Activating compounds of potassium channels KV7.2 / KV7.3

Abstract

The present invention relates to compounds of formula (I) as defined in the specification capable of promoting the opening of Kv7.2 / Kv7.3 potassium channels, a pharmaceutical composition comprising them, and their use as a drug, particularly in the treatment of disorders of the central nervous system (CNS), such as, for example, epilepsy and neurodegenerative disorders, and of the peripheral nervous system (PNS), such as, for example, chronic and neuropathic pain.

Description

[0001] “Activating compounds of potassium channels KV7.2 / KV7.3”

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compounds capable of promoting the opening of Kv7.2 / 7.3 potassium channels and their use as a drug, particularly in the treatment of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and of the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.

[0004] STATE OF THE ART

[0005] Voltage-gated potassium (Kv) channels conduct potassium (K+) ions across cell membranes in response to changes in membrane potential and can therefore regulate cellular excitability by modulating (increasing or decreasing) the cell's electrical activity.

[0006] Functional Kv channels exist as multimeric structures formed by the association of four alpha and four beta subunits. Alpha subunits comprise six transmembrane domains, a poreforming loop, and a voltage sensor and are arranged symmetrically around a central pore. Beta or auxiliary subunits interact with alpha subunits and can modify the properties of the channel complex to include, but not limited to, alterations in electrophysiological or biophysical properties of the channel, levels, or expression patterns.

[0007] Nine families of Kv channel alpha subunits have been identified, referred to as Kv1 -Kv9. The Kv7 channel family consists of at least five members including Kv7.1 , Kv7.2, Kv7.3, Kv7.4, and Kv7.5. Alternatively, the members of this family are referred to by the gene names KCNQ1 , KCNQ2, KCNQ3, KCNQ4, and KCNQ5, respectively (Dalby-Brown et al., Current Topics in Medicinal Chemistry, 2006, 6(10), 999-1023).

[0008] As mentioned above, neuronal Kv7 potassium channels play a role in the control of neuronal excitation. Kv7 channels, particularly the Kv7.2 / Kv7.3 heterotetramers, underlie the M- current (Wang et al Science. 1998 Dec 4;282(5395): 1890-1893).

[0009] The M current has a characteristic time and voltage dependence that results in the stabilization of the membrane potential in response to multiple excitatory stimuli. Thus, M current is involved in the control of neuronal excitability (Delmas & Brown, Nature, 2005, 6, 850-862).

[0010] The M current is a noninactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in the control of membrane excitability being the only sustained current in the range of action potential initiation (Marrion, Annual Review Physiology 1997, 59, 483-504).

[0011] The five members of this family of ion channels 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 dominant in the nervous system that includes the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion neurons. Kv7.4 is a subtype selectively expressed in the auditory pathway including hair cells of the inner ear. In addition to neurons, Kv7.4 and Kv7.5 are also expressed in various smooth muscle cells (Greene & Hoshi, Cellular and Molecular Life Sciences, 2017, 74(3), 495-508).

[0012] The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal seizures (Rogawski, Trends in Neuroscience 2000, 23, 393-398). Proteins encoded by the KCNQ2 and KCNQ3 genes are localized in pyramidal neurons of the human cortex and hippocampus, regions of the brain associated with seizure generation and propagation (Cooper et al., Proceedings National Academy of Science U S A, 2000, 97(9), 4914-4919).

[0013] In addition, mRNAs for Kv7.2, Kv7.3, and Kv7.5 are expressed in astrocytes and glial cells. Thus, Kv7.2, Kv7.3, and Kv7.5 channels may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel activators (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 chorea. mRNAs for Kv7.2 and Kv7. 3 are found in regions of the brain associated with anxiety and emotional behaviors such as depression and bipolar disorder, for example the hippocampus, ventral tegmental area, and amygdala (Saganich, et al. , Journal of Neuroscience 2001 , 21 (13), 4609-4624; Friedman et al., Nat Commun., 2016, 7, 11671 ).

[0014] Kv7.2 / Kv7.3 channels have also been reported to be upregulated in models of neuropathic pain (Wickenden, et al, Society for Neuroscience Abstracts 2002, 454.7), and modulators of potassium channels have been hypothesized to be active in both neuropathic pain and epilepsy (Schroder et al., Neuropharmacology 2001 , 40(7), 888-898). In addition to a role in neuropathic pain, mRNA expression for Kv7.2-5 in the trigeminal and dorsal root ganglia and in the trigeminal caudal nucleus implies that activators of these channels may also influence sensory processing of migraine pain (Goldstein, et al. Society for Neuroscience Abstracts 2003, 53.8).

[0015] Retigabine and flupirtine are known Kv7.2 / Kv7.3 potassium channel activating compounds that have been used in the treatment of epilepsy, migraine, neuropathic pain, acute pain, and tinnitus. Retigabine has been withdrawn from the market because of its adverse side effects, particularly urinary retention and changes in retinal and skin pigmentation. Flupirtine should be used by individuals who do not respond to other analgesic treatments and for no longer than two weeks because of its hepatic toxicity. SUMMARY OF THE INVENTION

[0016] The Applicant has addressed the problem of providing novel therapies for the treatment of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.

[0017] The Applicant focused its attention on potassium channel activating compounds Kv7.2 / 7.3, initiating research work that could provide alternative compounds to retigabine and flupirtine.

[0018] After extensive experimentation, the Applicant identified a number of novel compounds capable of acting as drugs, particularly for the treatment of disorders that are modulated by Kv7.2 / 7.3 potassium channels.

[0019] In particular, as demonstrated in the examples in the following experimental portion, the Applicant has identified a number of compounds capable of acting as activators of Kv7.2 / 7.3 potassium channels.

[0020] Based on the information known to the man skilled in the art, Applicant believes that these compounds may be effective in the treatment of a variety of disorders of the central nervous system (CNS), e.g., epilepsy and neurodegenerative disorders, and the peripheral nervous system (PNS), e.g., chronic and neuropathic pain.

[0021] Thus, in a first aspect, the present invention relates to a Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the following general formula (I) wherein

[0022] R1 is an aromatic ring having 6 members and comprising one or two nitrogen atoms, said aromatic ring being substituted by one or more substituent selected from

[0023] (i) a halogen atom,

[0024] (ii) a linear or branched C1-C6 alkyl chain, optionally substituted with one or more halogen atoms, and

[0025] (iii) a linear or branched C1 -C6 alkoxy chain, optionally substituted with one or more halogen atoms, or with C3-C6 cycloalkyl, or with 3-6 members heterocycloalkyl, R2 is a linear or branched C2-C4 alkyl or a C3-C6 cycloalkyl, said alkyl and cycloalkyl being optionally substituted with OH, CF3, one or more halogen atoms, or C1-C3 alkoxy,

[0026] R3 is an aliphatic ring, a bridged or condensed bicyclic ring, a spiro residue, or an alkyl group, wherein:

[0027] (i) said aliphatic ring has three to six members, optionally containing one or more heteroatoms selected from the group consisting of N, 0 and S, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, and C1 -C3 alkyl, or

[0028] (ii) said bridged or condensed bicyclic ring has five to twelve members, optionally containing one or more heteroatoms selected from the group consisting of N, 0 and S, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl, or

[0029] (iii) said spiro residue comprises two aliphatic rings having five to eight members, optionally containing one or more heteroatoms selected from the group consisting of N, 0 and S, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl, or

[0030] (iv) said alkyl group is a linear or branched C1 -C6 alkyl group.

[0031] In a second aspect, the present invention relates to a Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention for use as a drug.

[0032] In a third aspect, the present invention relates to a Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention for use in the treatment of disorders that are modulated by Kv7.2 / Kv7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0033] In a fourth aspect, the present invention relates to a pharmaceutical composition comprising (i) a Kv7.2 / 7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, and (ii) at least one pharmaceutically acceptable excipient.

[0034] Advantageously, the pharmaceutical composition according to the fourth aspect of the present invention can be used in the treatment of disorders that are modulated by Kv7.2 / 7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0035] In a fifth aspect, the present invention relates to a method for treating disorders that are modulated by Kv7.2 / 7.3 potassium channels in a subject in need thereof comprising administering a therapeutically effective amount of a Kv7.2 / 7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention.

[0036] For the purposes of this description and the claims that follow, the phrase "pharmaceutically acceptable" is intended to define, without any particular limitation, any material suitable for the preparation of a pharmaceutical composition to be administered to a living being.

[0037] For the purposes of this description and the claims that follow, the phrase "therapeutically effective amount" means an amount of compound sufficient to alleviate, arrest, partially arrest, remove or delay the clinical manifestations of a certain disease and its complications in a therapeutic treatment comprising the administration of said compound.

[0038] For the purposes of this description and the claims that follow, the term "treatment" or "treating" means the management and care of a patient for the purpose of alleviating, arresting, partially arresting, removing or delaying the progress of the clinical manifestation of disease. The patient to be treated is preferably a mammal, particularly a human being.

[0039] For the purposes of the present description and the following claims, the expression "for example" and the terms "preferably", "advantageously", "particularly", and the like are used to better illustrate the invention without adding any limitation to the scope of the invention, unless otherwise indicated.

[0040] For the purposes of the present description and the claims that follow, the phrase " Kv7.2 / 7.3 potassium channel activator" refers to a compound that causes a shift in voltage dependence for channel opening to more negative potentials, meaning that the Kv7.2 / 7.3 potassium channels open to more negative potentials in the presence of said compound, facilitating the transmission of ions through them.

[0041] DETAILED DESCRIPTION OF THE INVENTION

[0042] A first aspect of the present invention relates to a Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the general formula (I) described above.

[0043] In an embodiment of the present invention, R1 is pyridine, pyridazine, pyrimidine, or pyrazine, more preferably pyridine or pyrimidine.

[0044] In an embodiment of the present invention, R1 is substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.

[0045] In an embodiment of the present invention, R1 is substituted by a linear or branched C1 -C3 alkyl chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.

[0046] In an embodiment of the present invention, R1 is substituted by a linear or branched C1 -C3 alkoxy chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride. In an embodiment of the present invention, R1 is substituted by a linear or branched C1 -C3 alkoxy chain substituted by a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein one or more carbon atom is optionally substituted by a heteroatom selected from 0, N and S, such as for example, oxirane, aziridine, oxetane, azetidine, thietane, tetrahydrofuran, pyrrolidine, pyrazolidine, imidazoline, thiolane, oxazolidine, isoxazolidine, thiazolidine, 1 ,3-oxathiolane, piperidine, oxane, thiane, piperazine, morpholine, and thiomorpholine.

[0047] According to an embodiment of the present invention, R1 is substituted by one or more substituent selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.

[0048] According to an embodiment of the present invention, R1 is substituted by one or more substituent selected from methoxy, ethoxy, propoxy, and isopropoxy, wherein one or more hydrogen atoms is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.

[0049] According to a preferred embodiment of the present invention, R1 is substituted by one or more substituent selected from CF3-CH2-O- or CF3-CH(CH3)-O-.

[0050] In an embodiment of the present invention, R2 is selected from ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, optionally substituted with OH, CF3, one or more halogen atoms, or C1 -C3 alkoxy.

[0051] In a preferred embodiment of the present invention, R2 is selected from ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, wherein one or more hydrogen atom is substituted by a halogen atom, preferably fluoride and chloride, more preferably fluoride.

[0052] In a preferred embodiment of the present invention, R2 is selected from ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, wherein one or more hydrogen atom is substituted by a C1 -C3 alkoxy, preferably a methoxy and ethoxy, more preferably methoxy.

[0053] In an embodiment of the present invention, R2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, optionally substituted with OH, CF3, one or more halogen atoms, or C1 -C3 alkoxy.

[0054] In a preferred embodiment of the present invention, R2 is selected from cyclopropyl, and cyclobutyl, optionally substituted with OH, CF3, one or more halogen atoms, preferably fluoride and chloride, more preferably fluoride, or C1-C3 alkoxy, preferably methoxy and ethoxy.

[0055] In a more preferred embodiment of the present invention, R2 is cyclopropyl, optionally substituted with OH, CF3, one or more halogen atoms, preferably fluoride and chloride, more preferably fluoride, or C1 -C3 alkoxy, preferably methoxy and ethoxy. In an embodiment of the present invention, R3 is an aliphatic ring having three to six members, optionally containing one or more heteroatoms selected from the group consisting of N, 0 and S, preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, and tetrahydrothiopyran, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetane, tetrahydrofuran, tetrahydropyran, and tetrahydrothiopyran, and even more preferably cyclobutane and cyclohexane, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl, preferably with one or more substituents selected from the group consisting of fluoride, hydroxyl and C1 -C3 alkyl.

[0056] In an embodiment of the present invention, R3 is an aliphatic ring having the following formulas:

[0057] In another embodiment of the present invention, R3 is a bridged or condensed bicyclic ring having five to twelve members, preferably six to eleven members, optionally containing one or more heteroatoms selected from the group consisting of N and 0, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl.

[0058] Useful examples of bicyclic rings are 6-oxa-3-azabicyclo[3.1 ,1 ]heptane, bicyclo[2.2.2]octane, bicyclo[1 .1 ,1 ]pentane, indane (2,3-dihydro-1 H-indene), 2,3-dihydro- 1 H-indole, 6,7-dihydro-5H-cyclopenta[c]pyridine, chromane (3,4-dihydro-2 / - / -1 - benzopyran), coumaran (2, 3-dihydro-1 -benzofuran), tetralin (1 , 2,3,4- tetrahydronaphthalene), thiochroman (3, 4-dihydro-2 / - / -1 -benzothiopyran), 5,6-dihydro-4 / - / - cyclopenta[b]thiophene, 6,7-dihydro-5H-cyclopenta[b]pyridine, 5, 6,7,8- tetrahydroisoquinoline, 5,6,7,8-tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1 -benzoxepine, and 6,7,8,9-tetrahydro-5H-benzo[7]annulene, preferably bicyclo[2.2.2]octane, bicyclo[1 .1 ,1 ]pentane, and indane (2, 3-dihydro-1 H-indene), more preferably bicyclo[1 .1 ,1 ]pentane.

[0059] In another embodiment of the present invention, R3 is a spiro residue comprising two aliphatic rings having five to eight members, preferably six to eight members, optionally containing one or more heteroatoms selected from the group consisting of N and 0, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl. Useful examples of spiro residues are spirohexane, 5-azaspiro[2.3]hexane, spiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 5- azaspiro[2.4]heptane, and 6-azaspiro[3.4]octane. In further alternative embodiment, R3 is a linear or branched C1 -C6 alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl, pentyl, isopentyl, 2- methylpenthyl, 3-methylpenthyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, and hexyl group.

[0060] Advantageously, an embodiment of the present invention relates to a Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds of the following Table A:

[0061] Table A

[0062]

[0063] Some compounds of the present invention may exist in tautomeric forms, and the invention includes all tautomeric forms of such compounds unless otherwise noted. Unless otherwise stated, the structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds according to the present invention are within the scope of the invention. The present invention includes any diastereomer or enantiomer substantially free of other isomers (>90%, and preferably >95%, free of other stereoisomers on a molar basis), as well as a mixture of such isomers.

[0064] Particular optical isomers can be obtained by resolution of racemic mixtures according to conventional processes, for example, by formation of diastereomeric salts, by treatment with an optically active acid or base and subsequent separation of the mixture of diastereomers by crystallization of the corresponding salt followed finally by liberation of the optically active bases from such salts. Examples of appropriate acids include tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorosulfonic acids. A different process for the separation of optical isomers involves the use of a chiral chromatographic column optimally chosen to maximize the separation of enantiomers. Still another method involves the synthesis of covalent diastereomers by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to provide the enantiomerically pure compound. The optically active compounds of the invention can be obtained using active starting materials. These isomers may be in the form of a free acid, a free base, an ester, or a salt.

[0065] Compounds of the present invention may exist in radiolabeled form, i.e. , said compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Radioisotopes of hydrogen, carbon, phosphorus, fluorine, and chlorine include3H,14C,32P,35S,18F and36CI, respectively. Compounds of the present invention that contain these radioisotopes and / or other radioisotopes of other atoms are within the scope of the present invention. The triziated radioisotopes, i.e.,3H, and carbon-14, i.e.,14C, are particularly preferred because of their ease of preparation and detectability.

[0066] The radiolabeled compounds of this invention can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by performing the procedures described herein by substituting a non-radiolabeled reagent for a readily available non-radiolabeled reagent.

[0067] Compounds according to the present invention are preferably used as salts with pharmaceutically acceptable organic and inorganic acids or bases.

[0068] Preferably, the pharmaceutically acceptable organic acids are chosen from the group consisting of oxalic, maleic, methanesulfonic, paratoluenesulfonic, succinic, citric, malic, tartaric and lactic acids.

[0069] Preferably, pharmaceutically acceptable organic bases are selected from the group consisting of tromethamine, lysine, arginine, glycine, alanine and ethanolamine.

[0070] Preferably, the pharmaceutically acceptable inorganic acids are chosen from the group consisting of hydrochloric, hydrobromic, phosphoric and sulfuric acids.

[0071] Preferably, the pharmaceutically acceptable inorganic bases are chosen from the group consisting of hydroxide or carbonate of alkaline or alkaline-earth metals, such as sodium, potassium and calcium.

[0072] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be prepared by a variety of procedures known to a man skilled in the art, some of which are described in the preparations illustrated in the examples of the experimental part. Intermediates and final compounds may be recovered by conventional methods well known in the art, such as, for example, extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. Reagents and starting materials are known and readily available to the man skilled in the art.

[0073] Advantageously, the compounds of the present invention are used as a drug, particularly in the treatment of disorders that are modulated by Kv7.2 / Kv7.3 potassium channels, preferably in the treatment of central nervous system (CNS) and peripheral nervous system (PNS) disorders.

[0074] Central nervous system (CNS) disorders that are preferably treated with the compounds of the present invention are, for example, epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsivity disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, tinnitus, and so on.

[0075] Advantageously, the central nervous system (CNS) disorders that are preferably treated with the compounds of the present invention are epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, and amyotrophic lateral sclerosis.

[0076] Peripheral nervous system (PNS) disorders that are preferably treated with the compounds of the present invention are, for example, migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, muscle pain, and so forth.

[0077] Advantageously, the peripheral nervous system (PNS) disorders that are preferably treated with the compounds of the present invention are neuropathic pain, chronic pain, visceral pain, and inflammatory pain.

[0078] Typically, the compounds of the present invention are administered in the form of a pharmaceutical composition comprising a pharmaceutically acceptable excipient.

[0079] Thus, one aspect of the present invention relates to a pharmaceutical composition comprising (i) a Kv7.2 / Kv7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, and (ii) at least one pharmaceutically acceptable excipient.

[0080] Preferably, the pharmaceutical composition according to the present invention is for systemic use.

[0081] The pharmaceutical composition according to the present invention can be administered orally, parenterally, inhaled (spray, powder or aerosol), rectally, nasally, buccally, vaginally or via an implanted device. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

[0082] More preferably, the pharmaceutical composition according to the present invention is formulated for oral or parenteral administration.

[0083] Preferably, the pharmaceutical composition according to the present invention is prepared in suitable dosage forms comprising an effective amount of at least one compound according to the first aspect of the present invention, a salt thereof with a pharmaceutically acceptable organic or inorganic acid or base, and at least one pharmaceutically acceptable excipient.

[0084] Examples of suitable dosage forms include tablets, capsules, coated tablets, granules and solutions and syrups for oral administration; suppositories for rectal or vaginal administration; and solutions, suspensions, dispersions or emulsions for administration by injection or infusion.

[0085] Preferred dosage forms include tablets, coated tablets, capsules and solutions for oral administration, and aqueous to non-aqueous sterile solutions for administration by injection or infusion.

[0086] The amount of compound according to the first aspect of the present invention, or a pharmacologically acceptable salt thereof, present in the pharmaceutical composition of the present invention may vary over a wide range depending on known factors, for example, the type of disease, the severity of the disease, the body weight of the patient, the dosage form, the route of administration chosen, the number of administrations per day, and the efficacy of the compound itself. However, a person skilled in the art can determine the optimal amount easily and routinely.

[0087] Typically, the amount of compound according to the first aspect of the present invention or a pharmacologically acceptable salt thereof in the pharmaceutical composition of the present invention will be such as to provide a level of administration from 0.0001 to 100 mg / kg / day. Preferably, the level of administration is from 0.001 to 50 mg / kg / day, and even more preferably from 0.01 to 10 mg / kg / day.

[0088] As known to the man skilled in the art, lower or higher doses than those mentioned above may be required. The specific dosage and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, gender, diet, time of administration, rate of excretion, combination of drugs, severity and course of disease and the patient's disposition to the disease and the judgment of the treating physician. The dosage forms of the pharmaceutical composition of the present invention can be prepared according to techniques well known to a man skilled in the pharmaceutical art, including mixing, granulation, compression, dissolution, sterilization, and the like.

[0089] Advantageously, such dosage forms are formulated to provide controlled release of the active ingredient over time. In particular, depending on the type of therapy, the required release time may be very short, normal or long.

[0090] Preferably, the pharmaceutical composition of the present invention is contained in a single dosage form, to be administered once a day, or several times (two, three or four) a day.

[0091] The pharmaceutically acceptable excipient may be selected from the group consisting of thickeners, glidants, binders, disintegrants, fillers, diluents, preservatives, stabilizers, surfactants, buffers, fluidizers, lubricants, humectants, absorbents, salts to regulate osmotic pressure, emulsifiers, flavorings, colorants, sweeteners, and the like.

[0092] Particularly preferred excipients include water, ethanol, propylene glycol, glycerol, polyethylene glycols, polyoxamers, mono-, di- and tri-glycerides, coconut oil, palm oil, sodium carbonate, magnesium carbonate, magnesium stearate, stearic acid, talc, sugars, lactose, mannitol, sorbitol, polysorbate, povidone, pectin, dextrin, starch (especially com starch), sodium starch glycolate, croscarmellose sodium, sucrose, cyclodextrin, gelatin, microcrystalline cellulose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, povidone, glyceryl monostearate, hypromellose, cocoa butter, titanium dioxide (E171 ), red iron oxide and yellow iron oxide (E172), and the like.

[0093] EXPERIMENTAL PART

[0094] The following examples are intended to further illustrate the present invention, but do not limit it.

[0095] EXAMPLE 1

[0096] Analytical Methods

[0097] Analytical data is included within the procedures below, in the illustrations of the general procedures, or in the tables of examples. Unless otherwise stated, all1H NMR data were collected on a Broker Avance 400 MHz equipped with 5 mm QNP probe or Broker Avance III 400 MHz, 5 mm BBFO probe or Fourier 300 MHz, 5 mm dual probe instruments and chemical shifts are quoted in parts per million (ppm). LC / MS was performed on Acquity UPLC H-Class (quaternary pump / PDA detector) coupled to QDa Mass Spectrometer or Acquity UPLC (binary pump / PDA detector) coupled to ZQ Mass Spectrometer or Acquity UPLC with Waters DAD coupled to SQD2 Mass Spectrometer. LC / MS data is referenced to LC / MS conditions using the method number provided in Table 1 .

[0098] Table 1. LC / MS analysis methods

[0099] Purification Methods

[0100] For the general procedures, intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include flash chromatography performed on the COMBIFLASH® Companion purification system or the Biotage SP1 purification system, products were purified using an Isolute® SPE Si II cartridge, (‘Isolute SPE Si cartridge’ refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles with average size of 50 pm and nominal 60A porosity), and a solvent or combination of solvents (cyclohexane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; RP-HPLC purification performed on Waters Mass Directed FractionLynx systems (2767 autosampler, System Fluidics Organiser, 2998 Photodiode array, 2545 pump, 3x515 pump, QDa mass spectrometer), Gilson system (GX281 autosampler, 322 pump, 155 UV / vis detector), Interchim PuriFlash 4125 coupled to a UV DAD (see Table 2 for some non-limiting conditions); SFC purification performed on a Waters Thar Prepl OO system (P200 CO2 pump, 2545 modifier pump, 2998 UVA / IS detector, 2767 liquid handler with Stacked Injection Module) or Waters Thar Investigator semi preparative system (Waters Fluid Delivery Module, 2998 UVA / IS detector, Waters Fraction Collection Module) (see Table 2 for some non-limiting conditions); recrystallization from an appropriate solvent (MeOH, EtOH, / -PrOH, EtOAc, toluene, etc.) or combination of solvents (EtOAc / heptane, EtOAc / MeOH, etc.); precipitation from a combination of solvents (DMF / water, DMSO / DCM, EtOAc / heptane, etc.); trituration with an appropriate solvent (EtOAc, DCM, MeCN, MeOH, EtOH, / -PrOH, n-PrOH, etc.); extractions by dissolving a compound in a liquid and washing with an appropriately immiscible liquid (DCM / water, EtOAc / water, DCM / saturated NaHCOs, EtOAc / saturated NaHCOs, DCM / 10% aqueous HCI, EtOAc / 10% aqueous HCI, etc.); and / or distillation (simple, fractional, Kugelrohr, etc.). Descriptions of these techniques can be found in the following references: Gordon, A. J. and Ford, R. A. "The Chemist’s Companion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”, 2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem. 1978, 43(14), 2923-2925; Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry” 2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “Experimental Organic Chemistry: Standard and Microscale, 2ndEdition”, 1999.

[0101] Table 2. RP-HPLC and SFC purification methods

[0102] Preparations and Examples

[0103] Starting materials / reagents are commercially available from standard suppliers incl. but not limited to Sigma-Aldrich (including Fluka and Discovery CPR), Fluorochem, Enamine etc. Reagent / reactant names given are as named on the commercial bottle or as generated by IIIPAC conventions or ChemDraw 20.1 . None of the specific conditions and reagents noted herein is to be construed as limiting the scope of the invention and are provided for illustrative purposes only.

[0104] Abbreviations

[0105] °C Degrees Celsius

[0106] CAS Chemical Abstracts Service

[0107] CDI Carbonyldiimidazole

[0108] CPME Cyclopentyl methyl ether

[0109] DAD Diode array detector

[0110] DCM Dichloromethane

[0111] De Diastereomeric excess

[0112] DMSO Dimethyl sulfoxide

[0113] Ee Enantiomeric excess

[0114] EtOAc Ethyl acetate

[0115] EtOH Ethanol h Hour(s)

[0116] H Hydrogen

[0117] HATLI 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium

[0118] 3-oxide hexafluorophosphate

[0119] HCI Hydrogen chloride

[0120] HCOOH Formic acid

[0121] IMS Industrial methylated spirits

[0122] LiHMDS Lithium bis(trimethylsilyl)amide

[0123] LC / MS Liquid Chromatography / Mass Spectrometry m / z Mass-to-charge ratio

[0124] MeCN Acetonitrile

[0125] MeOH Methanol

[0126] MHz Megahertz

[0127] Min Minute(s)

[0128] MS Mass Spectrometer

[0129] NaHCOs Sodium hydrogen carbonate

[0130] Na2SO4 Sodium sulphate

[0131] NH4CI Ammonium chloride

[0132] NH4HCO3 Ammonium hydrogen carbonate

[0133] NMR Nuclear Magnetic Resonance

[0134] / -PrOH Propan-2-ol n-PrOH Propan-1-ol

[0135] RP-HPLC Reverse Phase-High Performance Liquid Chromatography

[0136] Rt Retention time

[0137] RT Room temperature

[0138] SFC Supercritical Fluid Chromatography tBuBrettPhosPdG3 [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1 , 1 '- biphenyl)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate

[0139] THF Tetrahydrofuran

[0140] LIPLC Ultra Performance Liquid Chromatograph

[0141] The synthesis of compounds 1 -26 can be accomplished as described below.

[0142] Intermediate 1

[0143] 2-(4,4-Difluoro-1 -hydroxycyclohexyl)acetic acid

[0144] (i) Ethyl 2-(4,4-difluoro-1 -hydroxycyclohexyl)acetate

[0145] To a reaction vessel charged with EtOAc (3.4 mL, 34.4 mmol) in THF (50.0 mL) under a nitrogen atmosphere at -78°C was added 1 M LiHMDS in THF (27.0 mL, 26.9 mmol). The reaction was stirred at -78°C for 40 min. 4,4-Difluorocyclohexanone (3.0 g, 22.4 mmol) in THF (30.0 mL) was added over 10 min. and the reaction was stirred at -78°C for 1 h. The reaction was allowed to warm to -20°C and aqueous NH4CI (5.0 mL) was added. The reaction was allowed to warm to RT and next partitioned between EtOAc and a 10% aqueous NH4CI solution. The organic layer was separated. The aqueous layer was reextracted with EtOAc. The combined organics layers were washed with distilled water, dried (Na2SO4) and concentrated in vacuo (12 mbar at RT) to afford the title compound (4.97 g, quant.).

[0146] 1H NMR (400 MHz, CDCI3) 6 4.13 (q, J=7.1 Hz, 2H), 3.65 (s, 1 H), 2.43 (s, 2H), 2.24-2.02 (m, 2H), 1.93-1.73 (m, 4H), 1.60-1.50 (m, 2H), 1.23 (t, J=7.1 Hz, 3H).

[0147] (ii) 2-(4,4-Difluoro-1 -hydroxycyclohexyl)acetic acid

[0148] A reaction vessel was charged with ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)acetate (1.0 g, 4.5 mmol) and solvated in MeOH (20 mL). 1 M NaOH (6.7 mL, 6.75 mmol) was added and reaction stirred at RT for 24 h. The crude reaction was solvated in distilled water and pH adjusted to pH=7 with citric acid. The reaction was partitioned between EtOAc and distilled water. The organic layer was separated. The aqueous layer was re-extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford the title compound as an off-white solid (455 mg, 52%).

[0149] 1H NMR (400 MHz, DMSO-d6) 12.12 (s, 1 H), 4.69 (s, 1 H), 2.38 (s, 2H), 2.13-1.93 (m, 2H), 1.89-1.77 (m, 2H), 1.77-1.61 (m, 4H).

[0150] Compound 1

[0151] / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(4,4-difluoro-1- hydroxycyclohexyl)acetamide (Isomer 1)

[0152] A reaction vessel was charged with (2-chloropyridin-4-yl)(cyclopropyl)methanamine (330 mg, 1.81 mmol, CAS: 1270444-14-8) and solvated in DCM (8.0 mL) under a nitrogen atmosphere. Triethylamine (0.50 mL, 3.61 mmol) was added and the reaction was set to stir at RT. The reaction was cooled to 0°C and di-te / t-butyl decarbonate (0.62 mL, 2.71 mmol) in DCM (8.0 mL) was added dropwise. The reaction was allowed to warm to RT and stirred at RT for 2 h. The reaction was next partitioned between DCM and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a white solid (440 mg, 86%).

[0153] LC / MS (Table 1 , Method A) Rt= 1.47 min; MS m / z: 283 [M+H]+.

[0154] (ii) (±)-te / Y-Butyl (cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)carbamate

[0155] A reaction vessel was charged with te / t-butyl ((2-chloropyridin-4- yl)(cyclopropyl)methyl)carbamate (440 mg, 1 .56 mmol), 2,2, 2-trifluoroethanol (0.91 mL, 12.4 mmol) and solvated in cyclopentyl methyl ether (10.5 mL). Sodium te / Y-butoxide (748 mg, 7.78 mmol) and fBuBrettPhosPdG3 (133 mg, 0.156 mmol) were added. The reaction was degassed and placed under argon. The reaction was set to stir at RT and next heated at 60°C for 1 h. The reaction was allowed to cool to RT and filtered in vacuo. The filtrate was partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a white solid (400 mg, 74%).

[0156] LC / MS (Table 1 , Method B) Rt= 1.47 min; MS m / z: 347 [M+H]+.

[0157] (iii) (±)-Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride

[0158] A reaction vessel was charged with te / Y-butyl (cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4- yl)methyl)carbamate (400 mg, 1.15 mmol) and solvated in DCM (8.0 mL). 3M hydrogen chloride in CPME (10.0 mL, 30.0 mmol) was added and the reaction was stirred at RT for 24 h. The solid precipitate was filtered in vacuo to afford the title compound (380 mg, quant.). The product was used without further purification in the subsequent reaction. LC / MS (Table 1 , Method A) Rt= 1.47 min; MS m / z: 247 [M+H-HCI]+.

[0159] 1H NMR (400 MHz, DMSO-d6) 5 8.77 (br s, 3H), 8.26 (d, J=5.3 Hz, 1 H), 7.30 (dd, J=1 .3, 5.3 Hz, 1 H), 7.17-7.16 (m, 1 H), 5.02 (q, J=9.1 Hz, 2H), 3.67-3.58 (m,1 H), 1.30-1.14 (m, 1 H), 0.73-0.44 (m, 4H).

[0160] (iv) (±)- / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(4,4-difluoro-1 - hydroxycyclohexyl)acetam ide

[0161] A reaction vessel was charged with cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4- yl)methanamine hydrochloride (72 mg, 0.255 mmol), 2-(4,4-difluoro-1 - hydroxycyclohexyl)acetic acid (intermediate 1 , 59 mg, 0.306 mmol), HATLI (116 mg, 0.306 mmol) and solvated in DCM (2.5 mL). Triethylamine (0.14 mL, 1 .02 mmoL) was added and the reaction was stirred at RT for 1.5 h. The reaction was next partitioned between DCM and a saturated NaHCOs solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to EtOAc, gradient elution) to afford the title compound as a white solid (92 mg, 85%).

[0162] LC / MS (Table 1 , Method B) Rt= 4.93 min; MS m / z: 423 [M+H]+.

[0163] (v) A / -(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(4,4-difluoro-1 - hydroxycyclohexyl)acetamide (Isomer 1 )

[0164] (±)- / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(4,4-difluoro-1 - hydroxycyclohexyl)acetamide (92 mg, 0.217 mmol) was purified by SFC (Table 2, Method 1 ) to afford the title compound (38 mg, 42%, 100% Ee) as an off-white solid.

[0165] LC / MS (Table 1 , Method B) RT 4.93 min; MS m / z 423 [M+H]+.

[0166] 1H NMR (400 MHz, DMSO-d6) 5 8.56 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.09 (dd, J=1 .3, 5.3 Hz, 1 H), 6.94 (s, 1 H), 4.97 (q, J=9.0 Hz, 2H), 4.83 (s, 1 H), 4.19 (t, J=8.5 Hz, 1 H), 2.35 (s, 2H), 2.10-1.95 (m, 2H), 1.85-1.78 (m, 2H), 1.66-1.59 (m, 4H), 1.13-1.04 (m, 1 H), 0.54-0.44 (m, 3H), 0.34-0.30 (m, 1 H).

[0167] Compound 2

[0168] / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(4,4-difluoro-1- hydroxycyclohexyl)acetamide (Isomer 2)

[0169] (±)- / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(4,4-difluoro-1 - hydroxycyclohexyl)acetamide (Compound 1 , step (iv), 92 mg, 0.217 mmol) was purified by SFC (Table 2, Method 1 ) to afford the title compound (37 mg, 40%, 100% Ee) as an off- white solid.

[0170] LC / MS (Table 1 , Method B) RT 4.93 min; MS m / z 423 [M+H]+.

[0171] 1H NMR (400 MHz, DMSO-d6) 5 8.56 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.09 (dd, J=1 .3, 5.3 Hz, 1 H), 6.94 (s, 1 H), 4.97 (q, J=9.0 Hz, 2H), 4.83 (s, 1 H), 4.19 (t, J=8.5 Hz, 1 H), 2.35 (s, 2H), 2.10-1.95 (m, 2H), 1.85-1.78 (m, 2H), 1.66-1.59 (m, 4H), 1.13-1.04 (m, 1 H), 0.54-0.44 (m, 3H), 0.34-0.30 (m, 1 H).

[0172] Compound 3

[0173] / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 1)

[0174] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). (±)- / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)- 2-(3,3-difluorocyclobutyl)acetamide was purified by SFC (Table 2, Method 1 ) to afford the title compound (43 mg, 27%, 100% Ee) as a white solid.

[0175] LC / MS (Table 1 , Method B) RT 4.95 min; MS m / z 379 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.55 (d, J=8.0 Hz, 1 H), 8.13 (d, J=5.3 Hz, 1 H), 7.08 (d, J=5.3 Hz, 1 H), 6.92 (s, 1 H), 4.98 (q, J=9.1 Hz, 2H), 4.17 (t, J=8.5 Hz, 1 H), 2.69-2.60 (m, 2H), 2.41-2.36 (m, 5H), 1.13-1.03 (m, 1 H), 0.53-0.41 (m, 3H), 0.33-0.29 (m, 1 H).

[0176] Compound 4

[0177] / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 2)

[0178] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). (±)- / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)- 2-(3,3-difluorocyclobutyl)acetamide was purified by SFC (Table 2, Method 1 ) to afford the title compound (44 mg, 27%, 100% Ee) as a white solid.

[0179] LC / MS (Table 1 , Method B) RT 4.95 min; MS m / z 379 [M+H]+.

[0180] 1H NMR (400 MHz, DMSO-d6) 5 8.55 (d, J=8.0 Hz, 1 H), 8.13 (d, J=5.3 Hz, 1 H), 7.08 (d, J=5.3 Hz, 1 H), 6.92 (s, 1 H), 4.98 (q, J=9.1 Hz, 2H), 4.17 (t, J=8.5 Hz, 1 H), 2.69-2.60 (m, 2H), 2.41-2.36 (m, 5H), 1.13-1.03 (m, 1 H), 0.53-0.41 (m, 3H), 0.33-0.29 (m, 1 H).

[0181] Compound 5

[0182] / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(3,3-difluoro-1- hydroxycyclobutyl)acetamide (Isomer 1)

[0183] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride and 2-(3,3-difluoro-1 - hydroxycyclobutyl)acetic acid (CAS: 2295815-26-6). (±)- / V-(Cyclopropyl(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)-2-(3,3-difluorocyclobutyl)acetamide was purified by SFC (Table 2, Method 1 ) to afford the title compound (18.8 mg, 14%, 100% Ee) as an off-white oil.

[0184] LC / MS (Table 1 , Method C) RT 4.52 min; MS m / z 395 [M+H]+.

[0185] 1H NMR (400 MHz, DMSO-d6) 5 8.52 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.11 (d, J=5.3 Hz, 1 H), 6.95 (s, 1 H), 5.61 (s, 1 H), 4.97 (q, J=9.1 Hz, 2H), 4.21 (t, J=8.5 Hz, 1 H), 2.91 - 2.75 (m, 2H), 2.63-2.51 (m, 4H), 1.14-1.03 (m, 1 H), 0.54-0.44 (m, 3H), 0.36-0.29 (m, 1 H).

[0186] Compound 6

[0187] / V-(Cyclopropyl(2-(2,2,2-trifluoroethoxy)pyridin-4-yl)methyl)-2-(3,3-difluoro-1- hydroxycyclobutyl)acetamide (Isomer 1)

[0188] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methanamine hydrochloride and 2-(3,3-difluoro-1 - hydroxycyclobutyl)acetic acid (CAS: 2295815-26-6). (±)- / V-(Cyclopropyl(2-(2,2,2- trifluoroethoxy)pyridin-4-yl)methyl)-2-(3,3-difluorocyclobutyl)acetamide was purified by SFC (Table 2, Method 1 ) to afford the title compound (20 mg, 15%, 100% Ee) as an off-white oil.

[0189] LC / MS (Table 1 , Method C) RT 4.52 min; MS m / z 395 [M+H]+.

[0190] 1H NMR (400 MHz, DMSO-d6) 5 8.52 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.11 (d, J=5.3 Hz, 1 H), 6.95 (s, 1 H), 5.61 (s, 1 H), 4.97 (q, J=9.1 Hz, 2H), 4.21 (t, J=8.5 Hz, 1 H), 2.91 - 2.75 (m, 2H), 2.63-2.51 (m, 4H), 1.14-1.03 (m, 1 H), 0.54-0.44 (m, 3H), 0.36-0.29 (m, 1 H).

[0191] Compound 7

[0192] / V-(Cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 2) ifluoropropan-2-yl)oxy)pyrimidine-4-carbonitrile

[0193] A reaction vessel was charged with 6-chloropyrimidine-4-carbonitrile (1.5 g, 35.8 mmol, CAS: 939986-65-9) and solvated in MeCN (45 mL). (R)-1 ,1 ,1 -Trifluoro-2-propanol (1.41 g, 12.4 mmol, CAS: 75-89-8) was added, and the solution was stirred at RT until dissolution had occurred. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (1 .8 mL, 12.4 mmol) was added dropwise and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo. The reaction was next partitioned between DCM and a saturated aqueous NH4CI solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a white solid (1 .68 g, 72%).

[0194] 1H NMR (400 MHz, DMSO-d6) 59.04 (d, J=1 .1 Hz, 1 H), 7.93 (d, J=1 .2 Hz, 1 H), 6.07-5.96 (m, 1 H), 1.51 (d, J=6.5 Hz, 3H).

[0195] LC / MS (Table 1 , Method B) Rt= 1.58 min; MS m / z: 218 [M+H]+.

[0196] (i) (R)-Cyclopropyl(6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanone

[0197] A reaction vessel was charged with ((R)-6-(( 1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrim idine-4- carbonitrile (1 .68 g, 7.74 mmol) and solvated in THF (25.0 mL). The reaction was set to stir at RT and next cooled to 0°C. Cyclopropylmagnesium bromide solution (0.5M in THF, 32 mL, 16.2 mmol) was added dropwise at 0°C. The reaction was stirred at 0°C for 1 h. 6M HCI (6 mL) was added at 0°C and the reaction was allowed to warm to RT and stirred at RT for 15 mins. The reaction was neutralised with a saturated NaHCOs solution and next partitioned with EtOAc. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a yellow oil (1.31 g, 65%).

[0198] 1H NMR (400 MHz, DMSO-d6) 5 9.10 (d, J=1 .1 Hz, 1 H), 7.37 (d, J=1 .1 Hz, 1 H), 6.10-5.99 (m, 1 H), 3.32-3.26 (m, 1 H), 1.51 (d, J=6.5 Hz, 3H), 1.22-1.09 (m, 4H).

[0199] LC / MS (Table 1 , Method A) RT 1 .65 min; MS m / z 261 [M+H]+.

[0200] (iii) Cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine (2 diastereoisomers)

[0201] To a solution of (R)-cyclopropyl(6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanone (1 .31 g, 5.03 mmol) in MeOH (35.0 mL) was added ammonium formate (3.81 g, 60.4 mmol) and sodium cyanoborohydride (1.26 g, 20.1 mmol). The reaction was set to stir at RT and next heated at 60°C for 18 h. The reaction was allowed to cool to RT and concentrated in vacuo. The reaction was partitioned between EtOAc and a 10% aqueous sodium hydroxide solution. The organic layers were separated, washed with distilled water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:2M NH3 in MeOH (15:1 ), gradient elution) to afford the title compound as a pale yellow oil (702 mg, 53%).

[0202] 1H NMR (400 MHz, CDCI3) 5 8.73 (d, J=0.9 Hz, 1 H), 6.89 (d, J=4.0 Hz, 1 H), 5.88-5.80 (m, 1 H), 3.34 (s, 2H), 3.25 (dd, J=3.8, 9.0 Hz, 1 H), 1.18-1.08 (m, 1 H), 0.75-0.59 (m, 2H), 0.53- 0.41 (m, 2H).

[0203] LC / MS (Table 1 , Method A) RT 1 .35 min; MS m / z 262 [M+H]+.

[0204] (iv) A / -(Cyclopropyl(6-(((R)-1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 2)

[0205] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). A / -(Cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin- 4-yl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (2 diastereoisomers) was purified by SFC (Table 2, Method 2) to afford the title compound (410 mg, 34%, 98.5% De) as a clear oil which crystallised on storage.

[0206] 1H NMR (400 MHz, DMSO-d6) 5 8.79 (s, 1 H), 8.51 (d, J=7.8 Hz, 1 H), 7.01 (s, 1 H), 6.02-5.90 (m, 1 H), 4.17 (t, J=8.3 Hz, 1 H), 2.52-2.49 (m, 2H), 2.40-2.26 (m, 5H), 1 .48 (d, J=6.5 Hz, 3H), 1.24-1.10 (m, 1 H), 0.52-0.32 (m, 4H).

[0207] LC / MS (Table 1 , Method C) Rt = 4.75 min; MS m / z: 394 [M+H]+.

[0208] Compound 8

[0209] / V-(Cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(4,4- difluoro-1 -hydroxycyclohexyl)acetamide (Isomer 2)

[0210] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 2-(4,4-difluoro-1- hydroxycyclohexyl)acetic acid (intermediate 1 ). / V-(Cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(4,4-difluoro-1 - hydroxycyclohexyl)acetamide (mixture of two diastereoisomers) was purified by SFC (Table 2, Method 3) to afford the title compound (19 mg, 6%, 100% De) as an off-white solid.

[0211] 1H NMR (400 MHz, DMSO-d6) 5 8.80 (s, 1 H), 8.51 (d, J=7.8 Hz, 1 H), 7.06 (s, 1 H), 6.00-5.92 (m, 1 H), 4.84 (s, 1 H), 4.21 (t, J=8.3 Hz, 1 H), 2.36 (s, 2H), 2.10-1.94 (m, 2H), 1.83-1.78 (m, 2H), 1.67-1.56 (m, 4H), 1.48 (d, J=6.5 Hz, 3H), 1.20-1.10 (m, 1 H), 0.53-0.43 (m, 3H), 0.38- 0.33 (m, 1 H).

[0212] LC / MS (Table 1 , Method B) RT 4.86 min; MS m / z 438 [M+H]+.

[0213] Compound 9

[0214] / V-(Cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(3,3- difluoro-1 -hydroxycyclobutyl )acetami de (Isomer 2)

[0215] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 2-(3,3-difluoro-1- hydroxycyclobutyl)acetic acid (CAS: 2295815-26-6). A / -(Cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(3,3-difluoro-1 - hydroxycyclobutyl)acetamide (mixture of two diastereoisomers) was purified by SFC (Table 2, Method 4) to afford the title compound (202 mg, 32%, 98.5% De) as an off-white solid.

[0216] 1H NMR (400 MHz, DMSO-d6) 5 8.80 (d, J=1 .0 Hz, 1 H), 8.50 (d, J=7.9 Hz, 1 H), 7.05 (d, J=0.8 Hz, 1 H), 6.01 -5.91 (m, 1 H), 5.64 (s, 1 H), 4.24 (t, J=8.2 Hz, 1 H), 2.87-2.78 (m, 2H), 2.62-2.51 (m, 4H), 1.48 (d, J=6.5 Hz, 3H), 1.24-1.11 (m, 1 H), 1.24-0.35 (m, 4H). LC / MS (Table 1 , Method C) Rt = 4.45 min; MS m / z: 410 [M+H]+.

[0217] Compound 10

[0218] / V-(Cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-3,3- dimethylbutanamide (Isomer 1)

[0219] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 3,3-dimethylbutanoic acid (CAS: 1070-83-3). A / -(Cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-

[0220] 3,3-dimethylbutanamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 4) to afford the title compound (40 mg, 29%, 100% De) as an off-white solid.

[0221] 1H NMR (400 MHz, DMSO-d6) 5 8.79 (d, J=0.8 Hz, 1 H), 8.33 (d, J=7.9 Hz, 1 H), 7.02 (d, J=0.7 Hz, 1 H), 6.00-5.92 (m, 1 H), 4.19 (t, J=8.4 Hz, 1 H), 2.04 (q, J=11 .5 Hz, 2H), 1.48 (d, J=6.5 Hz, 3H), 1.19-1.08 (m, 1 H), 0.94 (s, 9H), 0.52-0.32 (m, 4H).

[0222] LC / MS (Table 1 , Method C) Rt = 4.97 min; MS m / z: 360 [M+H]+.

[0223] Compound 11

[0224] / V-(Cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-3,3- dimethylbutanamide (Isomer 2)

[0225] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 3,3-dimethylbutanoic acid (CAS: 1070-83-3). A / -(Cyclopropyl(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-

[0226] 3,3-dimethylbutanamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 4) to afford the title compound (38 mg, 27%, 98% De) as an off-white solid.1H NMR (400 MHz, DMSO-d6) 6 8.79 (d, J=1 .1 Hz, 1 H), 8.32 (d, J=8.0 Hz, 1 H), 7.02 (d, J=0.9 Hz, 1 H), 6.00-5.92 (m, 1 H), 4.20 (t, J=8.4 Hz, 1 H), 2.04 (q, J=13.0 Hz, 2H), 1.48 (d, J=6.5 Hz, 3H), 1.21 -1.09 (m, 1 H), 0.94 (s, 9H), 0.51 -0.32 (m, 4H).

[0227] LC / MS (Table 1 , Method C) Rt = 5.01 min; MS m / z: 360 [M+H]+.

[0228] Compound 12

[0229] / V-(Cyclopropyl(6-(((R)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(3,3- difluoro-1 -methylcyclobutyl)acetamide (Isomer 1)

[0230] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 2-(3,3-difluoro-1- methylcyclobutyl)acetic acid (CAS: 1773507-87-1 ). A / -(Cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)-2-(3,3-difluoro-1 - methylcyclobutyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 4) to afford the title compound (24 mg, 31 %, 100% De) as an off-white gum.

[0231] 1H NMR (400 MHz, DMSO-d6) 5 8.79 (d, J=1 .1 Hz, 1 H), 8.56 (d, J=7.8 Hz, 1 H), 7.03 (d, J=1 .0 Hz, 1 H), 6.02-5.92 (m, 1 H), 4.16 (t, J=8.4 Hz, 1 H), 2.64 (q, J=14.4 Hz, 2H), 2.35 (s, 2H), 2.30-2.19 (m, 2H), 1.48 (d, J=6.5 Hz, 3H), 1.23-1.1 1 (m, 4H), 0.53-0.33 (m, 4H).

[0232] LC / MS (Table 1 , Method C) Rt = 5.73 min; MS m / z: 408 [M+H]+.

[0233] Compound 13

[0234] 2-(Bicyclo[1.1.1]pentan-1-yl)- / V-(cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)acetamide (Isomer 1)

[0235] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 2-(bicyclo[1 .1 .1 ]pentan-1 -yl)acetic acid (CAS: 131515-31-6). 2-(Bicyclo[1 .1 ,1]pentan-1-yl)-A / -(cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 7 next 8) followed by SFC (Table 2, Method 6) to afford the title compound (22 mg, 16%, 96% De) as an off-white solid.

[0236] 1H NMR (400 MHz, DMSO-d6) 5 8.79 (d, J=1 .0 Hz, 1 H), 8.33 (d, J=7.9 Hz, 1 H), 7.02 (d, J=1.0 Hz, 1 H), 6.02-5.91 (m, 1 H), 4.17 (t, J=8.4 Hz, 1 H), 2.42 (s, 1 H), 2.30 (dd, J=13.4, 19.1 Hz, 2H), 1.66 (s, 6H), 1.48 (d, J=6.6 Hz, 3H), 1.20-1.10 (m, 1 H), 0.52-0.33 (m, 4H).

[0237] LC / MS (Table 1 , Method C) Rt = 5.7 min; MS m / z: 370 [M+H]+.

[0238] Compound 14

[0239] 2-(Bicyclo[1.1.1]pentan-1-yl)- / V-(cyclopropyl(6-((( / ?)-1,1,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)methyl)acetamide (Isomer 2)

[0240] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methanamine and 2-(bicyclo[1 .1 .1 ]pentan-1 -yl)acetic acid (CAS: 131515-31-6). 2-(Bicyclo[1 .1 ,1]pentan-1-yl)-A / -(cyclopropyl(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)methyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 7 next 8) followed by SFC (Table 2, Method 6) to afford the title compound (7.8 mg, 11 %, 88% De) as an off-white solid.

[0241] 1H NMR (400 MHz, DMSO-d6) 5 8.80 (d, J=0.9 Hz, 1 H), 8.32 (d, J=8.0 Hz, 1 H), 7.02 (d, J=1 .1 Hz, 1 H), 6.01 -5.91 (m, 1 H), 4.18 (t, J=8.4 Hz, 1 H), 2.42 (s, 1 H), 2.30 (q, J=12.8 Hz, 2H), 1.67 (s, 6H), 1.48 (d, J=6.5 Hz, 3H), 1.24-1.11 (m, 1 H), 0.52-0.32 (m, 4H).

[0242] LC / MS (Table 1 , Method C) Rt = 5.7 min; MS m / z: 370 [M+H]+.

[0243] Compound 15

[0244] / V-(Cyclopropyl(2-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 1)

[0245] (i) (R)-2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)isonicotinonitrile

[0246] To a suspension of sodium hydride (60%, 721 mg, 18.0 mmol) in THF (65.0 mL) was added (R)-1 ,1 ,1 -Trifluoro-2-propanol (1.49 mL, 16.4 mmol, CAS: 75-89-8) at RT and the reaction was allowed to stir at RT for 1 h. 4-Cyano-2-fluoropyridine (2.0 g, 16.4 mmol, CAS: 3939- 14-8) was next added and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as an off-white solid (3.3 g, 93%).

[0247] 1H NMR (400 MHz, DMSO-d6) d 8.46 (dd, J=1 .0, 5.1 Hz, 1 H), 7.57-7.54 (m, 2H), 5.96-5.88 (m, 1 H), 1.47 (d, J=6.5 Hz, 3H).

[0248] (ii) (R)-Cyclopropyl(2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methanone

[0249] A reaction vessel was charged with (R)-2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)isonicotinonitrile (3.3 g, 15.3 mmol) and solvated in THF (50.0 mL). The reaction was set to stir at RT and next cooled to 0°C. Cyclopropylmagnesium bromide solution (0.5M in THF, 64 mL, 32.1 mmol) was added dropwise at 0°C. The reaction was stirred at 0°C for 1 h. 6M HCI (10.0 mL) was added at 0°C and the reaction was allowed to warm to RT and stirred at RT for 15 mins. The reaction was next partitioned between EtOAc and a saturated NaHCOs solution. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc, gradient elution) to afford the title compound as a yellow oil (2.98 g, 75%).

[0250] LC / MS (Table 1 , Method A) RT 1 .57 min; MS m / z 261 [M+H]+.

[0251] (iii) Cyclopropyl(2-(((R)-1 ,1 ,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine (2 Diastereoisomers)

[0252] To a solution of (R)-cyclopropyl(2-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methanone (2.98 g, 11.5 mmol) in MeOH (80.0 mL) was added ammonium formate (8.69 g, 0.138 mol) and sodium cyanoborohydride (2.89 g, 46.0 mmol). The reaction was set to stir at RT and next heated at 60°C for 18 h. The reaction was allowed to cool to RT and concentrated in vacuo. The reaction was partitioned between EtOAc and a 10% aqueous sodium hydroxide solution. The organic layers were separated, washed with distilled water, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:2M NH3 in MeOH (15:1 ), gradient elution) to afford the title compound as a pale yellow oil (1 .9 g, 64%).

[0253] LC / MS (Table 1 , Method A) RT 1 .57 min; MS m / z 261 [M+H]+.

[0254] (iv) A / -(Cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 1 )

[0255] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , steps (iv), using the appropriate starting materials, cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). A / -(Cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4- yl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 4) to afford the title compound (46.4 mg, 24%, 98% De) as an off-white solid.

[0256] 1H NMR (400 MHz, DMSO-d6) 5 8.53 (d, J=8.1 Hz, 1 H), 8.12 (d, J=5.5 Hz, 1 H), 7.05 (dd, J=1 .4, 5.2 Hz, 1 H), 6.87 (s, 1 H), 5.91 -5.83 (m, 1 H), 4.15 (t, J=8.6 Hz, 1 H), 2.67-2.56 (m, 2H), 2.40-2.22 (m, 5H), 1.44 (d, J=6.5 Hz, 3H), 1.12-1.03 (m, 1 H), 0.52-0.42 (m, 3H), 0.33- 0.28 (m, 1 H).

[0257] LC / MS (Table 1 , Method C) Rt = 5.02 min; MS m / z: 393 [M+H]+.

[0258] Compound 16

[0259] / V-(Cyclopropyl(2-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 2) The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , steps (iv), using the appropriate starting materials, cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). A / -(Cyclopropyl(2-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyridin-4- yl)methyl)-2-(3,3-difluorocyclobutyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 4) to afford the title compound (45 mg, 23%, 100% De) as an off-white solid.

[0260] 1H NMR (400 MHz, DMSO-d6) 5 8.53 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.06 (dd, J=1 .5, 5.5 Hz, 1 H), 6.87 (s, 1 H), 5.91 -5.83 (m, 1 H), 4.16 (t, J=8.6 Hz, 1 H), 2.67-2.57 (m, 2H), 2.40-2.23 (m, 5H), 1.44 (d, J=6.6 Hz, 3H), 1.11 -1.03 (m, 1 H), 0.53-0.43 (m, 3H), 0.33- 0.28 (m, 1 H).

[0261] LC / MS (Table 1 , Method C) Rt = 5.04 min; MS m / z: 393 [M+H]+.

[0262] Compound 17

[0263] / V-(Cyclopropyl(2-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3- difluoro-1 -hydroxycyclobutyl )acetami de (Isomer 1)

[0264] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , steps (iv), using the appropriate starting materials cyclopropyl(2-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine and 2-(3,3-difluoro-1- hydroxycyclobutyl)acetic acid (CAS: 2295815-26-6). A / -(Cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3-difluoro-1 -hydroxycyclobutyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 7) followed by SFC (Table 2, Method 2) to afford the title compound (34 mg, 18%, 96% De) as an off- white gum.

[0265] 1H NMR (400 MHz, DMSO-d6) 5 8.51 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.10 (dd, J=1 .2, 5.3 Hz, 1 H), 6.90 (s, 1 H), 5.92-5.82 (m, 1 H), 5.61 (s, 1 H), 4.20 (t, J=8.5 Hz, 1 H), 2.92- 2.76 (m, 2H), 2.63-2.52 (m, 2H), 2.50 (s, 2H), 1.44 (d, J=6.5 Hz, 3H), 1.14-1.04 (m, 1 H), 0.53-0.46 (m, 3H), 0.35-0.29 (m, 1 H).

[0266] LC / MS (Table 1 , Method C) Rt = 4.78 min; MS m / z: 409 [M+H]+.

[0267] Compound 18

[0268] / V-(Cyclopropyl(2-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3- difluoro-1 -hydroxycyclobutyl )acetami de (Isomer 2)

[0269] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , steps (iv), using the appropriate starting materials, cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methanamine and 2-(3,3-difluoro-1- hydroxycyclobutyl)acetic acid (CAS: 2295815-26-6). A / -(Cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)-2-(3,3-difluoro-1 -hydroxycyclobutyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 7) followed by SFC (Table 2, Method 2) to afford the title compound (20 mg, 11 %, 98% De) as an off- white gum.

[0270] 1H NMR (400 MHz, DMSO-d6) 5 8.51 (d, J=8.0 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.09 (dd, J=1 .3, 5.3 Hz, 1 H), 6.90 (s, 1 H), 5.93-5.82 (m, 1 H), 5.61 (s, 1 H), 4.20 (t, J=8.5 Hz, 1 H), 2.89- 2.76 (m, 2H), 2.61 -2.51 (m, 4H), 1.44 (d, J=6.5 Hz, 3H), 1.14-1.04 (m, 1 H), 0.55-0.44 (m, 3H), 0.36-0.30 (m, 1 H).

[0271] LC / MS (Table 1 , Method C) Rt = 4.77min; MS m / z: 409 [M+H]+.

[0272] Compound 19

[0273] 2-(Bicyclo[1.1.1]pentan-1-yl)- / V-(cyclopropyl(2-((( / ?)-1,1,1-trifluoropropan-2- yl)oxy)pyridin-4-yl)methyl)acetamide (Isomer 1)

[0274] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(2-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyridin-4-yl)methanam ine and 2-(bicyclo[1 .1.1 ]pentan-1 -yl)acetic acid (CAS: 131515-31-6). 2-(Bicyclo[1 .1 ,1]pentan-1-yl)-A / -(cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2 Method 5) followed by SFC (Table 2, Method 9) to afford the title compound (46 mg, 27%, 98% De) as an off-white gum.

[0275] 1H NMR (400 MHz, DMSO-d6) 5 8.38 (d, J=8.1 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.07 (dd, J=1.4, 5.3 Hz, 1 H), 6.89 (s, 1 H), 5.92-5.84 (m, 1 H), 4.14 (t, J=8.7 Hz, 1 H), 2.42 (s, 1 H), 2.29 (d, J=3.3 Hz, 2H), 1.68-1.67 (m, 6H), 1.44 (d, J=6.5 Hz, 3H), 1.11 -1.03 (m, 1 H), 0.53-0.42 (m, 3H), 0.34-0.28 (m, 1 H).

[0276] LC / MS (Table 1 , Method C) Rt = 5.22 min; MS m / z: 369 [M+H]+.

[0277] Compound 20

[0278] 2-(Bicyclo[1.1.1]pentan-1-yl)- / V-(cyclopropyl(2-((( / ?)-1,1,1-trifluoropropan-2- yl)oxy)pyridin-4-yl)methyl)acetamide (Isomer 1)

[0279] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, cyclopropyl(2-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyridin-4-yl)methanam ine and 2-(bicyclo[1 .1.1 ]pentan-1 -yl)acetic acid (CAS: 131515-31-6). 2-(Bicyclo[1 .1 ,1]pentan-1-yl)-A / -(cyclopropyl(2-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyridin-4-yl)methyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 9) to afford the title compound (46 mg, 27%, 98% De) as an off-white gum.

[0280] 1H NMR (400 MHz, DMSO-d6) 5 8.38 (d, J=8.3 Hz, 1 H), 8.12 (d, J=5.3 Hz, 1 H), 7.08 (dd, J=1.4, 5.3 Hz, 1 H), 6.88 (s, 1 H), 5.91 -5.83 (m, 1 H), 4.15 (t, J=8.7 Hz, 1 H), 2.43 (s, 1 H), 2.34- 2.24 (m, 2H), 1.68 (s, 6H), 1.44 (d, J=6.5 Hz, 3H), 1.12-1.02 (m, 1 H), 0.52-0.44 (m, 3H), 0.34-0.29 (m, 1 H).

[0281] LC / MS (Table 1 , Method C) Rt = 5.2 min; MS m / z: 369 [M+H]+.

[0282] Compound 21

[0283] / V-(3,3-Difluoro-1-(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propyl)-2-(3,3- difluorocyclobutyl)acetamide (2 Diastereoisomers)

[0284] (i) (R)-4-Bromo-6-((1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidine

[0285] A reaction vessel was charged with 4,6-dibromopyrimidine (2.1 g, 8.83 mmol, CAS: 36847- 10-6) and solvated in MeCN (40 mL). (R)-1 ,1 ,1 -Trifluoro-2-propanol (0.76 mL, 8.41 mmol, CAS: 75-89-8) was added, and the solution was stirred at RT until dissolution had occurred. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (1.3 mL, 8.83 mmol) was added dropwise and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo. The reaction was next partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to DCM, gradient elution) to afford the title compound as a colourless oil (1.26 g, 55%).

[0286] 1H NMR (400 MHz, CDCI3) 6 8.55-8.55 (m, 1 H), 7.07 (d, J=0.9 Hz, 1 H), 5.83-5.76 (m, 1 H), 1.52 (d, J=6.5 Hz, 3H).

[0287] (ii) Tert-Butyl (3, 3-dif luoro-1 -(6-(((R)-1 ,1 , 1 -trifluoropropan-2-yl)oxy)pyrimidin-4- yl)propyl)carbamate (2 Diastereoisomers)

[0288] A reaction vessel was charged with 4,4'-di-tert-butyl-2,2'-bipyridine (35 mg, 0.129 mmol), (R)-4-bromo-6-((1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidine (350 mg, 1 .29 mmol), (S)-2-((tert- butoxycarbonyl)amino)-4,4-difluorobutanoic acid (463 mg, 1.94 mmol), nickel(ll) chloride ethylene glycol dimethyl ether complex (28 mg, 0.129 mmol), potassium phosphate tribasic (822 mg, 3.87 mmol) and [lr{dF(CF3)ppy}2(dtbpy)]PF6 complex (29 mg, 0.0258 mmol, CAS: 870987-63-6) in dimethyl sulfoxide (10 mL). The reaction vessel was sealed, evacuated and purged with argon for 1 h. The reaction was next irradiated under blue light irradiation (I = 440 nm) for 24 h. The reaction was partitioned between EtOAc and distilled water. The organic layer was separated. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (cyclohexane to EtOAc gradient elution) to afford the title compound as a colourless oil (25 mg, 5%).

[0289] LC / MS (Table 1 , Method A) RT 1 .78 min; MS m / z 386 [M+H]+.

[0290] (iii) 3,3-Difluoro-1 -(6-(((R)-1 , 1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propan-1 -amine (2 Diastereoisomers)

[0291] A reaction vessel was charged with fe / Y-butyl (3,3-difluoro-1 -(6-(((R)-1 ,1 ,1-trifluoropropan- 2-yl)oxy)pyrimidin-4-yl)propyl)carbamate (25 mg, 0.0649 mmol) and solvated in DCM (0.5 mL). 3M hydrogen chloride in CPME (173 mL, 30.0 mmol) was added and the reaction was stirred at RT for 24 h. The reaction was concentrated in vacuo to afford the title compound (18.5 mg, quant.) as a colourless oil. The product was used without further purification in the subsequent reaction.

[0292] LC / MS (Table 1 , Method A) Rt= 1.36 min; MS m / z: 286 [M+H]+.

[0293] (iv) A / -(3,3-Difluoro-1 -(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propyl)-2-(3,3- difluorocyclobutyl)acetamide (2 Diastereoisomers)

[0294] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, 3,3-difluoro-1-(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propan-1 -amine and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). A / -(3,3-Difluoro-1-(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)propyl)-2-(3,3-difluorocyclobutyl)acetamide mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 10) to afford the title compound (19 mg, 73%) as an off-white solid.

[0295] 1H NMR (400 MHz, DMSO-d6) 5 8.82 (s, 1 H), 8.60-8.54 (m, 1 H), 6.98 (s, 1 H), 6.30-5.93 (m, 2H), 5.05-4.97 (m, 1 H), 2.70-2.60 (m, 2H), 2.45-2.26 (m, 7H), 1.48 (d, J=6.5 Hz, 3H).

[0296] LC / MS (Table 1 , Method C) Rt = 4.77 min; MS m / z: 418 [M+H]+.

[0297] Compound 22

[0298] / V-(3,3-Difluoro-1-(6-((( / ?)-1,1,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propyl)-2-(3,3- difluorocyclobutyl)acetamide (Isomer 2) The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, 3,3-difluoro-1-(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propan-1 -amine and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). A / -(3,3-Difluoro-1-(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)propyl)-2-(3,3-difluorocyclobutyl)acetamide Compound 21 (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 10) followed by SFC (Table 2, Method 2) to afford the title compound (4.0 mg, 21 %, 90% De) as an off-white solid.

[0299] 1H NMR (400 MHz, DMSO-d6) 5 8.82 (s, 1 H), 8.54 (d, J=8.1 Hz, 1 H), 6.98 (s, 1 H), 6.30-5.94 (m, 2H), 5.01 (td, J=4.7, 13.2 Hz, 1 H), 2.71 -2.58 (m, 2H), 2.45-2.27 (m, 7H), 1.48 (d, J=6.5 Hz, 3H).

[0300] LC / MS (Table 1 , Method C) Rt = 4.78 min; MS m / z: 418 [M+H]+.

[0301] Compound 23

[0302] 2-(3,3-Difluorocyclobutyl)- / V-(2-methoxy-1-(6-((( / ?)-1,1,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)ethyl)acetamide (Isomer 2)

[0303] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, 2-methoxy-1-(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)ethan-1 -amine hydrochloride and 2-(3,3- difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). 2-Methoxy-1-(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)ethan-1 -amine hydrochloride was prepared using an analogous reaction protocol to that described for Compound 21 , steps (ii-iii), using the appropriate starting materials, (R)-4-bromo-6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidine (Compound 21 , step (i)) and A / -(te / Y-butoxycarbonyl)-O-methyl-L-serine. 2-(3,3- Difluorocyclobutyl)- / V-(2-methoxy-1 -(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidin-4- yl)ethyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 3) to afford the title compound (12 mg, 8%, 90% De) as an off-white oil.

[0304] 1H NMR (400 MHz, DMSO-d6) 5 8.80 (d, J=1 .0 Hz, 1 H), 8.46 (d, J=8.1 Hz, 1 H), 6.97 (s, 1 H), 6.02-5.91 (m, 1 H), 5.00 (ddd, J=4.8, 6.2, 8.3 Hz, 1 H), 3.69-3.58 (m, 2H), 3.23 (s, 3H), 2.69- 2.55 (m, 2H), 2.42-2.23 (m, 5H), 1.48 (d, J=6.5 Hz, 3H).

[0305] LC / MS (Table 1 , Method C) Rt = 4.51 min; MS m / z: 398 [M+H]+. Compound 24

[0306] 2-(3,3-Difluorocyclobutyl)-N-((1 / ?,2S)-2-methoxy-1-(6-((( / ?)-1,1,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)propyl)acetamide

[0307] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv) using the appropriate starting materials, (1 R,2S)-2-methoxy-1-(6- (((R)-1 ,1 ,1-trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propan-1 -amine hydrochloride and 2-(3,3- difluorocyclobutyl)acetic acid (CAS: 1373503-48-0). (1R,2S)-2-Methoxy-1-(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propan-1 -amine hydrochloride was prepared using an analogous reaction protocol to that described for Compound 21 , steps (ii-iii), using the appropriate starting materials, (R)-4-bromo-6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidine (Compound 21 , step (i)) and A / -(te / Y-butoxycarbonyl)-O-methyl-L-threonine. 2-(3,3- Difluorocyclobutyl)- / V-((1 R,2S)-2-methoxy-1 -(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)propyl)acetamide was purified by flash column chromatography (cyclohexane to EtOAc gradient elution) to afford the title compound as a colourless oil (37 mg, 58%).

[0308] 1H NMR (400 MHz, DMSO-d6) 5 8.81 (d, J=1 .0 Hz, 1 H), 8.34 (d, J=9.0 Hz, 1 H), 6.96 (s, 1 H), 6.02-5.91 (m, 1 H), 4.88 (dd, J=3.3, 9.1 Hz, 1 H), 3.97-3.90 (m, 1 H), 3.10 (s, 3H), 2.71 -2.57 (m, 2H), 2.56-2.50 (m, 2H, partially obscured by solvent peak), 2.48-2.24 (m, 3H), 1.48 (d, J=6.5 Hz, 3H), 1.08 (d, J=6.3 Hz, 3H).

[0309] LC / MS (Table 1 , Method C) Rt = 4.9 min; MS m / z: 412 [M+H]+.

[0310] Compound 25

[0311] 2-(3,3-Difluorocyclobutyl)- / V-(2-methyl-1-(6-((( / ?)-1,1,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)propyl)acetamide (Isomer 2)

[0312] (i) Te / Y-Butyl (2-(3,3-difluorocyclobutyl)acetyl)-D-valinate The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, te / Y-butyl D-valinate hydrochloride (CAS: 13518-40-6) and 2-(3,3-difluorocyclobutyl)acetic acid (CAS: 1373503- 48-0). Tert-butyl (2-(3,3-difluorocyclobutyl)acetyl)-D-valinate was purified by flash column chromatography (DCM to DCM:MeOH 96:4 gradient elution) to afford the title compound as an off-white solid (304 mg, 83%).

[0313] LC / MS (Table 1 , Method A) Rt= 1 .65 min; MS m / z: 328 [M+Na]+.

[0314] (ii) (2-(3,3-Difluorocyclobutyl)acetyl)-D-valine

[0315] A reaction vessel was charged with tert-butyl (2-(3,3-difluorocyclobutyl)acetyl)-D-valinate (132 mg, 0.432 mmol) and solvated in DCM (2.2 mL). The reaction was stirred at RT for 1 .5 h. The reaction was azeotroped in vacuo with toluene to afford the title compound as an off- white solid (107 mg, quant.).

[0316] LC / MS (Table 1 , Method A) Rt = 1 .17 min; MS m / z: 250 [M+H]+.

[0317] (iii) 2-(3,3-Difluorocyclobutyl)- / V-(2-methyl-1 -(6-(((R)-1 ,1 ,1 -trifluoropropan-2- yl)oxy)pyrimidin-4-yl)propyl)acetamide (Isomer 2)

[0318] The title compound was prepared using an analogous reaction protocol to that described for Compound 21 , step (ii), using the appropriate starting materials, (R)-4-bromo-6-(( 1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidine (Compound 21 , step (i)) and (2-(3,3- difluorocyclobutyl)acetyl)-D-valine. 2-(3,3-Difluorocyclobutyl)- / V-(2-methyl-1 -(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)propyl)acetamide was purified by RP-HPLC (Table 2, Method 5 next 7) followed by SFC (Table 2, Method 4) to afford the title compound (2.77 mg, 5%, 2.5%, 98% De) as an off-white solid.

[0319] 1H NMR (400 MHz, DMSO-d6) 5 8.80 (d, J=1 .0 Hz, 1 H), 8.25 (d, J=8.8 Hz, 1 H), 6.96 (s, 1 H), 6.01 -5.90 (m, 1 H), 4.66 (dd, J=6.8, 8.8 Hz, 1 H), 2.69-2.57 (m, 2H), 2.45-2.23 (m, 5H), 2.22- 2.13 (m, 1 H), 1.48 (d, J=6.5 Hz, 3H), 0.80 (dd, J=6.8, 10.3 Hz, 6H). LC / MS (Table 1 , Method C) Rt = 4.97 min; MS m / z: 396 [M+H]+.

[0320] Compound 26

[0321] 2-(3,3-Difluoro-1-hydroxycyclobutyl)- / V-(3-methyl-1-(6-(((R)-1,1,1-trifluoropropan-2- yl)oxy)pyrimidin-4-yl)butyl)acetamide (Isomer 1 )

[0322] The title compound was prepared using an analogous reaction protocol to that described for Compound 1 , step (iv), using the appropriate starting materials, 3-methyl-1 -(6-(((R)-1 ,1 ,1 - trifluoropropan-2-yl)oxy)pyrimidin-4-yl)butan-1 -amine hydrochloride and 2-(3,3-difluoro-1 - hydroxycyclobutyl)acetic acid (CAS: 2295815-26-6). 3-Methyl-1 -(6-(((R)-1 ,1 ,1- trifluoropropan-2-yl)oxy)pyrimidin-4-yl)butan-1 -amine hydrochloride was prepared using an analogous reaction protocol to that described for Compound 21 , steps (ii-iii), using the appropriate starting materials, (R)-4-bromo-6-((1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrimidine (Compound 21 , step (i)) and (tert-butoxycarbonyl)-D-leucine. 2-(3,3-Difluoro-1 - hydroxycyclobutyl)- / V-(3-methyl-1 -(6-(((R)-1 ,1 ,1 -trifluoropropan-2-yl)oxy)pyrim idin-4- yl)butyl)acetamide (mixture of two diastereoisomers) was purified by RP-HPLC (Table 2, Method 5) followed by SFC (Table 2, Method 11 ) to afford the title compound (9.7 mg, 10%, 93% De) as an off-white solid.

[0323] 1H NMR (400 MHz, DMSO-d6) 5 8.78 (d, J=1 .0 Hz, 1 H), 8.35 (d, J=8.1 Hz, 1 H), 7.00 (s, 1 H), 6.00-5.90 (m, 1 H), 5.65 (s, 1 H), 4.83 (dd, J=7.9, 14.7 Hz, 1 H), 2.89-2.76 (m, 2H), 2.64-2.53 (m, 2H), 2.52-2.49 (m, 2H), 1 .68-1 .54 (m, 3H), 1 .47 (d, J=6.5 Hz, 3H), 0.89 (t, J=6.7 Hz, 6H).

[0324] LC / MS (Table 1 , Method C) Rt = 5.09 min; MS m / z: 426 [M+H]+.

[0325] EXAMPLE 2

[0326] Assessment of in vitro potency against Kv7.2 / 7.3 channels

[0327] An automated patch-clamp assay on the Sophion Qube 384 was developed for potency testing to identify small molecule activators of heteromeric Kv7.2 / 7.3 channels (KCNQ2, Uniprot ID 043526; KCNQ3, Uniprot 043525).

[0328] The cell line used was a stably transfected CHO-K1 cell line with constitutive Kv7.2 / 7.3 expression.

[0329] CHO-K1 / KV7.2 / KV7.3 cells were maintained in the following culture media:

[0330] DMEM / F-12 with GlutaMAX™ (Gibco 31331 -028), 10% Fetal clone 2 serum (Perbio Science SH30066.03), • 1 mg / ml Geneticin™ selective antibiotic (G418, Invitrogen 1013027), and

[0331] • 5 pg / ml BlasticidinS HCI (Invivogen Ant-bl-5).

[0332] On the day of the experiment, cells were resuspended in serum free media, counted and diluted to a final concentration of 3.5x106cells per ml of media.

[0333] Cells were then placed onto the Sophion Qube 384 and rested for a minimum of 1 hour.

[0334] The following solutions were used for recording:

[0335] • extracellular solution (in mM): 145 NaCI, 4 KCI, 1 MgCI2, 2 CaCI2, 10 HEPES, 10 glucose, pH 7.4, 315-320 mOsm.

[0336] • intracellular solution (in mM): 120 KCI, 5.74 CaCI2, 1.75 MgCI2, 10 EGTA, 10 HEPES, 5 Na2ATP, pH 7.2, adjusted to 315 mOsm with sucrose.

[0337] After establishing the whole-cell configuration, cells were held at -80 mV throughout the experiment. A current-voltage (l-V) protocol stepping from -100 to +20 mV for 1 second was applied to measure Kv7.2 / 7.3 currents, each step was followed by a 200 ms pulse to 0 mV to measure the tail currents. From the l-V protocol a Boltzmann fit was applied to generate activation curves. Data were sampled at 25 kHz and filtered at 5 kHz (Bessel). Data were produced using multihole QChips. The l-V protocol was applied several times to establish the response in control conditions (typically 0.3% DMSO) and in the presence of the test compound.

[0338] Data were reviewed in Sophion Analyser version 6.5.2 (Sophion Bioscience) for recording quality and filters were applied to remove any failed wells. Leak subtraction was applied to all recordings. Data filters for multihole QChips were typically: seal resistance >4 MQ, capacitance >20 pF, baseline VHalf between 0 to -40 mV, baseline holding current between -2 to 2 nA, baseline steady state current at 20 mV >4 nA unless otherwise stated.

[0339] Analysis of data for assessment of potency

[0340] 10 concentrations of test compounds were applied to individual wells in quadruplicate to assess potency as a 1 in 3 dilution series from the maximal concentration of 30 mM. The average shift in the voltage for half activation (Vhaif) for each concentration was used to generate concentration-response curves fitted with a 4-parameter logistic model to estimate the ECso from the point of inflection of the curve and the maximal shift in the Vhaif from the top of the curve.

[0341] The results of the tested compounds are summarized in Table 3 below. The lower the EC50 value, the higher the activity of the analyzed compound.

[0342] TABLE 3

[0343] The obtained EC50 values showed that all the tested compounds have an ability to activate Kv7.2 / 7.3 potassium channels.

Claims

CLAIMS1. A Kv7.2 / 7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, having the following general formula (I)whereinR1 is an aromatic ring having 6 members and comprising one or two nitrogen atoms, said aromatic ring being substituted by one or more substituent selected from a linear or branched C1 -C6 alkoxy chain, optionally substituted with one or more halogen atomsR2 is a linear or branched C2-C4 alkyl or a C3-C6 cycloalkyl, said alkyl and cycloalkyl being optionally substituted with OH, CF3, one or more halogen atoms, or C1-C3 alkoxy,R3 is an aliphatic ring, a bridged or condensed bicyclic ring, a spiro residue, or an alkyl group, wherein:(i) said aliphatic ring has three to six members, optionally containing one or more heteroatoms selected from the group consisting of 0 and S, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, and C1 -C3 alkyl, or(ii) said bridged or condensed bicyclic ring has five to twelve members, optionally containing one or more heteroatoms selected from the group consisting of 0 and S, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl, wherein said bicyclic ring comprises two aliphatic cycles, or(iii) said spiro residue comprises two aliphatic rings having five to eight members, optionally containing one or more heteroatoms selected from the group consisting of 0 and S, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl, or(iv) said alkyl group is a linear or branched C1 -C6 alkyl group.

2. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R1 is pyridine, pyridazine, pyrimidine, or pyrazine, more preferably pyridine or pyrimidine.

3. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R1 is substituted by one or more substituent selected from a linear or branched C1 -C3 alkoxy chain substituted by one or more halogen atoms selected from fluoride, chloride, bromide, and iodide, preferably fluoride and chloride.

4. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R2 is selected from ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, optionally substituted with OH, CF3, one or more halogen atoms, or C1 -C3 alkoxy.

5. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R2 is selected from ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl, wherein one or more hydrogen atom is substituted by(i) a halogen atom, preferably fluoride and chloride, more preferably fluoride, or(ii) a C1 -C3 alkoxy, preferably a methoxy and ethoxy, more preferably methoxy.

6. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl, and cyclobutyl, optionally substituted with OH, CF3, one or more halogen atoms, preferably fluoride and chloride, more preferably fluoride, or C1 -C3 alkoxy, preferably methoxy and ethoxy.

7. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R3 is an aliphatic ring selected from the group consisting of cyclopropane, cyclobutane, cyclopentane, cyclohexane, oxetane, tetrahydrofuran, tetrahydropyran, and tetrahydrothiopyran, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl.

8. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R3 is a bridged or condensed bicyclic ring selected from the group consisting of bicyclo[2.2.2]octane, bicyclo[1.1.1 ]pentane, indane (2,3-dihydro-1 H-indene), chromane (3, 4-dihydro-2 / - / -1 -benzopyran), coumaran (2,3-dihydro-1 -benzofuran), tetralin (1 ,2,3,4-tetrahydronaphthalene), thiochroman (3,4-dihydro- 2 / - / -1 -benzothiopyran), 5,6-dihydro-4 / - / -cyclopenta[b]thiophene, 2,3,4,5-tetrahydro-1 - benzoxepine, and 6,7,8,9-tetrahydro-5H-benzo[7]annulene, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl.

9. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R3 is a spiro residue selected from the group consisting of spirohexane, spiro[3.3]heptane, and 2-oxaspiro[3.3]heptane, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, oxo, CF3, C1 -C3 alkyl.

10. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , wherein R3 is a linear or branched alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl, pentyl, isopentyl, 2-methylpenthyl, 3-methylpenthyl, 2,3-dimethylbutyl, 2,2-dimethylbutyl, and hexyl group.

11. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to claim 1 , whereinR1 is pyridine or pyrimidine, substituted by a substituent selected from CF3-CH2-O- and CF3-CH(CH3)-O-.R2 is a cyclopropyl, andR3 is an aliphatic ring having the following formulas:

12. The Kv7.2 / Kv7.3 potassium channel activator compound according to claim 1 , wherein said compound is selected from the group consisting of the compounds of the following Table A, or a pharmaceutically acceptable salt thereofTable A13. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, wherein said pharmaceutically acceptable salt is chosen from the group consisting of salts with organic acids, preferably oxalic, maleic, methanesulfonic, paratoluenesulfonic, succinic, citric, malic, tartaric and lactic acids, salts with organic bases, preferably thromethamine, lysine, arginine, glycine, alanine and ethanolamine, salts with inorganic acids, preferably hydrochloric, hydrobromic, phosphoric and sulfuric acids, and salts with inorganic bases, preferably hydroxide or carbonate of alkaline or alkaline-earth metals, such as sodium, potassium and calcium.

14. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13 for use as a drug.

15. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, for use in treating disorders that are modulated by Kv7.2 / Kv7.3 potassium channels.

16. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, for use according to claim 15, wherein said disorders that aremodulated by Kv7.2 / Kv7.3 potassium channels are central nervous system (CNS) and peripheral nervous system (PNS) disorders.

17. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, for use according to claim 16, wherein said central nervous system (CNS) disorders are selected from the group consisting of epilepsy, epileptic syndromes, epileptic symptoms, epilepsy resistant or refractory to treatment, seizures, bipolar disorder, bipolar depression, schizophrenia, psychosis, mania, stress-related disorders, acute stress reactions, major depressive disorder, anxiety, panic attacks, social phobia, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, impulsivity disorders, personality disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and tinnitus.

18. The Kv7.2 / Kv7.3 potassium channel activator compound, or a pharmaceutically acceptable salt thereof, for use according to claim 16, wherein said peripheral nervous system (PNS) disorders are selected from the group consisting of migraine, chronic pain, acute pain, neuropathic pain, visceral pain, inflammatory pain, and muscle pain.

19. A pharmaceutical composition comprising (i) the Kv7.2 / Kv7.3 potassium channel activating compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 13, and (ii) at least one pharmaceutically acceptable excipient.

20. The pharmaceutical composition according to claim 18, for use as defined in any one of claims 15 to 18.

21. A method of treatment of disorders that are modulated by Kv7.2 / Kv7.3 potassium channels, selected from the group consisting of central nervous system (CNS) and peripheral nervous system (PNS) disorders, by the administration to a human being in need thereof of an effective amount of a compound as defined in any one of claims 1 to 13.

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