stated.

[0105] MDL enhanced stereo representation is used to describe the unknown stereochemistry of the compounds of the invention. Thus, the label "or1" on a chiral carbon atom is used to indicate that the absolute stereo configuration at that atom is unknown; for example, the stereo configuration of that carbon atom is (S) or (R).

[0106] Furthermore, chiral bonds from carbon atoms labeled "or1" using either an upward wedge or a downward wedge are represented identically; for example, both diagrams have the same meaning, which is that the absolute stereo configuration at the carbon atom labeled "or1" is unknown and can be either (S) or (R).

[0107] Thus, the use of upward- and downward-wedge bonds from the atom labeled "or1" is intended merely to provide a visual cue that the figures represent different stereoisomers, where the conformation of the "or1" labeled carbon atom is unknown.

[0108] Furthermore, some of the compounds of the present invention may exist in different tautomeric forms and any tautomeric forms that these compounds are able to form are intended to be included within the scope of the present invention.

[0109] Therapeutically effective amount:

[0110] In the context of the present invention, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, retard, partially retard, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of the compound. 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 and the weight and general state of the subject. It should be understood that determining the appropriate dosage can be achieved using routine experimentation by constructing a matrix of values ​​and testing different points in the matrix, all within the ordinary skill of a trained physician.

[0111] Treatment and treating:

[0112] In the context of the present invention, "treatment" or "treating" is intended to indicate the management and care of a patient with the purpose of alleviating, arresting, partially arresting, eliminating the clinical manifestations of a disease or delaying its progression. The patient to be treated is preferably a mammal, in particular a human being.

[0113] All documents (including publications, patent applications, and patents) cited herein are hereby incorporated by reference in their entirety and to the same extent as if each document were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by law).

[0114] Treating epilepsy

[0115] The classification of epilepsy can be based on ICD-10 (2016, published by WHO) and described in sections G40 and G41, and is included in the treatment of epilepsy according to the present invention.

[0116] G40.0 Locality-related (focal)(partial) idiopathic epilepsy and epilepsy syndromes with focal-onset seizures

[0117] G40.1 Locality-related (focal) (partial) symptomatic epilepsy and epilepsy syndromes with simple partial seizures

[0118] G40.2 Locality-related (focal) (partial) symptomatic epilepsy and epilepsy syndromes with complex partial seizures

[0119] G40.3 Idiopathic generalized epilepsy and epileptic syndromes

[0120] G40.4 Other generalized epilepsy and epileptic syndromes

[0121] G40.5 Specific epilepsy syndromes

[0122] G40.6 Grand mal seizure, unspecified (with or without petit mal seizures)

[0123] G40.7 Petit mal seizure, unspecified, not characterized by grand mal seizure

[0124] G40.8 Other epilepsy

[0125] G40.9 Epilepsy, unspecified

[0126] G41 Status epilepticus

[0127] Treating epileptic seizures

[0128] A seizure is a sudden, uncontrolled electrical disturbance in the brain. It can cause changes in behavior, movement or sensation, and level of consciousness. A person is diagnosed with epilepsy if they have two or more seizures or have a tendency to have recurring seizures.

[0129] There are many types of seizures that vary in severity. Types of seizures differ by where in the brain they start and how they start. Most seizures last from 30 seconds to 2 minutes. A seizure that lasts more than 5 minutes is a medical emergency.

[0130] Focal epileptic seizures

[0131] Focal seizures are caused by abnormal electrical activity in one area of ​​the brain. Focal seizures may occur with or without loss of consciousness:

[0132] Focal seizures with cognitive impairment. These seizures involve changes or loss of consciousness or cognition. The person may stare into space, not respond normally to the environment, or perform repetitive movements such as rubbing their hands together, chewing, swallowing, or walking in circles.

[0133] Focal seizures without loss of consciousness. These seizures may cause changes in mood or in the way things look, smell, feel, taste, or hear, but the person does not lose consciousness. These seizures may also cause involuntary jerking of a body part (such as an arm or leg), as well as spontaneous sensory symptoms (such as tingling, dizziness, and flashing lights).

[0134] Generalized epileptic seizures

[0135] Seizures that seem to involve all areas of the brain are called generalized seizures. Different types of generalized seizures include:

[0136] Absence seizures. Absence seizures, previously called petit mal seizures, often occur in children and are characterized by staring into space or subtle body movements, such as blinking or smacking the lips. These seizures may occur in clusters and cause brief periods of cognitive loss.

[0137] Tonic seizures. Tonic seizures cause muscle stiffness. These seizures usually affect the muscles in the back, arms, and legs.

[0138] Atonic seizures. Atonic seizures, also called drop seizures, cause a loss of muscle control, which may cause a sudden fainting or fall.

[0139] Clonic seizures. Clonic seizures are associated with repetitive or rhythmic jerking muscle movements. These seizures usually affect the neck, face, and arms.

[0140] Myoclonic seizures. Myoclonic seizures usually present as sudden, brief jerks or twitches of the arms and legs.

[0141] Tonic-clonic seizures. Tonic-clonic seizures, previously called grand mal seizures, are the most violent type of seizure and may cause sudden loss of consciousness, body rigidity and shaking, and sometimes loss of bladder control or tongue biting.

[0142] Many times, seizures may be related to or caused by:

[0143] a high fever, which may be related to an infection (such as meningitis)

[0144] Lack of sleep

[0145] Low blood sodium (hyponatremia), which may occur with diuretic therapy

[0146] Medications that lower the seizure threshold, such as certain pain medications, antidepressants, or smoking cessation therapy

[0147] Head trauma that produces an area of ​​brain bleeding

[0148] Stroke

[0149] Brain tumors

[0150] drug

[0151] alcohol

[0152] Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0153] Unless otherwise indicated, any and all examples or exemplary language (including "for instance", "for example", "eg", "such as", and "as such") used in this specification are intended merely to better illuminate the invention and do not pose a limitation on the scope of the invention.

[0154] The citation and incorporation of patent documents herein is for convenience only and does not reflect any view of the validity, patentability, and / or enforceability of such patent documents.

[0155] This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

[0156] Experimental Section

[0157] Biological Assessment:

[0158] Cell culture

[0159] The synthetic cDNA fragment encoding human Kv7.3 and human Kv7.2 separated by the P2A sequence was inserted into the pcDNA5 / FRT / TO vector using BamHI and XhoI restriction sites. Then, the construct was transfected into HEKFlp-In 293 cells using Lipofectamine2000. The transfected cells were grown for 48 hours in DMEM containing 10% (v / v) FBS and 1% PenStrep, and then maintained under selection at 37°C in a humidified atmosphere of 5% CO2 in DMEM containing 10% (v / v) FBS, 1% PenStrep and 200ug / mL hygromycin B. The generated stable hKv7.2 / hKv7.3 cell line (HEK-hKv7.2 / hKv7.3) was functionally tested with automated whole-cell patch clamps, and typical Kv7 currents were shown, which were sensitive to XE991 and enhanced by retigabine.

[0160] Thallium flux determination

[0161] Thallium flux assays for potassium channel activation were performed similarly to published procedures (CD Weaver et al., J Biomol Screen 2004, 9, 671-677) using the FLIPR potassium assay kit (Molecular Devices). HEK-hKv7.2 / hKv7.3 cells were plated at a density of 80,000 cells / well (100 μl / well) (if the cells were assayed the next day) or 40,000 cells / well (100 μl / well) (if the cells were assayed two days after seeding) in 96-well, black-walled, clear-bottom culture plates (Corning, Acton, MA, USA).

[0162] On the day of the assay, the culture medium was removed, after which 50 uL / well of the test compound was diluted to 2x final concentration in HBSS containing 20 mM HEPES, and 50 uL / well of 2x dye loading buffer was added. The cells were then incubated at room temperature in the dark for 60 min. During the incubation, a 5x final concentration (5x concentration in both cases: 5 mM) of T1 + and K + The stimulation buffer without chloride and the test compound of 1x final concentration were added. Then these cells were measured in FDSS7000EX functional drug screening system (Hamamatsu Co., Ltd. (Hamamatsu)). After 0.1Hz continued for 60sec and 1Hz continued for 10sec baseline fluorescence signal reading, the stimulation buffer of 25uL / hole was added, and at 1Hz, fluorescence was continuously measured for 50sec, and then at 0.1Hz, 4min was continued. AUC was used as reading to quantify the compound effect, and it was normalized to the reference compound included on each flat plate.

[0163] Effect of compounds

[0164] In the assays described above, the compounds of the invention have the following biological activities:

[0165] Examples <![CDATA[EC 50 ,nM]]> 1a 680 1b 3300 2a 460 2b 1800 3a 11000 3b 1500 4a 11000 4b 1200 5 1800 6 3000 7a 220 7b 1500 8a 430 8b 3000 9 560 10a 650 10b 1300 11a 1500 11b 4500 12a 1600 12b 5900 13a 1900 13b 2900 14a 2000 14b 6600 15a 2100 15b 11000 16a 3000 16b 10000 17 2500 18a 1300 18b 7100 19a 1700 19b 3400 20a 3100 20b 14000 21a 3500 21b 250

[0166] Synthesis of the compounds of the present invention:

[0167] General approach:

[0168] Recorded at 400.13 MHz on a Bruker Avance III 400 instrument or at 300.13 MHz on a Bruker Avance 300 instrument 1H NMR spectra. Deuterated dimethyl sulfoxide or deuterated chloroform was used as solvent. Tetramethylsilane was used as internal reference standard. Chemical shift values ​​are expressed in ppm relative to tetramethylsilane. The following abbreviations are used for the multiplicities of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = septet, dd = doublet of doublet, ddd = doublet of two doublets, dt = doublet of triplet, dq = doublet of quadruplets, tt = triplet of triplet, m = multiplet and brs = broad singlet.

[0169] The chromatographic systems and methods for evaluating chemical purity (LCMS method) and chiral purity (SFC and HPLC methods) are described below.

[0170] LCMS Method 1: Apparatus: Agilent 1200 LCMS system with ELS detector.

[0171]

[0172] LCMS Method 2: Apparatus: Agilent 1200 LCMS system with ELS detector

[0173]

[0174] LCMS Method 3: Apparatus: Agilent 1200 LCMS system with ELS detector

[0175]

[0176]

[0177] LCMS Method 4: Instrument: Agilent 1200 LCMS system with ELS detector

[0178]

[0179] LCMS Method 5: Apparatus: Agilent 1200 LCMS system with ELS detector

[0180]

[0181] LCMS Method 6: Apparatus: Agilent 1200 LCMS system with ELS detector

[0182]

[0183] SFC Method 1: Apparatus: Agilent 1260 with DAD detector

[0184]

[0185] SFC method 2: Apparatus: Waters UPC2

[0186]

[0187] SFC method 3: Apparatus: Waters UPC2

[0188]

[0189]

[0190] SFC method 4: Apparatus: Agilent 1260

[0191]

[0192] SFC method 5: Apparatus: Agilent 1260

[0193]

[0194] SFC method 6: Apparatus: Waters UPC2

[0195]

[0196]

[0197] SFC method 7: Apparatus: Waters UPC2

[0198]

[0199] SFC method 8: Apparatus: Agilent 1260

[0200]

[0201] SFC method 9: Apparatus: Agilent 1260

[0202]

[0203]

[0204] SFC Method 10: Apparatus: Agilent 1260

[0205]

[0206] SFC method 11: Apparatus: Waters UPC2

[0207]

[0208] SFC Method 12: Apparatus: Agilent 1260

[0209]

[0210]

[0211] SFC Method 13: Apparatus: Agilent 1260

[0212]

[0213] SFC Method 14: Apparatus: Agilent 1260

[0214]

[0215] SFC Method 15: Apparatus: Agilent 1260

[0216]

[0217] SFC Method 16: Apparatus: Agilent 1260

[0218]

[0219]

[0220] Chiral HPLC Method 1: Apparatus: SHIMADZU LC-20AB

[0221]

[0222] Chiral HPLC Method 2: Apparatus: SHIMADZU LC-20AB

[0223]

[0224] The general procedures for the synthesis of intermediates and compounds having the general formula I are described in Reaction Scheme 1 and are specifically illustrated in the Preparations and Examples. Variations on the described procedures known to those skilled in the art are within the scope of the present invention.

[0225] The compounds of the present invention are prepared as described in Scheme 1. Several of the compounds having the general formula I contain two chiral carbon atoms and are formed as a mixture of diastereomers. When this is the case, the diastereomers can be separated to yield single stereoisomers Ia and Ib.

[0226] Scenario 1:

[0227]

[0228] Scheme I depicts the preparation of compounds of Formula I by two general routes. The first route is to synthesize compounds of Formula I by reacting an enantiomerically pure amine of Formula II and an acid of Formula III by methods known in the art for converting acids and amines to amides. This method involves the formation of 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 to carry out the condensation in the presence of HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) and a suitable base (such as DIPEA (diisopropylethylamine)) in a solvent such as dichloromethane.

[0229] Alternatively, when R 2 When R is H, compounds of formula I can be prepared via a second general route wherein an intermediate of formula V is treated with a suitable reducing agent such as NaBH4 in a suitable solvent such as methanol. Intermediates of formula V can be obtained from enantiomerically pure amines of formula II and carboxylic acids of formula IV (R = H). This transformation can be carried out using similar reaction conditions as described above for the condensation of II and III to form I.

[0230] A variation of this procedure is the direct coupling reaction between a chiral amine of general formula II and a carboxylic acid ester of general formula IV (R = Me, Et). This reaction can be carried out by heating the reactants to reflux in a suitable solvent such as toluene, in the presence of a suitable base such as DIPEA and in the presence of a catalytic amount of a suitable catalyst such as DMAP (4-dimethylaminopyridine).

[0231] The optional reactive amine having the general formula II can be prepared as outlined in Scheme 2:

[0232] Solution 2

[0233]

[0234] In a suitable solvent (such as ethylene dichloride), in the presence of a drying agent (such as titanium (IV) isopropoxide, or copper sulfate), an aldehyde having the general formula VI can be condensed with (R)-2-methylpropane-2-sulfenamide. 3 The resulting sulfinyl imine is treated with MgBr to yield the corresponding substituted (R)-2-methyl-N-((S)-1-aryl-alkyl)propane-2-sulfinamide VII, which is converted to compounds of general formula II by treatment with a suitable acid in a suitable solvent such as HCl in MeOH.

[0235] The aldehydes of formula VI used for preparing the compounds according to the invention are commercially available or can be prepared as described, for example, in the literature (see Journal of Medicinal Chemistry, 45 (18), 3891-3904; 2002).

[0236] In a variation of this procedure, chiral amines of formula II can be obtained from aryl ketones by hydride reduction of the intermediate sulfinyl imine with reagents such as lithium tri-sec-butylborohydride, as shown in Scheme 3.

[0237] Solution 3

[0238]

[0239] The ketones used to prepare the compounds of the present invention are either commercially available or can be prepared by methods known to those skilled in the art.

[0240] Another variation of this procedure, as outlined in Scheme 4, is particularly suitable for obtaining chiral amines of the general formula II (wherein R 3 is a hydroxymethylene derivative).

[0241] Solution 4:

[0242]

[0243] In this procedure, the glyoxylate sulfinyl imine formed in the condensation reaction between glyoxylate and (R)-2-methylpropane-2-sulfinamide can be reacted with a suitably substituted boronic acid using a suitable catalyst such as bis(acetonitrile)(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate in a suitable solvent such as dioxane as described in JP 2017 / 095366A. The resulting intermediate VIII can be hydrolyzed and reprotected to yield an intermediate of formula IX, which can be further derivatized to obtain the desired R 3 Substituents. 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 difluoromethylated using a suitable reagent such as 2,2-difluoro-2-(fluorosulfonyl)acetic acid under the following conditions, such as CuI catalysis, in a suitable solvent such as acetonitrile.

[0244] Those skilled in the art will recognize that other transformations are possible from intermediates of general formula IX; the present invention is intended to encompass such alternative transformations.

[0245] Carboxylic acids of general formula III can be prepared as outlined in Scheme 5:

[0246] Solution 5

[0247]

[0248] Ketone with general formula X is reacted with the alkyl ester of bromoacetic acid activated by, for example, Zn and iodine, to produce the corresponding aldol adduct. In alternative procedures, bromoacetic acid ester can be activated using Zn and TMSCl (trimethylsilyl chloride). In the final step, the hydrolysis of alkyl ester is completed by handling with suitable alkali (such as NaOH or LiOH) in suitable solvent (such as water, or alcohol in water), and acidified with suitable acid subsequently, to produce the compound of formula III.

[0249] Preparation of intermediates :

[0250] IIa: (S)-1-(3-(trifluoromethoxy)phenyl)ethaneamine hydrochloride

[0251]

[0252] Step 1: Preparation of (R)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfenamide

[0253]

[0254] At 55 ° C, 3- (trifluoromethoxy) benzaldehyde (24.8g, 130.4mmol), (R) -2- methylpropane -2- sulfinamide (19g, 156.5mmol) and CuSO4 (31.2g, 195.7mmol) in DCE (1,2- dichloroethane) (500mL) was stirred for 24 hours. The mixture was filtered and the filter cake was washed with DCM (dichloromethane) (200mL). The organic phase was merged and concentrated. The residue was purified by flash silica gel chromatography (wherein the eluent was 0-15% ethyl acetate / petroleum ether (gradient)) to yield product (33g, 86% yield).

[0255] 1 H NMR (CDCl3400 MHz): δ8.59 (s, 1H), 7.79-7.71 (m, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 1.28 (s, 9H).

[0256] Step 2: Preparation of (R)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfenamide

[0257]

[0258] At 0°C, MeMgBr (3M in Et2O, 40mL) was added dropwise to a solution of (R)-2-methyl-N-[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamide (17.6g, 59.8mmol) in DCM (250mL). The resulting mixture was stirred at 0°C for 1 hour and at 15°C for 16 hours. The mixture was cooled to 0°C, and a saturated solution of NH4Cl was added. The resulting mixture was extracted with DCM (100mL×2). The organic phase was washed with brine (200mL), dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (wherein the eluent was 0-50% ethyl acetate / petroleum ether (gradient)) to give the product (10.3g, 56% yield).

[0259] 1 H NMR (CDCl3400 MHz): δ7.37(t,J=8.0Hz,1H),7.27-7.24(m,1H),7.21(s,1H),7.13(br d,J=8.0Hz,1H),4.65-7.59(m,1H),3.32(br d,J=2.4Hz,1H),1.54(d,J=6.4Hz,3H),1.22(s,9H).

[0260] Step 3: Preparation of (S)-1-(3-(trifluoromethoxy)phenyl)ethaneamine hydrochloride

[0261]

[0262] (R)-2-Methyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]propane-2-sulfenamide (10 g, 32.3 mmol) in MeOH (75 mL) was treated with HCl / MeOH (75 mL) and stirred at 15° C. for 16 h. The mixture was concentrated to give (S)-1-(3-(trifluoromethoxy)phenyl)ethanamine hydrochloride (9 g, crude) which was used directly without further purification.

[0263] IIb: (1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethanamine hydrochloride

[0264]

[0265] Step 1: Preparation of 3-(2,2,2-trifluoroethoxy)benzaldehyde

[0266]

[0267] At 20 ℃, by 3-hydroxybenzaldehyde (5g, 40.9mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (10.5g, 45mmol) and CsCO(26.7g, 81.9mmol) mixture in DMF (60mL) was stirred for 2 hours.The mixture was filtered and the filter cake was washed with ethyl acetate (200ml).The filtrate was washed with water (100mL x 2) and saline (100mL x 2), over NaSODry and concentrate.The crude product was purified by column chromatography (20% ethyl acetate in petroleum ether) on silica gel to give product (8.0g, 95% yield).

[0268] 1 HNMR (CDCl3400 MHz): δ7.58-7.51 (m, 2H), 7.42 (s, 1H), 7.27-7.25 (m, 1H), 4.42 (q, J=12.0Hz, J=8.0Hz, 2H).

[0269] Step 2: Preparation of (R)-2-methyl-N-[[3-(2,2,2-trifluoro-ethoxy)phenyl]methylene]propane-2-sulfenamide

[0270]

[0271] At 55 ° C, a mixture of 3-(2,2,2-trifluoroethoxy)benzaldehyde (8.0 g, 39.2 mmol), (R)-2-methylpropane-2-sulfinamide (5.2 g, 43.1 mmol) and CuSO4 (9.4 g, 58.8 mmol) in DCE (70 mL) was stirred for 20 hours. The mixture was filtered and the filter cake was washed with DCM (100 mL). The organic phases were concentrated and purified by column chromatography on silica gel (11% ethyl acetate in petroleum ether) to yield the product (10.0 g, 83% yield).

[0272] 1 H NMR (CDCl3400 MHz): δ8.55 (s, 1H), 7.50-7.42 (m, 3H), 7.13 (d, J = 5.2Hz, 1H), 4.41 (q, J = 12.0Hz, J = 8.0Hz, 2H), 1.27 (s, 9H).

[0273] Step 3: Preparation of (R)-2-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)propane-2-sulfenamide

[0274]

[0275] At 0 ° C, to (R) -2- methyl -N- [[3- (2,2,2- trifluoroethoxy) phenyl] methylene] propane -2- sulfinamide (10g, 32.5mmol) in DCM (100mL) solution was added dropwise MeMgBr (3M, 43mL). 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 NH4Cl saturated solution was added. The resulting mixture was extracted with DCM (100mL x 2). The organic phase was washed with brine (200mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) on silica gel to give the product (9g, 79% yield).

[0276] 1 H NMR (CDCl3400 MHz): δ7.27 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 4.56-4.54 (m, 1H), 4.34 (dd, J = 16.4 Hz, J = 8.4 Hz, 1H), 3.30 (br s, 1H), 1.51 (d, J = 8.4 Hz, 3H), 1.20 (s, 9H). NH was not observed.

[0277] Step 4: Preparation of (1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethaneamine hydrochloride

[0278]

[0279] To a solution of (R)-2-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]propane-2-sulfinamide (9 g, 27.8 mmol) in MeOH (100 mL) was added HCl / MeOH (80 mL, 4 M). The resulting mixture was stirred at 20 °C for 4 hours and concentrated to give the crude product (8 g) which was used directly without further purification.

[0280] IIc: (S)-1-(3-(difluoromethoxy)phenyl)ethan-1-amine hydrochloride

[0281]

[0282] Step 1: Preparation of (R)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfenamide

[0283]

[0284] To a mixture of 3-(difluoromethoxy)benzaldehyde (2 g, 11.6 mmol) and 2-methylpropane-2-sulfinamide (1.7 g, 13.9 mmol) in DCE (60 mL) was added CuSO (9.3 g, 58.1 mmol) at 55° C. under N2. The mixture was stirred at 55° C. for 12 hours, filtered and the filtrate was concentrated. The crude product was purified by silica gel column (eluted with petroleum ether / ethyl acetate=20:1-10:1) to give (R)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2.5 g, 70% yield).

[0285] Step 2: Preparation of (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide

[0286]

[0287] At 0 ° C, (R)-N-(3-(difluoromethoxy)benzylidene)-2-methylpropane-2-sulfinamide (2g, 7.3mmol) was added dropwise to a solution of (methyl) magnesium (3M in Et2O, 4.8mL) in DCM (30mL). The resulting mixture was stirred at 0 ° C for 1 hour and at 20 ° C for 16 hours. The reaction was quenched with NH4Cl (saturated aqueous solution, 10mL), and the aqueous phase was extracted with ethyl acetate (30mL×3). The combined organic phases were washed with brine (40mL×2), dried over anhydrous Na2SO4, filtered, concentrated, and purified by silica gel chromatography (petroleum ether / ethyl acetate=5:1-1:1) to provide (R)-N-((S)-1-(3-(difluoromethoxy)phenyl))-2-methylpropane-2-sulfinamide (960mg, 45.4% yield).

[0288] Step 3: Preparation of (S)-1-(3-(difluoromethoxy)phenyl)ethaneamine hydrochloride

[0289]

[0290] To a solution of (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide (0.8 g, 2.8 mmol) in MeOH (4 mL) was added HCl / MeOH (4 M, 2 mL). The resulting mixture was stirred at 25 °C for 3 h, and the reaction was concentrated to afford 1.6 g crude yield of (S)-1-(3-(difluoromethoxy)phenyl)ethanamine, which was used directly without further purification.

[0291] IId: (S)-1-(3-(Trifluoromethyl)phenyl)ethan-1-amine hydrochloride

[0292]

[0293] Step 1: Preparation of (R)-2-methyl-N-(3-(trifluoromethyl)benzylidene)propane-2-sulfenamide

[0294]

[0295] At 55 ℃, a mixture of 3-(trifluoromethyl)benzaldehyde (4.5 g, 25.8 mmol), (R)-2-methylpropane-2-sulfinamide (3.8 g, 31 mmol) and CuSO (6.2 g, 38.8 mmol) in DCE (20 mL) was stirred for 24 hours. The mixture was filtered and the filtrate was washed with DCM (100 mL). The filtrate was concentrated and the residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate) to provide a product with a yield of 4.6 g (58%).

[0296] 1 H NMR (CDCl 3, 400MHz): δ8.60(s,1H),8.09(s,1H),7.98(d,J=7.6Hz,1H),7.73(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H),1.25(s,9H).

[0297] Step 2: Preparation of (R)-2-methyl-N-((S)-1-(3-trifluoro-methyl)phenyl)ethyl)propane-2-sulfenamide

[0298]

[0299] At 0°C, MeMgBr (3M in EtO, 9.6 mL) was added dropwise to a solution of (R)-2-methyl-N-(3-(trifluoromethyl)benzylidene)propane-2-sulfinamide (2 g, 7.2 mmol) in DCM (50 mL). 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 NH4Cl was added. The mixture was extracted with DCM (50 mL×3). The combined organic phases were washed with brine (50 mL×2), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate) to provide the desired product (1.3 g, 61% yield).

[0300] 1 H NMR (CDCl 3,400 MHz): δ 7.40-7.65 (4H), 4.11-4.06 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.17 (s, 9H). NH was not observed.

[0301] Step 3: Preparation of (S)-1-[3-(trifluoromethyl)phenyl]ethaneamine hydrochloride

[0302]

[0303] To a solution of (R)-2-methyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfonamide (1.3 g, 4.4 mmol) in MeOH (20 mL) was added HCl / MeOH (4 M, 20 mL). The resulting mixture was stirred at 25 °C for 20 hours and then concentrated to afford the product in 850 mg yield. The crude product was used directly without further purification.

[0304] IIe: (S)-1-(3-(trifluoromethoxy)phenyl)propan-1-amine hydrochloride

[0305]

[0306] Step 1: Preparation of (R)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfenamide:

[0307]

[0308] A mixture of 3-(trifluoromethoxy)benzaldehyde (10.0 g, 52.60 mmol), (R)-2-methylpropane-2-sulfinamide (7.7 g, 63.1 mmol) and CuSO4 (12.6 g, 78.9 mmol) in DCE (200 mL) was stirred at 55°C for 16 hours. The mixture was filtered and the filter cake was washed with DCM (200 mL). The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (eluent 0-10% ethyl acetate / petroleum ether gradient) to give (R)-2-methyl-N-[[3-(trifluoromethoxy)phenyl]methylene]propane-2-sulfinamide in a yield of 12.6 g (81.7%).

[0309] Step 2: Preparation of (R)-2-methyl-N-((S)-1-(3-(trifluoro-methoxy)phenyl)propyl)propane-2-sulfenamide

[0310]

[0311] To a solution of (R)-2-methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (2.0 g, 6.8 mmol) in DCM (40 mL) was added dropwise EtMgBr (3M in EtO, 9.1 mL) at 0°C. The resulting mixture was stirred at 0°C for 1 hour and at 20°C for 3 hours. The mixture was cooled to 0°C and saturated aqueous NH4Cl (100 mL) was added. The mixture was extracted with DCM (100 mL×2), the phases were separated, and the organic layer was washed with brine (200 mL), dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (eluent 0-50% ethyl acetate / petroleum ether gradient) to yield the product (1.4 g, 62% yield).

[0312] Step 3: Preparation of (S)-1-[3-(trifluoromethoxy)phenyl]propan-1-amine hydrochloride

[0313]

[0314] To a solution of (R)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)propane-2-sulfinamide (1.4 g, 4.2 mmol) in MeOH (40 mL) was added HCl / MeOH (4M, 20 mL). The resulting mixture was stirred at 30° C. for 12 h and then concentrated to yield crude (S)-1-[3-(trifluoromethoxy)phenyl]propan-1-amine hydrochloride, which was used without further purification (1 g).

[0315] IIf: (R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethan-1-amine

[0316]

[0317] Step 1: Preparation of 2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanone

[0318]

[0319] To a solution of 2-bromo-1-(3-(trifluoromethoxy)phenyl)ethanone (3.5 g, 12.4 mmol) in MeOH (60 mL) was added AgCO (3.8 g, 13.6 mmol) and BF.EtO (2.1 g, 14.8 mmol). The mixture was stirred at 50°C under N for 16 hours. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO, eluent 0-5% ethyl acetate / petroleum ether) to give 2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethanone (2.1 g, 64% yield).

[0320] 1 H NMR (400MHz, CDCl3) δ7.87 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.52 (t, J = 8.4 Hz, 1H), 7.46-7.42 (m, 1H), 4.68 (s, 2H), 3.51 (s, 3H).

[0321] Step 2: Preparation of (R)-N-(2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethylidene)-2-methylpropane-2-sulfenamide

[0322]

[0323] To a solution of 2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethanone (500 mg, 2.1 mmol) in THF (15 mL) was added titanium (IV) isopropoxide (910 mg, 3.2 mmol) and (R)-2-methylpropane-2-sulfinamide (336 mg, 2.8 mmol). The mixture was stirred at 50 ° C under N2 for 1 hour. The reaction mixture was quenched with brine (40 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, eluent 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).

[0324] Step 3: Preparation of (R)-N-((R)-2-methoxy-1-(3-(trifluoro-methoxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide

[0325]

[0326] To a solution of (R)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethylidene)-2-methylpropane-2-sulfinamide (160 mg, 0.5 mmol) in THF (5 mL) was added tri-sec-butyl lithium borohydride (1 M in THF, 1.42 mmol, 1.42 mL) at 0°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with methanol (20 mL) and then filtered and concentrated. The residue was purified by column chromatography (SiO2, eluent 0-10% ethyl acetate / petroleum ether) to give the desired product (100 mg, 59% yield).

[0327] 1H NMR (400 MHz, DMSO-d 6 )δ7.46-7.40(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).

[0328] Step 4: Preparation of (R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethaneamine

[0329]

[0330] (R)-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-2-methylpropane-2-sulfinamide (280 mg, 0.8 mmol) in HCl / MeOH (10 mL, 4 M) was stirred for 14 hours at 20°C. The reaction mixture was concentrated, and the residue was diluted with water (30 mL), ammonium hydroxide was added to pH=8-9, and extracted with ethyl acetate (30 mL×2). The combined organic extracts were dried over MgSO4, filtered and concentrated to give the product as a yellow oil (170 mg, 88% yield). The product was used directly without further purification.

[0331] IIg: (1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine

[0332]

[0333] Step 1: Preparation of ethyl 2-[(R)-tert-butylsulfinyl]imidoacetate

[0334]

[0335] To a solution of 2-oxoethyl acetate (7.5 g, 36.7 mmol) and (R)-2-methylpropane-2-sulfinamide (4.9 g, 40.4 mmol) in DCM (150 mL), CuSO (12.9 g, 80.8 mmol) was added, and the reaction mixture was stirred at 25 ° C for 24 hours. The solid was filtered out, washed with ethyl acetate (50 mL), and the organic phase was combined and concentrated. The resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate, 5 / 1) to yield the desired product (5.1 g, 67.6% yield).

[0336] Step 2: Preparation of ethyl (2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate

[0337]

[0338] To a solution of ethyl 2-[(R)-tert-butylsulfinyl]imidoacetate (7 g, 34.1 mmol) and [3-(trifluoromethoxy)phenyl]boronic acid (8.4 g, 40.9 mmol) in dioxane (100 mL) was added [Rh(COD)(MeCN)2]BF4 (1.3 g, 3.4 mmol), and the mixture was stirred at 80° C. for 16 hours. The product was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1) to yield 9.8 g (78%).

[0339] Step 3: Preparation of ethyl (2R)-2-amino-2-[3-(trifluoro-methoxy)phenyl]acetate hydrochloride

[0340]

[0341] To a solution of ethyl (2R)-2-[[(R)-tert-butylsulfinyl]amino]-2-[3-(trifluoromethoxy)phenyl]acetate (9.8 g, 26.7 mmol) in MeOH (100 mL) was added HCl / MeOH (4 M, 100 mL), and this mixture was stirred at 25 °C for 2 hours and then concentrated to give ethyl (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]acetate (7.8 g, crude).

[0342] Step 4: Preparation of ethyl (2R)-2-(tert-butoxycarbonylamino)-2-[3-(trifluoromethoxy)phenyl]acetate

[0343]

[0344] To a mixture of (2R)-2-amino-2-[3-(trifluoromethoxy)phenyl]ethyl acetate hydrochloride (6 g, 20 mmol) in THF (150 mL) was added Boc2O (8.7 g, 40 mmol). NaHCO3 (1.7 g, 20 mmol) was then added to the solution and stirred at 25°C for 16 hours. The mixture was concentrated and purified by chromatography on silica gel (petroleum ether:ethyl acetate=10:1) to provide the product (7.2 g, 99% yield).

[0345] Step 5: Preparation of tert-butyl N-[(1R)-2-hydroxy-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate

[0346]

[0347] To a suspension of LiAlH4(1.7g, 44mmol) in THF(200mL), add (2R)-2-(tert-butoxycarbonylamino)-2-[3-(trifluoro-methoxy)phenyl]ethyl acetate (4g, 11mmol) in THF(25mL), while ice cooling. After addition, allow the reactant to be heated to 25°C and stirred for 2 hours. Add anhydrous magnesium sulfate, and then add a drop of water and ethyl acetate in sequence. Filter out insoluble material through a diatomaceous earth pad. The filtrate is concentrated and purified by chromatography (SiO2; petroleum ether: ethyl acetate = 5:1) on silica gel (2.1g, 59% yield).

[0348] Step 6: Preparation of tert-butyl N-[(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate

[0349]

[0350] To a solution of tert-butyl N-[(1R)-2-hydroxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]carbamate (1.5 g, 4.7 mmol) in MeCN (20 mL) was added CuI (360 mg, 1.9 mmol) and stirred at 25° C. under N2 atmosphere for 30 minutes. 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 minutes and the reaction was stirred at 45° C. for 1 hour. This mixture was concentrated and then diluted with ethyl acetate (100 mL), filtered and concentrated to provide the desired product (1.5 g, crude).

[0351] Step 7: Preparation of (1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine

[0352]

[0353] To a solution of tert-butyl N-[(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]carbamate (1.5 g, 4 mmol) in MeOH (15 mL) was added HCl / MeOH (4 M in MeOH, 30 mL) at 25° C., and the reaction was stirred at 25° C. for 30 minutes. Ammonium hydroxide (30%) was added to pH=9, and the solution was concentrated and purified by chromatography on silica gel (SiO 2 ; petroleum ether:ethyl acetate=2:1) ​​to provide (1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethanamine (700 mg, 64% yield).

[0354] IIIa: 2-(1-Hydroxycyclobutyl)acetic acid

[0355]

[0356] Step 1: Preparation of ethyl 2-(1-hydroxycyclobutyl) acetate

[0357]

[0358] To Zn (14.9g, 228.3mmol) in THF (20mL) was added TMSCl (1.9g, 17.1mmol) in batches. At 20°C, the resulting mixture was stirred for 15min and then refluxed. The reaction mixture was cooled to room temperature, and ethyl 2-bromoacetate (28.6g, 171.2mmol) 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 (10g, 142.7mmol) in THF (5mL) was added. At 20°C, the mixture was stirred for another 2 hours. The mixture was poured into NH on ice. H2O (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 Na2SO4 and concentrated to give the product (12g, crude product).

[0359] 1 H NMR(CDCl3400 MHz): δ4.20-4.14(m,2H),3.69(s,1H),2.65(s,2H),2.17-2.12(m,2H),2.03-2.00(m,2H),1.78(m,1H),1.58(m,1H),1.27(t,J=7.6Hz,3H).

[0360] Step 2: Preparation of 2-(1-hydroxycyclobutyl)acetic acid

[0361]

[0362] NaOH (6.3 g, 158.05 mmol) was dissolved in MeOH (150 mL) and H2O (50 mL), and ethyl 2-(1-hydroxycyclobutyl)acetate (10 g, 63.2 mmol) was added. The mixture was stirred at 20 ° C for 16 hours, and then concentrated, and the residue was acidified to pH=2-3 by 2N HCl solution, and extracted with ethyl acetate (200 ml x 2). The organic extract was washed with water (100 mL x 2) and brine (100 mL x 2), dried over Na2SO4, and concentrated to give a crude product (6 g, crude product).

[0363] 1 H NMR (CDCl3400 MHz): δ2.74(s,2H),2.23-2.05(m,4H),1.81(m,1H),1.63-1.58(m,1H).

[0364] IIIb: 2-(3,3-difluoro-1-hydroxycyclobutyl)acetic acid

[0365]

[0366] Step 1: Preparation of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate

[0367]

[0368] Under N2, ethyl 2-bromoacetate (378 mg, 2.3 mmol) was added dropwise to a solution of 3,3-difluorocyclobutanone (0.2 g, 1.9 mmol), Zn (198 mg, 3 mmol) and I2 (10 mg, 0.04 mmol) in THF (13 mL). The mixture was stirred at 55 ° C for 6 hours. At 0 ° C, H2SO4 (10%, 10 mL) was carefully added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic extract was washed with NaHCO3 (saturated aqueous solution, 10 mL), dried over Na2SO4 and concentrated. The crude product (0.26 g) was used directly without further purification.

[0369] Step 2: Preparation of 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetic acid

[0370]

[0371] To a solution of ethyl 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetate (0.26 g, 1.3 mmol) in MeOH (10 mL) and H2O (2 mL) was added NaOH (107 mg, 2.7 mmol) at 0°C. The mixture was stirred at 20°C for 8 hours. The reaction solution was cooled to 0°C, and 1N HCl was added to the solution until the pH reached 1-2. The residue was diluted with brine (10 mL) and extracted with methyl-tert-butyl ether (30 mL×5). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product (0.24 g) was used without further purification. IIIc: 3-Hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid

[0372]

[0373] Step 1: Preparation of ethyl 3-hydroxy-4-methyl-3-(trifluoro-methyl)pentanoate

[0374]

[0375] At 15 ° C, ethyl 2-bromoacetate (524 mg, 3.1 mmol) and 1,1,1-trifluoro-3-methyl-butan-2-one (0.4 g, 2.9 mmol) were added to a mixture of Zn (560 mg, 8.6 mmol), I (7 mg, 0.03 mmol) in THF (5 mL). The mixture was stirred at 60 ° C for 6 hours. H2SO4 (10% aqueous solution, 4 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 4). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give 3-hydroxy-4-methyl-3-(trifluoromethyl) ethyl pentanoate (1 g, crude product).

[0376] Step 2: Preparation of 3-hydroxy-4-methyl-3-(trifluoromethyl)pentanoic acid

[0377]

[0378] At 15 ° C, 3-hydroxy-4-methyl-3-(trifluoro-methyl) ethyl pentanoate (1.5g, crude product) and LiOH.H o (552mg, 13.2mmol) in THF (20mL) and H o (10mL) were stirred for 16 hours. pH was adjusted to about 3 with 2M HCl, and the mixture was extracted with ethyl acetate (5mL x 4). The combined organic extracts were washed with salt water (15mL), dried over Na sO, filtered and concentrated to give 3-hydroxy-4-methyl-3-(trifluoromethyl) pentanoic acid (1.1g, crude product) as a yellow solid, which was used directly in the next step without further purification.

[0379] IIId: 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoic acid

[0380]

[0381] Step 1: Preparation of ethyl 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoate

[0382]

[0383] Under N2, at 20°C, ethyl 2-bromoacetate (2.4 g, 14.3 mmol) was added dropwise to a solution of 3,3,4,4-tetrafluorobutan-2-one (2.00 g, 13.88 mmol), Zn (1.0 g, 15.7 mmol) and I2 (35.2 mg, 0.14 mmol) in THF (20 mL). The mixture was stirred at 60°C for 6 hours. The reaction mixture was cooled to 0°C, and H2SO4 (15 ml, 10% aqueous solution) was added carefully. The mixture was extracted with ethyl acetate (80 mL×3), and the combined organic extracts were washed with NaHCO3 saturated aqueous solution (30 mL), dried over Na2SO4 and concentrated. The title compound (2.5 g, crude product) was obtained and used in the next step without further purification.

[0384] Step 2: Preparation of 4,4,5,5-tetrafluoro-3-hydroxy-3-methylpentanoic acid

[0385]

[0386] At 0 ° C, NaOH (1.1 g, 26.9 mmol) was added to a solution of 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-pentanoic acid ethyl ester (2.5 g, 10.8 mmol) in MeOH (80 mL) and H2O (25 mL). The mixture was stirred for 8 hours and concentrated at 20 ° C. The aqueous layer was acidified to pH = 1-2 with 1N HCl aqueous solution and extracted with methyl-tert-butyl ether (30 mL × 5). The combined organic extracts were dried over Na2SO4 and concentrated. The title compound (2.10 g, crude product) was obtained and used without further purification.

[0387] IIIe: 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

[0388]

[0389] Step 1: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid ethyl ester

[0390]

[0391] At 15 ° C, 4,4,4-trifluorobutan-2-one (4.4 g, 34.9 mmol) and ethyl 2-bromoacetate (6.4 g, 38.4 mmol) were added to a mixture of Zn (6.9 g, 104.7 mmol) and I2 (89 mg, 0.35 mmol) in THF (80 mL). The mixture was stirred at 60 ° C for 6 hours. The reaction mixture was cooled to 0 ° C and quenched with H2SO4 (100 mL, 10% aqueous solution). The mixture was extracted with ethyl acetate (15 mL × 3). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated. The product (11.00 g, crude) was obtained and used directly without further purification.

[0392] Step 2: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methylpentanoic acid

[0393]

[0394] At 15 ° C, a mixture of 5,5,5-trifluoro-3-hydroxy-3-methyl-pentanoic acid ethyl ester (11 g, crude) and NaOH (4.1 g, 102.7 mmol) in H2O (150 mL) was stirred for 16 hours. The pH was adjusted to about 2 at 0 ° C with saturated KHSO4, and the mixture was extracted with ethyl acetate (200 mL×3). The combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to provide the product (10 g, crude).

[0395] IIIf: 3-(1-fluorocyclopropyl)-3-hydroxybutyric acid

[0396]

[0397] Step 1: Preparation of ethyl 3-(1-fluorocyclopropyl)-3-hydroxybutyrate

[0398]

[0399] To a mixture of 1-(1-fluorocyclopropyl)ethanone (0.8 g, 7.8 mmol), Zn (1.5 g, 23.5 mmol) and I2 (20 mg, 0.8 mmol) in THF (15 mL) was added ethyl 2-bromoacetate (1.4 g, 8.6 mmol) at 15 ° C. The mixture was stirred at 65 ° C for 6 hours. The reaction mixture was cooled to 0 ° C. and H2SO4 (10% aqueous solution, 10 mL) was added dropwise. Water (30 mL) was added to the mixture and extracted with ethyl acetate (20 mL×3). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The obtained product was used without further purification. Yield: 1.6 g, crude product.

[0400] Step 2: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxybutyric acid

[0401]

[0402] A mixture of 3-(1-fluorocyclopropyl)-3-hydroxy-butyric acid ethyl ester (1.6 g, crude) and NaOH (670 mg, 16.8 mmol) in H2O (30 mL) was stirred at 15°C for 16 hours. The pH was adjusted to about 2 with 10% HCl (aq.). The mixture was extracted with ethyl acetate (20 mL x 4), and the combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated to yield a crude product, which was used directly without further purification. (1.50 g, crude).

[0403] IIIg: 3-cyclopropyl-3-hydroxybutyric acid

[0404]

[0405] Step 1: Preparation of methyl 3-cyclopropyl-3-hydroxybutyrate

[0406]

[0407] To Zn (12.4g, 190.2mmol) in THF (150mL), TMSCl (1.3g, 11.9mmol) is added, and the resulting mixture is stirred at 20°C for 15 minutes, and then heated to 70°C. Stop heating, and 2-bromoacetic acid methyl ester (21.8g, 142.7mmol) is added dropwise at a rate that makes ether slowly boil. The resulting mixture is stirred at 70°C for 1 hour, and at 20°C for 1 hour, and then a solution of 1-cyclopropyl ethyl ketone (10g, 118.9mmol) in THF (50mL) is added. The reaction is stirred at 20°C for 16 hours. The mixture is poured into NH on ice H O (100mL, 28%), and extracted with ethyl acetate (150mL x 2). The organic extract was washed with water (150 mL) and brine (150 mL), dried over Na2SO4 and concentrated to give the desired product (8.9 g, crude).

[0408] Step 2: Preparation of 3-cyclopropyl-3-hydroxybutyric acid

[0409]

[0410] At 20 ℃, the mixture of crude 3-cyclopropyl-3-hydroxybutyric acid methyl ester (8.9g, 56.3mmol) and LiOH H O (11.8g, 281.3mmol) in THF (100mL) and H O (50mL) was stirred for 16 hours. H O (50ml) was added and extracted with ethyl acetate (100mL x 2). The organic extract was discarded. The pH of the aqueous layer was adjusted to about 5 with 2N HCl, extracted with ethyl acetate (100mL x 3), and the combined organic fractions were washed with brine (100mL x 10), dried over Na SO, filtered and concentrated to give the desired product in 30% overall yield (5.1g).

[0411] 1 H NMR (400MHz, CDCl3) δ2.67-2.51(m,2H),1.25(s,3H),0.90-1.00(m,1H),0.33-0.50(m,4H).

[0412] IVa: 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propionic acid ethyl ester

[0413]

[0414] Step 1: Preparation of 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-propionic acid ethyl ester

[0415]

[0416] Et3N (2.34 g, 23.5 mmol) and MgCl2 (1.8 g, 18.4 mmol) were added to a suspension of (3-ethoxy-3-oxo-propionyl)oxy potassium salt (2.6 g, 15.4 mmol) in MeCN (30 mL) and stirred at 20°C for 2 hours. A pre-stirred mixture of CDI (carbonyl-diimidazole) (1.4 g, 8.8 mmol) and 1-(difluoromethyl)cyclopropanecarboxylic acid (1 g, 7.4 mmol) in MeCN (20 mL) was added at 0°C and stirred at 20°C for 14 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent 0-10% ethyl acetate / petroleum ether gradient). The product was obtained in a yield of 0.98 g (65%).

[0417] IVb: 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoic acid ethyl ester

[0418]

[0419] Step 1: Preparation of ethyl 3-oxo-3-[1-(trifluoromethyl)cyclopropyl]propanoate

[0420]

[0421] Et3N (6.3g, 62.3mmol) and MgCl2 (4.6g, 48.7mmol) were added to a suspension of 3-ethoxy-3-oxo-propionic acid potassium (6.9g, 40.5mmol) in CH3CN (25mL) and stirred at 20°C for 2 hours. A pre-stirred mixture of carbonyldiimidazole (CDI) (3.8g, 23.3mmol) and 1-(trifluoromethyl)cyclopropanecarboxylic acid (3g, 19.5mmol) in CH3CN (25mL) was added at 0°C and stirred at 20°C for 14 hours. The mixture was poured into water (20mL). The aqueous phase was extracted with ethyl acetate (30mL×3). The combined organic phases were washed with brine (40mL×2), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 30: 1-10: 1) to afford the product in 3.5 g (80%) yield.

[0422] Va: 4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

[0423]

[0424] At 25 ° C, a solution of (1S)-1-[3-(trifluoromethoxy)phenyl]ethaneamine hydrochloride (IIa) (5g, 20.69mmol), 4,4-dimethyl-3-oxo-pentanoic acid (3.28g, 22.76mmol), HATU (9.44g, 24.83mmol) and DIPEA (8g, 62.1mmol) in DCM (250mL) was stirred for 16 hours. The resulting mixture was washed with water (500mL) and extracted with DCM (500mL×2). The organic layer was washed with brine (350mL×2), dried over Na2SO4 and concentrated. The residue was purified by chromatography (SiO2, petroleum ether / ethyl acetate=1:0 to 3:1) to provide 4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (11.2g, crude product).

[0425] The following intermediates were prepared by a similar method to Va using the related intermediates:

[0426] Vb: 4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]pentanamide

[0427]

[0428] Prepared from lib (2.6 g, 10.1 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (1.6 g, 11.1 mmol).

[0429] Yield: 2.6 g (75%).

[0430] Vc: (S)-N-(1-(3-(difluoromethoxy)phenyl)ethyl)-4,4-dimethyl-3-oxopentylamide

[0431]

[0432] Prepared from IIc (0.8 g, 4.3 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (616 mg, 4.3 mmol) Yield: 1.3 g crude

[0433] Vd: (S)-4,4-dimethyl-3-oxo-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

[0434]

[0435] Prepared from IId (850 mg, 3.77 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (597 mg, 4.14 mmol).

[0436] Yield: 1.12 g (94%)

[0437] Ve: (S)-4,4-dimethyl-3-oxo-N-(1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

[0438]

[0439] Prepared from IIe (1.04 g, 4.07 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (645 mg, 4.47 mmol).

[0440] Yield: 1.28 g (91%).

[0441] Vf: (S)-4-methyl-3-oxo-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0442]

[0443] Prepared from lib (2.89 g, 11.32 mmol) and 4-methyl-3-oxo-pentanoic acid (1.62 g).

[0444] Yield: 2.6 g (69%).

[0445] Vi: (S)-4-methyl-3-oxo-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0446]

[0447] Prepared from IIa (2.7 g, 13.16 mmol) and 4-methyl-3-oxo-pentanoic acid (1.60 g)

[0448] Yield: 2.00 g (47%).

[0449] Vj: N-[(1R)-2-(difluoromethoxy)-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-3-oxo-pentanamide

[0450]

[0451] Prepared from IIg (600 mg, 2.21 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (382 mg, 2.66 mmol)

[0452] Yield: 520 mg (51%).

[0453] Vk: N-[(1R)-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-3-oxo-pentanamide

[0454]

[0455] Prepared from IIf (40 mg, 0.15 mmol) and 4,4-dimethyl-3-oxo-pentanoic acid (25 mg, 0.17 mmol)

[0456] Yield: 100 mg, (94%).

[0457] Vg: 3-[1-(difluoromethyl)cyclopropyl]-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]propionamide

[0458]

[0459] A mixture of IIa (557 mg, 2.30 mmol), IVa (0.95 g, 4.61 mmol), DMAP (57 mg, 0.46 mmol) and EtN (2.33 g, 23.04 mmol) in toluene (30 mL) was degassed and purged 3 times with N, then the mixture was stirred at 110° C. for 12 hours under N. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (0-35% ethyl acetate / petroleum ether gradient as eluent) to yield the desired product (0.61 g, 72% yield).

[0460] The following were prepared by analogous procedures as described for Vg using the relevant intermediates:

[0461] Vh: 3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-[1-(trifluoromethyl)cyclopropyl]propionamide

[0462]

[0463] Prepared from IVb (2 g, 8.9 mmol) and IIa (915.3 mg, 4.5 mmol)

[0464] Yield: 1.7 g (97%).

[0465] Vl: (S)-3-(3,3-difluorocyclobutyl)-3-oxo-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide

[0466]

[0467] Prepared from methyl 3-(3,3-difluorocyclobutyl)-3-oxopropanoate (600 mg, 3.12 mmol) and IIa (377 mg, 1.56 mmol).

[0468] Yield: 470 mg, (82%).

[0469] 1 H NMR(CDCl3,400MHz)δ7.39-7.35(m,1H),7.26-7.23(m,1H),7.15-7.11(m,2H),5. 16-5.08(m,1H),3.44(d,J=2.4Hz,2H),2.86-2.71(m,5H),1.51(d,J=7.2Hz,3H).

[0470] Examples:

[0471] Example 1a:

[0472] (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0473]

[0474] and example 1b:

[0475] (R)-3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

[0476]

[0477] Step 1: Preparation of 3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

[0478]

[0479] To a mixture of 4,4-dimethyl-3-oxo-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (Va) (5.6 g, 16.90 mmol) in MeOH (50 mL) was added NaBH4 (1.28 g, 33.8 mmol) in portions at 0°C. The mixture was stirred at 0°C for 1 hour. Water (50 mL) was added in portions 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:

[0480] 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 Na2SO4, filtered and concentrated to provide 3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (16.5 g, crude).

[0481] Step 2: Separation of (S)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide and (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide

[0482]

[0483] 3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide (27 g, 83 mmol) was isolated by chromatography.

[0484] Example 1a:

[0485] Yield: 10.5g

[0486] 1 H NMR(CDCl3400 MHz): δ7.33(t,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),7.05-7.20(2H),6.40(br,1H),5.15(m,1H),3 .64(dd,J=2.0Hz,8.4Hz,1H),3.05(br,1H),2.15-2.40(m,2H),1.45(d,J=7.2Hz,3H),0.88(s,9H).

[0487] LC-MS:t R =2.548 min (LCMS method 1), m / z=334.0 [M+H] + .

[0488] SFC:t R =1.89min (SFC method 4), de = 95%, [α] D 20 =-71.7(c=0.72g / 100mL,

[0489] MeOH).

[0490] Example 1b:

[0491] Yield: 10.5g

[0492] 1 H NMR(CDCl3400 MHz): δ7.32(t,J=8.0Hz,1H),7.22(d,J=7.6Hz,1H),7.13(s,1H),7.10-7.07(m,1H),6.52(d,J=7.6Hz,1H),5.13-5.06(m,1H) ,3.62(dd,J=2.0Hz,8.4Hz,1H),3.45-3.33(m,1H),2.38-2.33(m,1H),2.23-2.17(m,1H),1.44(d,J=7.2Hz,3H),0.88(s,9H). LC-MS:t R =2.553 min (LCMS method 1), m / z=334.0 [M+H] + .

[0493] SFC:t R =1.87min (SFC method 5), de = 100%, [α] D 20 =-42.3(c = 0.61 g / 100 mL,

[0494] MeOH).

[0495] The following examples were prepared by analogous methods as described for 1a and 1b using the relevant intermediates:

[0496] Example 2a:

[0497] 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0498]

[0499] and example 2b:

[0500] 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0501]

[0502] Step 1: Preparation of 3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0503]

[0504] 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide was prepared in 84% yield from Vb.

[0505] Step 2: Separation of (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide and (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0506]

[0507] 3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]pentanamide (0.84 g, 2.52 mmol) was separated by chiral SFC.

[0508] Example 2a:

[0509] Yield: 0.25g

[0510] 1 H NMR (CDCl3, 400MHz) δ7.30 (t, J = 7.6Hz, 1H), 7.01 (d, J = 7.6Hz, 1H), 6.93 (s, 1H), 6.85 (dd, J = 8.4Hz, 2.8Hz, 1H), 6.08 (br d,J=5.2Hz,1H),5.13(m,1H),4.36(q,J=16.0Hz,8.0Hz,2H),3.68(dd,J=10.4Hz,3.0 Hz,1H),3.24(d,J=3.2Hz,1H),2.39-2.23(m,2H),1.49(d,J=6.8Hz,3H),0.93(s,9H)

[0511] LC-MS:t R =2.68 min (LCMS method 2), m / z = 348.0 [M+H] + .

[0512] SFC:t R =1.78min (SFC method 1), de = 98.3%, [α] D 20 =-68.0 (c=0.25, MeOH).

[0513] Example 2b:

[0514] Yield: 0.37 g

[0515] 1H NMR(CDCl3,400MHz)δ7.29(t,J=8.0Hz,1H),7.01(d,J=8.0Hz,1H),6.94(s,1H),6.84(dd,J=8.0,2.4Hz,1H),6.04(m,1H),5.13(m,1H), 4.36(q,J=16.0Hz,8.0Hz,2H),3.70-3.67(m,1H),3.15(d,J=2.8Hz,1H),2.40-1.96(m,2H),1.50(d,J=7.2Hz,3H),0.93(s,9H)LC-MS:t R =2.543 min (LCMS method 2), m / z=348.0 [M+H] + .

[0516] SFC:t R =1.87min (SFC method 1), de = 92.0%, [α] D 20 =-53.3 (c=0.21, MeOH).

[0517] Example 3a: N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0518]

[0519] and

[0520] Example 3b: N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0521]

[0522] Step 1: Preparation of N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0523]

[0524] Prepared from Vc, 84% yield.

[0525] Step 2: Separation of (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide and (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0526]

[0527] N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide (450 mg) was separated by chiral SFC.

[0528] Example 3a:

[0529] Yield: 168 mg

[0530] 1 H NMR(CDCl3400 MHz): δ7.31-7.29(m,1H),7.26-7.24(m,1H),7.16-7.14(m,1H),7.10-6.98(m,1H),6.49(t,J=76Hz,1H),6.14(brs,1H),5. 14-5.07(m,1H),3.66(d,J=10.4Hz,1H),3.17(s,1H),2.38-2.34(m,1H),2.28-2.18(m,1H),1.47-1.40(m,3H),0.98(s,9H).

[0531] LC-MS:t R =2.161 min (LCMS method 3), m / z=316.1 [M+H] + .

[0532] SFC:t R =2.15min (SFC method 2), de = 96.6%, [α] D 20 = -16 (c = 0.25, MeOH).

[0533] Example 3b:

[0534] Yield: 126 mg

[0535] 1 H NMR(CDCl3400 MHz): δ7.34-7.30(m,1H),7.16-7.12(m,1H),7.04-6.97(m,2H),6.31(t,J=76Hz,1H),6.14(brs,1H),5.12-5.0 6(m,1H),3.67-3.62(m,1H),3.29(s,1H),2.37-2.31(m,1H),2.26-2.19(m,1H),1.47-1.43(m,3H),0.98(s,9H).

[0536] LC-MS:t R =2.16 min (LCMS method 3), m / z=316.1 [M+H] + .

[0537] SFC:t R =2.42min (SFC method 2), de=100%, [α] D 20 =-57.6 (c=0.5, MeOH).

[0538] Example 4a: 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoro-methyl)phenyl)ethyl)pentanamide

[0539]

[0540] and

[0541] Example 4b: 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoro-methyl)phenyl)ethyl)pentanamide

[0542]

[0543] Step 1: Preparation of 3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

[0544]

[0545] Prepared from Vd (980 mg, 87% yield).

[0546] Step 2: Separation of (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide and (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide

[0547]

[0548] 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide was separated by chromatography on silica gel (petroleum ether:ethyl acetate=3:1).

[0549] Example 4a: Yield: 220 mg

[0550] 1H NMR(CDCl3400 MHz): δ7.56(s,1H),7.52-7.43(m,3H),6.22-6.21(m,1H),5.21-5.14(m,1H),3.68-3.64(m,1H), 3.14(d,J=3.2Hz,1H),2.40-2.36(m,1H),2.26-2.20(m,1H),1.50(d,J=7.2Hz,3H),0.91(s,9H).

[0551] LC-MS:t R =2.48 min (LCMS method 1), m / z=318.0 [M+H] + .

[0552] SFC:t R =1.56min (SFC method 3), de = 100%, [α] D 20 =-25.5(c=0.19g / 100mL,

[0553] MeOH).

[0554] Example 4b: Yield: 270 mg

[0555] 1 H NMR(CDCl3400 MHz): δ7.54-7.45(m,4H),6.25-6.23(m,1H),5.20-5.13(m,1H),3.69-3.65(m,1H),3.24( d,J=3.2Hz,1H),2.39-2.35(m,1H),2.27-2.21(m,1H),1.49(d,J=6.8Hz,3H),0.91(s,9H).

[0556] LC-MS:t R =2.48 min (LCMS method 1), m / z=318.0 [M+H] + .

[0557] SFC:t R =1.93min (SFC method 3), de = 100%, [α] D 20 =-61.4(c=0.57g / 100mL,

[0558] MeOH).

[0559] Example 8a: 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoro-methoxy)phenyl)propyl)pentanamide

[0560]

[0561] and

[0562] Example 8b: 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoro-methoxy)phenyl)propyl)pentanamide

[0563]

[0564] Step 1: Preparation of 3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

[0565]

[0566] Prepared from Ve, yield: 1.22 g

[0567] Step 2: Separation of (S)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide and (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide

[0568]

[0569] 3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide was separated by flash chromatography on silica gel (0-30% ethyl acetate in petroleum ether gradient as eluent).

[0570] Example 8a: Yield: 0.51 g

[0571] 1 H NMR(CDCl3400 MHz): δ7.40-7.34(m,1H),7.25-7.21(m,1H),7.14-7.10(m,2H),6.22-6.15(m,1H),4.92(q,J=7.6Hz,1H) ,3.71-3.65(m,1H),3.21(d,J=2.8Hz,1H),2.40-2.23(m,2H),1.82(q,J=7.2Hz,2H),0.94-0.90(m,12H).

[0572] LC-MS:t R =2.486 min (LCMS method 5), m / z=348.0 [M+H] + .

[0573] SFC:t R=1.775min. (SFC method 3), de = 98.7%, [α] D 20 =-80.0(c=0.31g / 100mL,

[0574] MeOH).

[0575] Example 8b: Yield: 0.59 g

[0576] 1 H NMR (CDCl3400 MHz): δ7.39-7.33(m,1H),7.25-7.20(m,1H),7.14-7.09(m,2H),6.24(br d,J=8.0Hz,1H),4.92(q,J=7.6Hz,1H),3.69-3.63(m,1H),3.15(d,J=3.2Hz,1H),2.40-2.25(m,2H),1.81(q,J=7.6Hz,2H),0.94-0.90(m,12H).

[0577] LC-MS:t R =2.506 min (LCMS method 5), m / z=348.0 [M+H] + .

[0578] SFC:t R =1.609min. (SFC method 3) de = 98.7%, [α] D 20 =-40.0(c=0.27g / 100mL,

[0579] MeOH).

[0580] Example 11a: 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

[0581]

[0582] and

[0583] Example 11b: 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)acrylamide

[0584]

[0585] Step 1: Preparation of 3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide

[0586]

[0587] Prepared from Vl. Yield: 300 mg, (60.7%).

[0588] Step 2: Separation of (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide and (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

[0589]

[0590] Separation was performed by chiral SFC.

[0591] Example 11a: Yield 90 mg

[0592] 1 H NMR (400MHz, CDCl3) δ7.42-7.35(m,1H),7.25(d,J=7.6Hz,1H),7.17-7.11(m,2H),5.93(d,J=7.2Hz,1H),5.19-5. 09(m,1H),4.01-3.93(m,1H),3.86(d,J=3.6Hz,1H),2.62-2.48(m,3H),2.46-2.13(m,4H),1.50(d,J=6.8Hz,3H).

[0593] LC-MS:t R =2.513 min (LCMS method 2), m / z=368.0 [M+H] + .

[0594] SFC:t R =2.169min. (SFC method 3), de = 97.4%, [α] D 20 =-42.0(c=2.0mg / mL,

[0595] MeOH).

[0596] Example 11b: Yield 90 mg

[0597] 1H NMR(400MHz, CDCl3)δ7.40-7.36(m,1H),7.25(d,J=7.6Hz,1H),7.16-7.11(m, 2H),5.99(d,J=7.2Hz,1H),5.18-5.09(m,1H),3.98(t,J=7.2Hz,1H),3.83(br s,1H),2.61-2.49(m,3H),2.45-2.12(m,4H),1.50(d,J=6.8Hz,3H).

[0598] LC-MS:t R =2.235 min (LCMS method 3), m / z=368.0 [M+H] + .

[0599] SFC:t R =2.013min. (SFC method 3), de = 99.6%, [α] D 20 =-17.0(c=2.0mg / mL,

[0600] MeOH).

[0601] Example 12a: 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)pentanamide

[0602]

[0603] and

[0604] Example 12b: 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)pentanamide

[0605]

[0606] Step 1: Preparation of 3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0607]

[0608] Prepared from Vf.

[0609] Yield: 0.88 g (87%)

[0610] Step 2: Separation of (S)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide and (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide

[0611] 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide was separated by chiral SFC.

[0612] Example 12a: Yield: 0.362 g

[0613] 1 H NMR (CDCl3, 400MHz) δ7.31(t,J=8.0Hz,1H),7.01(d,J=7.2Hz,1H),6.92(t,J=2.0Hz,1H),6.83(dd,J=8.0,2.4Hz,1H),6.08(br d,J=7.2Hz,1H),5.12(m,1H),4.36(q,J=8.0Hz,2H),3.80-3.74(m,1H),3.36(d,J=3.2Hz,1H ),2.37-2.27(m,2H),1.73-1.70(m,1H),1.49(d,J=6.8Hz,3H),0.94(dd,J=10.4,6.8Hz,6H);

[0614] LC-MS:t R =2.531 min (LCMS method 2), m / z=334.0 [M+H] + .

[0615] SFC:t R =2.864min (SFC method 3), de = 99.2%, [α] D 20 =-74.0 (c=0.20, MeOH).

[0616] Example 12b: Yield: 0.245 g

[0617] 1H NMR(CDCl3,400MHz)δ7.30(t,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.92(t,J=2.0Hz,1H),6.83(dd,J=8.0,2.4Hz,1H),6.14(br d,J=6.8Hz,1H),5.11(m,1H),4.36(q,J=16.4,8.0Hz,2H),3.79-3.75(m,1H),3.34(d,J=3.2Hz, 1H),2.38-2.25(m,2H),1.73-1.62(m,1H),1.49(d,J=7.2Hz,3H),0.94(dd,J=10.0,6.8Hz,6H);

[0618] LC-MS:t R =2.543 min (LCMS method 2), m / z=334.0 [M+H] + .

[0619] SFC:t R =3.071min (SFC method 3), de = 99.7%, [α] D 20 =-47.0 (c=0.20, MeOH).

[0620] Example 14a: 3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

[0621]

[0622] and

[0623] Example 14b: 3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide

[0624]

[0625] Step 1: Preparation of 3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide

[0626]

[0627] Prepared from Vg.

[0628] Yield: 0.58 g

[0629] Step 2: Separation of (S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide and (R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide

[0630]

[0631] 3-(1-(Difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propanamide was isolated by flash silica chromatography, eluent 0-41% ethyl acetate in petroleum ether gradient.

[0632] Example 14a: 0.2g

[0633] 1 H NMR (CDCl3400 MHz): δ7.40-7.34(m,1H),7.26-7.22(m,1H),7.16-7.11(m,2H),6.11(br d,J=7.2Hz,1H),5.88(t,J=58.4Hz,1H),5.12(quin,J=7.2Hz,1H),3.91(d,J=3.2Hz,1H),3.81 -3.75(m,1H),2.62-2.48(m,2H),1.49(d,J=7.2Hz,3H),0.87-0.76(m,2H),0.76-0.62(m,2H).

[0634] LC-MS:t R =2.448 min (LCMS method 1), m / z=368.0 [M+H] + .

[0635] SFC:t R =2.282min. (SFC method 3), de = 97.9%, [α] D 20 =-62.0(c=0.27g / 100mL,

[0636] MeOH).

[0637] Example 14b: Yield: 0.18 g

[0638] 1H NMR (CDCl3400 MHz): δ7.40-7.34(m,1H),7.24(d,J=7.6Hz,1H),7.17-7.10(m,2H),6.06(br d,J=7.6Hz,1H),5.84(t,J=58.4Hz,1H),5.12(quin,J=7.2Hz,1H),3.86-3.79(m,2H) ,2.55(d,J=5.6Hz,2H),1.50(d,J=6.8Hz,3H),0.83-0.75(m,2H),0.74-0.66(m,2H). LC-MS:t R =2.467 min (LCMS method 1), m / z = 368.0 [M+H] + .

[0639] SFC R =1.960min. (SFC method 3), de = 96.3%, [α] D 20 =-54.4(c=0.25g / 100mL,

[0640] MeOH).

[0641] Example 16a: 3-Hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

[0642]

[0643] and

[0644] Example 16b: 3-Hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide

[0645]

[0646] Step 1: Preparation of 3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide

[0647]

[0648] Prepared from Vh and used directly in the next step.

[0649] Step 2: Separation of (R)-3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide and (S)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide

[0650]

[0651] The crude product from Step 1 was separated by chiral SFC to yield the desired product.

[0652] Example 16a: Yield: 556 mg

[0653] 1 H NMR (DMSO-d 6 400 MHz): δ8.37(d,J=7.6Hz,1H),7.43-7.39(m,1H),7.31-7.29(m,1H),7.23(s,1H),7.18-7.16(m,1H),5.21(d,J= 5.2Hz,1H),4.96-4.88(m,1H),3.85-3.75(m,1H),2.35-2.25(m,2H),1.30(d,J=7.2Hz,3H),0.85-0.77(m,4H).

[0654] LC-MS:t R =2.626 min (LCMS method 2), m / z = 386.0 [M+H] + .

[0655] SFC:t R =2.010min. (SFC method 3), de = 99.9%, [α] D 20 =-56.0(c=0.01g / 100mL,

[0656] MeOH).

[0657] Example 16b: Yield: 692 mg

[0658] 1 H NMR (DMSO-d 6400 MHz): δ8.36(d,J=8.0Hz,1H),7.42-7.38(m,1H),7.32(d,J=8.0Hz,1H),7.25(s,1H),7.17-7.15(m,1H),5.20(d, J=5.2Hz,1H),4.95-4.91(m,1H),3.75-3.85(m,1H),2.25-2.35(m,2H),1.30(d,J=6.8Hz,3H),0.80-0.79(m,4H).

[0659] LC-MS:t R =2.649 min (LCMS method 2), m / z=386.0 [M+H] + .

[0660] SFC:t R =1.615min. (SFC method 3), de = 95.7%, [α] D 20 =-46.0(c=0.01g / 100mL,

[0661] MeOH).

[0662] Example 20a: 3-Hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0663]

[0664] and

[0665] Example 20b: 3-Hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0666]

[0667] Step 1: Preparation of 3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0668]

[0669] Prepared from Vi. Yield: 1.80 g (72%)

[0670] Step 2: Separation of (S)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide and (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0671]

[0672] 3-Hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide was separated by chromatography (SiO 2 , petroleum ether / ethyl acetate=0:1 to 1:1).

[0673] Example 20a: 250 mg

[0674] 1 H NMR(CDCl3,400MHz)δ7.37(t,J=8.0Hz,1H),7.27-7.21(m,1H),7.16-7.11(m,2H ),6.15(d,J=6.8Hz,1H),5.16(quin,J=6.8Hz,1H),3.83-3.74(m,1H),3.26(d,J =3.2Hz,1H),2.37(dd,J=15.2,3.2Hz,1H),2.31(dd,J=15.2,8.8Hz,1H),1.74-1 .68(m,1H),1.50(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H).

[0675] LC-MS:t R =2.629 min (LCMS method 2), m / z=320.0 [M+H] + .

[0676] SFC:t R =2.404min (SFC method 13), de = 98.6%, [α] D 20 =-80.0(c=0.475g / 100mL,

[0677] MeOH).

[0678] Example 20b: Yield 470 mg

[0679] 1H NMR(CDCl3,400MHz)δ7.37(t,J=7.6Hz,1H),7.28-7.23(m,1H),7.16(s,1H),7.14- 7.11(m,1H),6.19(d,J=6.8Hz,1H),5.15(quin,J=7.2Hz,1H),3.80-3.74(m,1H),3. 20(d,J=3.6Hz,1H),2.38(dd,J=14.8,2.4Hz,1H),2.30(dd,J=14.8,9.2Hz,1H),1.7 3-1.66(m,1H),1.49(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H),0.93(d,J=6.8Hz,3H).

[0680] LC-MS:t R =2.654 min (LCMS method 2), m / z=320.0 [M+H] + .

[0681] SFC:t R =1.979min (SFC method 13), de = 100%, [α] D 20 =-52.0(c=0.53g / 100mL,

[0682] MeOH).

[0683] Example 21a: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0684]

[0685] and

[0686] Example 21b: N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0687]

[0688] Step 1: Preparation of N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide

[0689]

[0690] Prepared from Vj. Yield = 350 mg, (96%)

[0691] Step 2: Separation of N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethyl-pentanamide and N-((R)-2-(difluoromethoxy)-1-(3-(trifluoro-methoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide

[0692]

[0693] N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide was separated by chiral SFC.

[0694] Example 21a: Yield: 98 mg

[0695] 1 H NMR(CDCl3400 MHz): δ7.39(t,J=8.0Hz,1H),7.29-7.26(m,1H),7.20(s,1H),7.16(d,J=8.0Hz,1H),6.65(d,J=7.6Hz,1H),6.22(t,J=74.0Hz,1H ),5.34-5.30(m,1H),4.18-4.09(m,2H),3.69(d,J=10.8Hz,1H),2.91(s,1H),2.45-2.43(m,1H),2.34-2.27(m,1H),0.93(s,9H).

[0696] LC-MS:t R =2.471 min (LCMS method 5), m / z=400.0 [M+H] + .

[0697] SFC:t R =1.935min (SFC method 14), de = 98.2%, [α] D 20 =-2.4(c = 1.0 g / 100 mL,

[0698] MeCN).

[0699] Example 21b: 160 mg

[0700] 1 H NMR (DMSO-d 6400 MHz): δ8.54(d,J=8.4Hz,1H),7.49(d,J=8.0Hz,1H),7.41(d,J=8.0Hz,1H),7.39(s,1H),7.28(d,J=8.0Hz,1H),6.67(t,J=76.0Hz, 1H),5.21-5.18(m,1H),4.67(s,1H),4.04-3.98(m,2H),3.53(d,J=10.2Hz,1H),2.31-2.26(m,1H),2.19-2.12(m,1H),0.82(s,9H).

[0701] LC-MS:t R =2.496 min (LCMS method 5), m / z=400.0 [M+H] + .

[0702] SFC:t R =2.461min (SFC method 14), de = 97.1%, [α] D 20 =-11.2(c=1.0g / 100mL,

[0703] MeCN).

[0704] Example 22a: 3-Hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide

[0705]

[0706] and

[0707] Example 22b: 3-Hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoro-methoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide

[0708]

[0709] Step 1: Preparation of 3-hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide

[0710]

[0711] Prepared from Vk. Yield: 84 mg, (60%).

[0712] Step 2: Separation of (S)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide and (R)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide

[0713]

[0714] 3-Hydroxy-N-[(1R)-2-methoxy-1-[3-(trifluoromethoxy)phenyl]ethyl]-4,4-dimethyl-pentanamide was separated by chiral SFC.

[0715] Example 22a: Yield: 40 mg

[0716] 1 H NMR(CDCl3400 MHz): δ7.35(t,J=8.0Hz,1H),7.27-7.26(m,1H),7.20(s,1H),7.12(d,J=7.6Hz,1H),6.66(d,J=7.2Hz,1H), 5.18-5.14(m,1H),3.70-3.60(m,3H),3.36(s,3H),2.44(d,J=14.8Hz,1H),2.25-2.33(m,1H),0.93(s,9H).

[0717] LC-MS:t R =2.410 min (LCMS method 3), m / z=364.0 [M+H] + .

[0718] SFC:t R =1.889min (SFC method 16), de = 100%, [α] D 20 =-0.4(c=1.0g / 100mL,

[0719] MeCN).

[0720] Example 22b: Yield: 38 mg

[0721] 1H NMR(CDCl3400 MHz): δ7.36(t,J=8.0Hz,1H),7.27-7.25(m,1H),7.18(s,1H),7.12(d,J=7.6Hz,1H),6.56(d,J=7.2Hz,1H),5.20- 5.15(m,1H),3.69-3.60(m,3H),3.40(s,1H),3.36(s,3H),2.44(d,J=14.8Hz,1H),2.25-2.33(m,1H),0.93(s,9H).

[0722] LC-MS:t R =2.523 min (LCMS method 1), m / z=364.0 [M+H] + .

[0723] SFC:t R =2.106min (SFC method 16), de = 98.2%, [α] D 20 =-2.7(c = 1.0 g / 100 mL,

[0724] MeCN).

[0725] Example 5: (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide

[0726]

[0727] Step 1:

[0728]

[0729] A mixture of (1S)-1-[3-(trifluoromethoxy)phenyl]ethaneamine hydrochloride (IIa) (291 mg, 1.20 mmol), 2-(3,3-difluoro-1-hydroxy-cyclobutyl)acetic acid (IIIb) (0.22 g, 1.32 mmol), HATU (549 mg, 1.44 mmol) and DIPEA (467 mg, 3.6 mmol) in DCM (15 mL) was stirred at 20°C for 16 hours. The mixture was washed with water (40 mL×2) and extracted with DCM (40 mL). The organic layer was washed with brine (10 mL×2), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (eluent was 0-35% ethyl acetate / petroleum ether gradient) to give the product (0.2 g, 47% yield).

[0730] 1 H NMR (CDCl3, 400MHz): δ7.41-7.37(m,1H),7.26-7.23(m,1H),7.18-7.13(m,2H),5.93(br d,J=6.8Hz,1H),5.15(quin,J=7.2Hz,1H),5.01(br s, 1H), 2.84-2.42 (m, 6H), 1.53 (d, J = 6.8Hz, 3H).

[0731] LC-MS:t R =2.53 min (LCMS method 2), m / z = 354.0 [M+H] + .

[0732] HPLC:t R =13.3min. (Chiral HPLC method 1), de = 100%. [α] 20 D =-51.1(c=0.23g / 100

[0733] mL, MeOH).

[0734] The following examples were prepared by a similar method to Example 5 using relevant starting materials:

[0735] Example 6: (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide

[0736]

[0737] Step 1: Preparation of (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide

[0738]

[0739] Prepared from lib (5.0 g, 22.81 mmol) and IIIa (3.3 g, 25.09 mmol).

[0740] Yield: 5.2 g, (45%).

[0741] 1 H NMR (CDCl 3,400MHz): δ7.29(t,J=8.0Hz,1H),6.99(d,J=7.6Hz,1H),6.90(s,1H),6.83(dd,J=8.4Hz,J=2.4Hz,1H),6.25(d,J=6.8Hz,1H),5.14 -5.07(m,1H),4.35(q,J=8.0Hz,2H),4.14(s,2H),2.53(s,2H),2.15-1.99(m,4H),1.76(m,1H),1.55(m,1H),1.48(d,J=6.8Hz,3H).

[0742] LC-MS:t R =2.49 min (LCMS method 2), m / z=332.0 [M+H] + .

[0743] SFC:t R =2.67min (SFC method 3), de = 96.9%, [α] D 20 =-69.0 (c=0.1, MeOH).

[0744] Example 7a: 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(trifluoromethyl)pentanamide

[0745]

[0746] and

[0747] Example 7b: 3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoro-ethoxy)phenyl)ethyl)-3-(trifluoromethyl)pentanamide

[0748]

[0749] Step 1: Preparation of 3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)-3-(trifluoromethyl)pentanamide

[0750]

[0751] Prepared from IIb and IIIc. Yield: 0.65 g, (crude). The crude product was used directly without purification.

[0752] Step 2: Separation of (3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide and (3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide

[0753]

[0754] Separation was achieved by flash silica chromatography, eluent: 0-15% ethyl acetate in petroleum ether gradient.

[0755] Example 7a: Yield: 0.29 g

[0756] 1 H NMR (CDCl3, 400MHz): δ7.32(t,J=8.0Hz,1H),7.00(d,J=7.6Hz,1H),6.91(d,J =2.0Hz, 1H), 6.85 (dd, J = 8.0, 2.4Hz, 1H), 6.32 (s, 1H), 5.99 (d, J = 7.6Hz, 1H). 5.15-5.07(m,1H),4.36(q,J=8.0Hz,2H),2.45(d,J=15.2Hz,1H),2.34(d,J=15.2Hz,1H) ,2.13-2.06(m,1H),1.50(d,J=6.8Hz,3H),1.03(d,J=6.8Hz,3H),0.97(d,J=6.8Hz,3H).

[0757] LC-MS:t R =2.883 min (LCMS method 4), m / z=402.0 [M+H] + .

[0758] SFC:t R =2.454min. (SFC method 6), de = 100%, [α] D 20 =-43.5(c = 0.0058 g / mL,

[0759] MeOH).

[0760] Example 7b: Yield: 0.23 g

[0761] 1H NMR (CDCl3, 400MHz): δ7.32 (t, J = 8.0Hz, 1H), 7.00 (d, J = 7.6Hz, 1H), 6.91- 6.84(m,2H),6.33(s,1H),5.90(d,J=7.6Hz,1H),5.19-5.10(m,1H),4.35(q ,J=8.4Hz,2H),2.51(d,J=14.8Hz,1H),2.35(d,J=14.8Hz,1H),2.15-2.06( m, 1H), 1.52 (d, J = 7.2Hz, 3H), 1.05 (d, J = 6.8Hz, 3H), 0.98 (d, J = 6.8Hz, 3H).

[0762] LC-MS:t R =2.834 min (LCMS method 6), m / z=402.0 [M+H] + .

[0763] SFC:t R =2.262min. (SFC method 7) de = 99.8%, [α] D 20 =-37.1(c = 0.0034 g / mL,

[0764] MeOH).

[0765] Example 9: 4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoro-methoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide

[0766]

[0767] Step 1:

[0768]

[0769] Prepared from IIa and 4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoic acid. Yield: 650 mg, (63%)

[0770] 1 H NMR (DMSO-d 6 400 MHz): δ9.14(d,J=7.2Hz,1H),8.45(s,1H),7.44(t,J=8.0Hz,1H),7.32(d,J=7.6Hz,1H),7 .24(s,1H),7.21(d,J=8.4Hz,1H),5.01-4.93(m,1H),2.89(s,2H),1.34(d,J=6.8Hz,3H).

[0771] LC-MS:t R =2.850 min (LCMS method 4), m / z=413.9 [M+H] + .

[0772] Chiral HPLC:t R =15.61min,(HPLC method 2),de=98.4%,[α] D 20 =-41.1 (c=0.185g / 100mL, MeOH).

[0773] Example 10a: 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0774]

[0775] and

[0776] Example 10b: 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0777]

[0778] Step 1: Preparation of 4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0779]

[0780] Prepared from IIa and IIId. Yield: 1 g (53%)

[0781] Step 2: Separation of (R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide and (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0782]

[0783] The diastereomers were separated by chiral SFC.

[0784] Example 10a: Yield = 0.268 g

[0785] 1H NMR (CDCl3400 MHz): δ7.42-7.36(m,1H),7.24(d,J=7.6Hz,1H),7.17-7.12(m,2H),6.28-5.97(m,2H),5.93(br d,J=6.0Hz,1H),5.16(quin,J=6.8Hz,1H),2.69(d,J=15.2Hz,1H),2.37(d,J=15.2Hz,1H),1.53(d,J=6.8Hz,3H),1.40(s,3H).

[0786] LC-MS:t R =2.759 min (LCMS method 2), m / z=392.0 [M+H] + .

[0787] SFC:t R =1.550min. (SFC method 15), de = 100%, [α] D 20 =-50.5(c=0.19g / 100mL,

[0788] MeOH).

[0789] Example 10b: Yield = 0.148 g

[0790] 1 H NMR (CDCl3400 MHz): δ7.44-7.36(m,1H),7.26(d,J=8.0Hz,1H),7.19-7.12(m,2H),6.33-6.01(m,2H),5.91(br d,J=6.8Hz,1H),5.16(quin,J=6.8Hz,1H),2.70(d,J=15.2Hz,1H),2.35(d,J=15.2Hz,1H),1.52(d,J=6.8Hz,3H),1.35(s,3H).

[0791] LC-MS:t R =2.782 min (LCMS method 2), m / z = 392.0 [M+H] + .

[0792] SFC:t R =1.329min. (SFC method 15), de = 100%, [α] D 20 =-48.6(c = 0.21 g / 100 mL,

[0793] MeOH).

[0794] Example 13a: 5,5,5-Trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxyphenyl)ethyl)pentanamide

[0795]

[0796] and

[0797] Example 13b: 5,5,5-Trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0798]

[0799] Step 1: Preparation of 5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0800]

[0801] Prepared from IIa and IIIe. Yield: 1 g, (43%)

[0802] Step 2: Separation of (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide and (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide

[0803] Separation was carried out by flash chromatography on silica gel, eluent 0-31% ethyl acetate in petroleum ether gradient.

[0804] Example 13a: Yield = 0.421 g

[0805] 1 H NMR (CDCl3400 MHz): δ7.42-7.36(m,1H),7.24(d,J=8.0Hz,1H),7.17-7.12(m,2H),5.98(br d,J=6.8Hz,1H),5.15(quin,J=6.8Hz,1H),5.00(s,1H),2.54-2.44(m,2H),2.44-2.31(m,2H),1.51(d,J=7.2Hz,3H),1.38(s,3H).

[0806] LC-MS:t R =2.666 min (LCMS method 2), m / z=374.0 [M+H] + .

[0807] SFC:t R =1.277min. (SFC method 8), de = 100%, [α] D 20 =-51.3(c=0.23g / 100mL,

[0808] MeOH).

[0809] Example 13b: 0.261g

[0810] 1 H NMR (CDCl3400 MHz): δ7.42-7.36(m,1H),7.25(d,J=8.0Hz,1H),7.17-7.12(m,2H),5.96(br d,J=7.2Hz,1H),5.16(quin,J=6.8Hz,1H),4.98(s,1H),2.57-2.36(m,4H),1.52(d,J=6.8Hz,3H),1.36(s,3H).

[0811] LC-MS:t R =2.674 min (LCMS method 2), m / z=374.0 [M+H] + .

[0812] SFC:t R =1.197min. (SFC method 8), de = 93.4%, [α] D 20 =-43.2(c=0.19g / 100mL,

[0813] MeOH).

[0814] Example 15a: 3-(1-Fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

[0815]

[0816] and

[0817] Example 15b: 3-(1-Fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide

[0818]

[0819] Step 1: Preparation of 3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butyramide

[0820]

[0821] Prepared from IIa and IIIf. The crude product was used directly in the next step

[0822] Step 2: Separation of (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide and (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide

[0823]

[0824] Separation was carried out by flash chromatography on silica gel, eluent 0-30% ethyl acetate in petroleum ether gradient.

[0825] Example 15a: Yield = 1.05 g

[0826] 1 H NMR (CDCl3400 MHz): δ7.37(t,J=8.0Hz,1H),7.27-7.24(m,1H),7.17-7.12(m,2H),6.11(br s,1H),5.18-5.10(m,1H),5.02(s,1H),2.61(dd,J=14.4,2.4Hz,1H),2.46(dd,J=14.4 ,1.6Hz,1H),1.51(d,J=7.2Hz,3H),1.33(s,3H),0.78-0.68(m,3H),0.52-0.50(m,1H).

[0827] LC-MS:t R =2.359 min (LCMS method 3), m / z=350.0 [M+H] + .

[0828] SFC:t R =2.027min. (SFC method 9), de = 93.9%, [α] D 20 =-48.3(c=0.24g / 100mL,

[0829] MeOH).

[0830] Example 15b: Yield: 0.80 g

[0831] 1H NMR(CDCl3400 MHz): δ7.38(t,J=8.0Hz,1H),7.27-7.23(m,1H),7.15-7.12(m,2H),6.06(d,J=7.2Hz,1H),5.19-5.11(m,1H),4.99(s,1H),2.62(dd,J=1 4.4, 2.0Hz, 1H), 2.47 (d, J = 1.6Hz, 1H), 2.43 (d, J = 1.6Hz, 1H), 1.51 (d, J = 7.2Hz, 3H), 1.33 (s, 3H), 0.97-0.87 (m, 1H), 0.85-0.81 (m, 3H).

[0832] LC-MS:t R =2.655 min (LCMS method 2), m / z=350.0 [M+H] + .

[0833] SFC:t R =1.937min. (SFC method 9), de = 98.7%, [α] D 20 =-64.4(c=0.27g / 100mL,

[0834] MeOH).

[0835] Example 17: (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide

[0836]

[0837] Prepared from IIa and 2-(1-hydroxycyclopentyl)acetic acid. Yield: 30 mg, (12.8%).

[0838] 1 H NMR (400MHz, CDCl3) δ7.37(t,J=8.0Hz,1H),7.26-7.25(m,1H),7.19(s,1H),7.16-7.11(m,1H),6.66(br d,J=7.2Hz,1H),5.21-5.15(m,1H),3.82(s,1H),3.70-3.60(m,2H),3.37(s,3H),2.59-2.49(m,2H),1.86-1.81(m,4H),1.59-1.56(m,4H).

[0839] LC-MS:t R =2.481 min (LCMS method 2), m / z=362.0 [M+H]+ ,

[0840] SFC:t R =2.33min. (SFC method 10), de = 100%, [α] D 20 =-44.0, (c = 1 mg / mL, MeOH).

[0841] Example 18a: 3-Cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

[0842]

[0843] and

[0844] Example 18b: 3-Cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

[0845]

[0846] Step 1: Preparation of 3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyramide

[0847]

[0848] Prepared from IIb and IIIg. Yield: 3.7 g, (30.9%)

[0849] Step 2: Separation of (R)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide and (S)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

[0850]

[0851] Separation was performed by chiral SFC.

[0852] Example 18a: Yield: 1.59 g

[0853] 1H NMR(400MHz, DMSO-d6)δ8.32(d,J=8.0Hz,1H),7.28(t,J=8.0Hz,1H),7.04-6.98(m,2H),6.93-6.90(m,1H),4.97-4.91(m,1H),4 .73(q,J=8.8Hz,2H),4.61(s,1H),2.37-2.25(m,2H),1.34(d,J=7.2Hz,3H),1.10(s,3H),0.87-0.84(m,1H),0.30-0.09(m,4H).

[0854] LC-MS:t R =2.629 min (LCMS method 2), m / z=328.0 [M+H-18] + .

[0855] SFC:t R =3.154min (SFC method 11), de = 99.7%, [α] D 20 =-62.0(c=2mg / mL,

[0856] MeOH).

[0857] Example 18b: Yield: 1.44 g

[0858] 1 H NMR(400MHz,DMSO-d6)δ8.19(br d,J=8.0Hz,1H),7.12(t,J=8.0Hz,1H),6.87-6.79(m,2H),6.77-6.74(m,1H),4.81-4.73(m,1H),4.57(q,J=8.8H z,2H),4.42(s,1H),2.19-2.08(m,2H),1.17(d,J=6.8Hz,3H),0.94(s,3H),0.73-0.64(m,1H),0.19-0.00(m,4H).

[0859] LC-MS:t R =2.643 min (LCMS method 2), m / z=328.0 [M+H-18] + .

[0860] SFC:t R =2.570min.(SFC method 11),de=97.0%,[α] D 20 =-58.0(c=2mg / mL,

[0861] MeOH).

[0862] Example 19a: 4,4,4-Trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

[0863]

[0864] and

[0865] Example 19b: 4,4,4-Trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

[0866]

[0867] Step 1: Preparation of 4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butyramide

[0868]

[0869] Prepared from IIb and 4,4,4-trifluoro-3-hydroxy-3-methyl-butyric acid. Yield: 6.67 g, (73%)

[0870] Step 2: Separation of (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy))ethyl)butanamide and (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide

[0871]

[0872] Example 19a: 2.3g

[0873] 1 H NMR(CDCl3,400MHz)δ7.32(t,J=8.0Hz,1H),6.99(d,J=7.8Hz,1H),6.92-6.88(m,1H),6.88-6.83(m,1H),5.99(br d,J=6.8Hz,1H),5.84(s,1H),5.12(quin,J=7.2Hz,1H),4.35(q,J=8.0Hz,2H ), 2.51 (dd, J=53.2, 15.2Hz, 2H), 1.51 (d, J=7.2Hz, 3H), 1.41 (s, 3H); LC-MS: t R=2.732 min (LCMS method 2), m / z=374.0 [M+H] + .

[0874] SFC:t R =1.721min (SFC method 12), de = 99.6%, [α] D 20 =-51.0 (c=0.20, MeOH).

[0875] Example 19b: 0.86g

[0876] 1 H NMR(CDCl3,400MHz)δ7.33(t,J=8.0Hz,1H),7.00(d,J=7.2Hz,1H),6.93-6.90(m,1H),6.88-6.83(m,1H),5.98-5.91(m,1H),5. 91(s,1H),5.12(quin,J=7.2Hz,1H),4.36(q,J=8.0Hz,2H),2.50(dd,J=57.6,14.8Hz,2H),1.51(d,J=6.8Hz,3H),1.39(s,3H);

[0877] LC-MS:t R =2.737 min (LCMS method 2), m / z=374.0 [M+H] + .

[0878] SFC:t R =1.904min (SFC method 12), de = 100%, [α] D 20 =-57.1 (c=0.21, MeOH).

[0879] Example: Epilepsy in Kv7

[0880] Genetic loss-of-function mutations in Kv7 channels have been described as causing seizures and convulsions in KCNQ epileptic encephalopathy (KCNQEE) and benign familial neonatal convulsions (BFNC) (Schroeder BC et al. Nature. 1998 Dec 17;396(6712):687-90; Kato M et al. Epilepsy. 2013 Jul;54(7):1282-7).

[0881] Retigabine has been approved for the treatment of partial seizures, and there are also reports that retigabine affects seizures in epilepsy syndromes such as Lennox-Gastaut syndrome and Dravet syndrome. Retigabine affects several pharmacological targets and has been described as a Kv7 activator. A link between Kv7 activation threshold and clinically effective exposure has been described (Gunthorpe MJ et al., Epilepsya. [Epilepsia] 2012 March; 53(3): 412-24).

[0882] Kv7 activators have shown anticonvulsant properties in various rodent seizure models for both partial and generalized seizures (Roeloffs R et al. J Pharmacol Exp Ther. 2008 Sep;326(3):818-28). This also includes animal models for specific epilepsy syndromes such as Dravet syndrome (Reid CA et al. Brain. 2014 Jun;137(Pt 6):1701-15. doi:10.1093 / brain / awu077. Epub 2014 Apr 17) and KCNQ epileptic encephalopathy (KCNQEE) (Ihara Y et al. PLoS One. 2016 Feb 24;11(2).

[0883] The anticonvulsant properties of (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide were tested in mice and rats using the Maximum Electric Seizure Threshold Test (MEST) (Giardina and Gasior, Curr Protocols in Pharm, 5.22.1-5.22.37, June 2009), in which corneal electrodes were used to induce tonic convulsions. In mice, a significant dose-dependent increase in the current required to induce electroconvulsions (i.e., seizure threshold) was produced. In rats, the effects of pretreatment with (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, both acutely and repeatedly (once daily for 15 days), significantly increased the seizure threshold.

[0884] Data generated from treatment groups of n=12-16 were used to calculate CC50 sem values ​​according to the following method: Kimball et al. Radiat Res. 1957; 7(1): 1-12.

[0885] Significant differences between drug-treated animals and controls were assessed according to: Litchfield and Wilcoxon, Pharmacol Exp Ther. 1949; 96(1): 99-113.

Claims

1. Compounds having formula I in R1 is selected from the group consisting of: C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R2 is H, C1-C6 alkyl or CF3; or R1 and R2 combine to form a C3-C5 cycloalkyl group optionally substituted with 1 or 2 F, CHF2 or CF3; R3 is C1-C3 alkyl or CH2O-C 1-3 Alkyl, the C1-C3 alkyl or CH2O-C 1-3 The alkyl group may be optionally substituted with 1 or 2 F groups; R4 is selected from the group consisting of OCF3, OCH2CF3 or OCHF2, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating epilepsy, epileptic syndrome, epileptic symptoms, treatment-resistant or refractory epilepsy or epileptic seizures.

2. Compounds having formula I in R1 is selected from the group consisting of: C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R2 is H, C1-C6 alkyl or CF3; or R1 and R2 combine to form a C3-C5 cycloalkyl group optionally substituted with 1 or 2 F, CHF2 or CF3; R3 is C1-C3 alkyl or CH2O-C 1-3 Alkyl, the C1-C3 alkyl or CH2O-C 1-3 The alkyl group may be optionally substituted with 1 or 2 F groups; R4 is selected from the group consisting of OCF3, OCH2CF3 or OCHF2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of focal (partial) epilepsy with simple partial seizures, focal (partial) epilepsy with complex partial seizures, idiopathic generalized epilepsy, grand mal seizures, status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and benign familial neonatal seizures and other epilepsy syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with sustained spikes during slow wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and early myoclonic encephalopathy Ohtahara syndrome), or epileptic seizures associated with stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancer, autism spectrum disorder or metabolic disorders (such as hyponatremia).

3. Compounds having formula I in R1 is selected from the group consisting of: C1-C6 alkyl, CF3, CH2CF3, CF2CHF2, C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl may be substituted with 1 or 2 F, CHF2 or CF3, and R2 is H, C1-C6 alkyl or CF3; or R1 and R2 combine to form a C3-C5 cycloalkyl group optionally substituted with 1 or 2 F, CHF2 or CF3; R3 is C1-C3 alkyl or CH2O-C 1-3 Alkyl, the C1-C3 alkyl or CH2O-C 1-3 The alkyl group may be optionally substituted with 1 or 2 F groups; R4 is selected from the group consisting of OCF3, OCH2CF3 or OCHF2, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating epilepsy symptoms as part of a neurodegenerative disorder such as Alzheimer's disease, Lewy body disease, juvenile Huntington's disease, frontotemporal lobar degeneration.

4. The method according to any one of claims 1 to 3, wherein R4 is OCF3 or OCHF2.

5. The use according to any one of the preceding claims, wherein R2 is H or CH3.

6. The use according to any one of the preceding claims, wherein R3 is CH2O-C 1-3 alkyl.

7. Use according to any one of the preceding claims, wherein R1 is C3-C4 cycloalkyl optionally substituted by 1 or 2 F, CHF2 or CF3.

8. Use according to any one of the preceding claims, wherein R1 is tert-butyl and R2 is H and R4 is OCF3, OCH2CF3, OCHF2 or CF3.

9. The use according to any one of the preceding claims, wherein R1 and R2 combine to form a cyclobutyl group optionally substituted with 1 or 2 Fs, and R4 is OCF3, OCH2CF3, OCHF2 or CF3.

10. The use according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of: (S)-3-Hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]pentanamide, (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, (S)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide, (R)-N-((S)-1-(3-(difluoromethoxy)phenyl)ethyl)-3-hydroxy-4,4-dimethylpentanamide, (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)pentanamide, (S)-3-Hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, (R)-3-hydroxy-4,4-dimethyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)propyl)pentanamide, (S)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, (R)-3-(3,3-difluorocyclobutyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, (S)-3-Hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)pentanamide, (S)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)propionamide, (R)-3-(1-(difluoromethyl)cyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propionamide, (R)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propanamide, (S)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(1-(trifluoromethyl)cyclopropyl)propionamide, (S)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-3-hydroxy-4-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(R)-hydroxy-4,4-dimethylpentanamide, N-((R)-2-(difluoromethoxy)-1-(3-(trifluoromethoxy)phenyl)ethyl)-3-(S)-hydroxy-4,4-dimethylpentanamide, (S)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, (R)-3-hydroxy-N-((R)-2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)-4,4-dimethylpentanamide, (S)-2-(3,3-difluoro-1-hydroxycyclobutyl)-N-(1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, (S)-2-(1-hydroxycyclobutyl)-N-(1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)acetamide, (3R)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide, (3S)-3-hydroxy-4-methyl-N-[(1S)-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethyl]-3-(trifluoromethyl)pentanamide, 4,4,4-Trifluoro-3-hydroxy-N-[(1S)-1-[3-(trifluoromethoxy)phenyl]ethyl]-3-(trifluoromethyl)butanamide, (R)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (S)-4,4,5,5-tetrafluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (S)-5,5,5-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)pentanamide, (R)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)butanamide, (S)-3-(1-fluorocyclopropyl)-3-hydroxy-N-((S)-1-(3-(trifluoro-methoxy)phenyl)ethyl)butanamide, (R)-2-(1-hydroxycyclopentyl)-N-(2-methoxy-1-(3-(trifluoromethoxy)phenyl)ethyl)acetamide, (R)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide, (S)-3-cyclopropyl-3-hydroxy-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide, (R)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide, and (S)-4,4,4-trifluoro-3-hydroxy-3-methyl-N-((S)-1-(3-(2,2,2-trifluoroethoxy)phenyl)ethyl)butanamide, or a pharmaceutically acceptable salt of any of these compounds.

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