Compounds and methods for treating spasticity

Abstract

Provided herein are methods for the treatment and prevention of spasticity in a patient in need thereof. Certain methods comprise administering an effective amount of an adaptor associated kinase 1 inhibitor of formula (I). TIFF2025514644000048.tif63170

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 331,547, filed April 15, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to compounds, compositions, and methods useful for the treatment and prevention of spasticity. [Background technology]

[0003] The present invention relates to compounds, compositions, and methods useful for the treatment and prevention of spasticity.

[0004] Spasticity is defined as a velocity-dependent increase in the tonic stretch reflex with excess of movement due to hyperexcitability of the stretch reflex. Chang, E., et al., Crit Rev Phys Rehabil Med., 2013, 25(1-2): 11-22. It is a well-known phenomenon seen in patients of all ages with a wide range of central nervous disorders and can be a feature of a single traumatic attack or from a chronic neurological condition. Id.; Stevenson V, Playford D., Medicine, 2012, 40: 513-7. It is often recognized as one component of upper motor neuron syndromes, which are alterations in motor control seen after damage to the upper motor neurons that control voluntary skeletal movement. Some examples of upper motor neuron pathology include spinal cord injury (SCI), cerebral palsy, stroke, amyotrophic lateral sclerosis, and multiple sclerosis (MS). In fact, spasticity is the most commonly reported symptom of MS, seen in 90% of patients with this disorder. Ashton JC., Degener Neurol Neuromuscul Dis.,2011,1:15-23.

[0005] Spasticity can be disabling and can be triggered at any time by a variety of stimuli. External factors such as constipation, urinary tract infections, and bedsores can exacerbate spasticity and its symptoms. Kischka U.,Medicine,2008 36:616-9. Spasticity can also have functionally limiting and painful sequelae, including reduced joint mobility, reduced muscle flexibility, and sleep disorders secondary to airway obstruction. Left untreated, spasticity can lead to deformities such as kyphoscoliosis and contractures, the correction of which can be difficult. Chang,supra.

[0006] Existing therapeutic agents used to treat spasticity include centrally acting drugs such as baclofen, clonidine, and tizanidine, anticonvulsants such as benzodiazepines and gabapentin, and peripherally acting agents such as dantrolene. Each of these therapies is associated with side effects. Id. For example, side effects of baclofen, a GABA B agonist used as a first-line treatment for spasticity, include generalized muscle relaxation, sedation, and fatigue. Chou R.et al.,J Pain Symptom Manage.,2004,28:140-75. Due to potential hepatotoxicity, use of baclofen requires monitoring of liver function. Oral baclofen is not recommended for elderly patients due to excessive drowsiness. In addition, caution should be exercised when treating patients recovering from brain injury, as there is some evidence of detrimental effects on brain plasticity. Withdrawal from baclofen treatment has been associated with hyperthermia, seizures, and altered mental status. Chang,supra.

[0007] Alpha-2 agonists used to treat spasticity include clonidine and tizanidine. Clonidine is rarely used as a single agent to treat spasticity due to side effects including hypotension, bradycardia, and drowsiness. Rabchevsky AG, Kitzman PH., Neurotherapeutics 2011, 8:274-82. Tizanidine is often combined with other oral medications such as baclofen, which requires frequent dosing due to its short half-life and may be associated with side effects such as sedation, hypotension, xerostomia, muscle weakness, and hallucinations. Tizanidine is contraindicated in patients taking hypertensive medications and is known to prolong the QT interval. Chang, supra.

[0008] Anticonvulsants used to treat spasticity are also associated with various side effects. For example, diazepam and clonazepam cause significant sedation, and their long-term use can lead to increased dependence and tolerance. Gabapentin, which is not usually used as a first-line treatment, can cause somnolence, tremors, and nystagmus. Lapeyre E, et al., Neuro Rehabilitation, 2010, 27:193-200.

[0009] While skilled physicians often modify the types and dosages of drugs used to treat a patient's spasticity, there is a clear need for new treatment methods, especially methods that avoid the side effects and risk of addiction associated with existing drugs. Summary of the Invention

[0010] The present invention is based on the discovery that spasticity can be reduced by inhibiting adaptor associated kinase 1 (AAK1).Accordingly, one embodiment of the present invention includes a method for treating or preventing spasticity, comprising inhibiting adaptor associated kinase 1 (AAK1) in a patient who needs to treat or prevent spasticity.Another embodiment includes a method for treating or preventing spasticity, comprising administering a therapeutically or prophylactically effective amount of an AAK1 inhibitor to a patient who needs to treat or prevent spasticity.

[0011] In certain embodiments of the invention, the patient suffers from spinal cord injury, cerebral palsy, stroke, amyotrophic lateral sclerosis, or multiple sclerosis. In certain embodiments, the AAK1 inhibitor has formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein A is, [ka] is selected from During the ceremony, [ka] indicates the point of attachment to B, B is, [ka] wherein "*" is selected from R 5 indicates the point of attachment to ring A; R 1 is hydrogen, amino, -CO 2 H, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methyl, -NHC(O)CH 3 , -NHCO 2 CH 3 , trifluoromethoxy, and trifluoromethyl; R 2 is hydrogen, cyano, -CH 2 OH, halo, and methyl; R 3 is hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, -CH 2 N(CH 3 ) 2 and a 5-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R4 is selected from hydrogen, halo, and methyl; R 5 teeth, [ka] is selected from R 6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl; R 7 is methyl.

[0012] In some embodiments, the AAK1 inhibitor has formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein A is, [ka] is selected from [ka] indicates the point of attachment to B, B is selected from phenyl and pyridinyl; R 1 is hydrogen, difluoromethyl, halo, methoxy, methyl, -NHC(O)CH 3 , -NHCO 2 CH 3 and trifluoromethyl; R 2 is hydrogen, -CH 2 OH, and halo; R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, trifluoromethoxy, trifluoromethyl, and a 5-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R 4 is selected from hydrogen, halo, and methyl; R 6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl.

[0013] In certain embodiments of the invention, A is [ka] It is.

[0014] In certain embodiments, B is [ka] It is.

[0015] In certain embodiments, R 5 teeth, [ka] It is.

[0016] Certain embodiments of the invention encompass methods of treating or preventing spasticity, the methods comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of an adaptor associated kinase 1 (AAK1) inhibitor, wherein the AAK1 inhibitor is (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine, [ka] or a pharma- ceutically acceptable salt thereof. One particular salt is ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate, which may be administered orally.

[0017] Aspects of the invention may be better understood by reference to one or more of the following drawings. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 provides a schematic diagram of the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) mouse model used herein. [Diagram 2] Von Frey (VF) results on day 9 post-dose of the study are shown: #p<0.05 vs. vehicle (group 1) using one-way ANOVA followed by Dunnett's test, ##p<0.01 vs. vehicle using one-way ANOVA followed by Dunnett's test, ###p<0.001 vs. vehicle using one-way ANOVA followed by Dunnett's test. [Diagram 3] Results of electromyography (EMG) measurements are shown: #p<0.05 vs. vehicle (group 1) using one-way ANOVA followed by Dunnett's test, ##p<0.01 vs. vehicle using one-way ANOVA followed by Dunnett's test. [Figure 4] Results of measurements of latency to main event are shown. ##p<0.05 vs. vehicle (group 1) using one-way ANOVA followed by Dunnett's test. [Diagram 5] Results of peak-to-peak (P2P) amplitude measurements show: ###p<0.001 vs. vehicle using one-way ANOVA followed by Dunnett's test; and ####p<0.0001 vs. vehicle using one-way ANOVA followed by Dunnett's test (Group 1). [Figure 6] Representation of the Hoffmann reflex. (A) provides a schematic showing how the Hoffmann reflex can be elicited: 1) by direct activation of motor axons, 2) by monosynaptic activation of motor neurons (α) by Ia afferents, (B) provides an example of an electromyogram recording. Each trace is the response to a single stimulus at 0.2 Hz. [Figure 7] FIG. 1 shows that the effect of Compound 1 (10, 30 mg / kg) on ​​the mean relative amplitude of the H-reflex lasted for at least 6 hours. [Figure 8]Figure 1 shows how more spastic, sustained muscle contractions are evoked in chronic SCI rats. (A) shows FDB EMG responses to stimulation of the tibial nerve (single pulse every 60 s, 10 sweeps) in acute SCI rats (1 week after injury); (B) shows the effect in chronic SCI rats (5 weeks after injury); (C) shows how more spastic, sustained muscle contractions are evoked in chronic SCI rats (n=70) than in acute SCI rats (n=8, ****P<0.0001; Mann-Whitney test). Data are presented as mean ± SEM. [Figure 9] FIG. 1 shows a dose-dependent reduction in muscle spasms in SCI rats 3 hours after administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention is based on the discovery that inhibition of adaptor associated kinase 1 (AAK1) (eg, by administration of a centrally acting AAK1 inhibitor) can reduce spasticity in established animal models.

[0020] Adaptor associated kinase 1 is a member of the Ark1 / Prk1 family of serine / threonine kinases. Recently, it has been disclosed in the literature that many AAK1 inhibitors may be useful for treating neuropathic pain. See, for example, U.S. Pat. No. 9,902,722; Hartz, RA, et al., J. Med. Chem., 2021 Aug12; 64(15): 11090-11128; Luo G., et al., J Med Chem. 2022 Mar24; 65(6): 4534-4564; and Luo G, et al., J Med Chem. 2022 Mar24; 65(6): 4457-4480. However, the mechanism by which the compounds exert their pharmacological effects remains unclear. Much work remains to be done before those skilled in the art fully understand how AAK1 inhibition can reduce neuropathic pain.

[0021] definition In describing and claiming the present disclosure, the following terminology will be used in accordance with the definitions set out below.

[0022] Unless otherwise specified, the terms "manage," "managing," and "management" include preventing the recurrence of a particular disease or disorder in a patient already suffering from the disease or disorder and / or increasing the time that a patient suffering from a disease or disorder remains in remission. The term includes modulating the threshold, onset, and / or duration of the disease or disorder, or altering the way in which a patient responds to a disease or disorder.

[0023] Unless otherwise indicated, the terms "prevent", "preventing", and "prevention" refer to an action that occurs before a patient becomes afflicted with a particular disease or disorder, thereby inhibiting the disease or disorder or reducing the severity of the disease or disorder. In other words, these terms encompass prophylaxis.

[0024] Unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease or condition, or one or more symptoms associated with a disease or condition. A "prophylactically effective amount" of a compound is an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of a disease. The term "prophylactically effective amount" encompasses an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0025] Unless otherwise specified, a "therapeutically effective amount" of a compound refers to an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or condition, or an amount sufficient to delay or minimize one or more symptoms associated with a disease or condition. A "therapeutically effective amount" of a compound refers to an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment or management of a disease or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0026] Unless otherwise indicated, the terms "treat," "treating," and "treatment" contemplate actions that occur while a patient is afflicted with a particular disease or disorder, and that reduce the severity of the disease or disorder, retard, or slow the progression of the disease or disorder. As used herein, the term encompasses the management of the disease or disorder.

[0027] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0028] Unless otherwise specified, the term "about" used herein means within the typical tolerance in the art. For example, "about" can be understood as about 2 standard deviations from the mean. In certain embodiments, about means ±10%. In certain embodiments, about means ±5%. When about is present before a series of numbers or ranges, it is understood that "about" can modify each of the numbers in the series or ranges.

[0029] AAK1 inhibitors The present invention encompasses methods of using compositions comprising the adaptor associated kinase 1 (AAK1) inhibitors disclosed in U.S. Patent No. 9,902,722. Certain compounds include those having the formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein: A is, [ka] is selected from the group consisting of [ka] indicates the point of attachment to B, B is, [ka] wherein "*" is selected from R 5 indicates the point of attachment to ring A; R 1 is hydrogen, amino, -CO 2 H, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methyl, -NHC(O)CH 3 , -NHCO 2 CH 3 , trifluoromethoxy, and trifluoromethyl; R 2 is hydrogen, cyano, -CH 2 OH, halo, and methyl; R 3 is hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, -CH 2 N(CH 3 ) 2 and a 5-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R 4 is selected from hydrogen, halo, and methyl; R 5 teeth, [ka] is selected from R6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl; R 7 is methyl.

[0030] In some embodiments of Formula (I), A is [ka] is selected from.

[0031] In some embodiments of Formula (I), B is [ka] is selected from.

[0032] In some embodiments of Formula (I), B is [ka] It is.

[0033] In some embodiments of Formula (I), R 5 teeth, [ka] It is.

[0034] Certain AAK1 inhibitors include those of formula (II): [ka] or a pharma- ceutically acceptable salt thereof, wherein A is, [ka] is selected from [ka] indicates the point of attachment to B, B is selected from phenyl and pyridinyl; R 1 is hydrogen, difluoromethyl, halo, methoxy, methyl, -NHC(O)CH 3 , -NHCO 2 CH 3 and trifluoromethyl; R 2 is hydrogen, -CH 2 OH, and halo; R 3 is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, trifluoromethoxy, trifluoromethyl, and a 5-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R 4 is selected from hydrogen, halo, and methyl; R 6 is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl.

[0035] In some embodiments of Formula (II), A is [ka] is selected from.

[0036] In some embodiments of Formula (II), B is pyridinyl.

[0037] In some embodiments of Formula (II), B is [ka] and During the ceremony, [ka] represents the point of attachment to A, [ka] represents the point of attachment to the oxygen atom.

[0038] In some embodiments of Formula (II), A is [ka] is selected from B is, [ka] It is.

[0039] Specific AAK1 inhibitors include: (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methoxyphenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide, (S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-aminopyridin-4-yl)benzonitrile, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3,5-difluorophenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-chloro-5-fluorophenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-2,5-difluorophenyl)pyridin-2-yl)acetamide, (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate, (S)-methyl(4-(4-((2-amino-4-methylpentyl)oxy)-3-(isoxazol-5-yl)phenyl)pyridin-2-yl)carbamate, (S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile, (S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-methoxypyridin-4-yl)benzonitrile, (S)-2-((2-amino-4-methylpentyl)oxy)-5-(2-(trifluoromethyl)pyridin-4-yl)benzonitrile, (S)-1-(2-(isoxazol-5-yl)-4-(2-methylpyridin-4-yl)phenoxy)-4-methylpentan-2-amine, (S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)carbamate, (S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)carbamate, (S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)acetamide, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(difluoromethyl)phenyl)pyridin-2-yl)carbamate, (S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)acetamide, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethoxy)phenyl)pyridin-2-yl)carbamate, (S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)carbamate, methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-chlorophenyl)pyridin-2-yl)carbamate, methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-methylphenyl)pyridin-2-yl)carbamate, methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-2,3-dimethylphenyl)pyridin-2-yl)carbamate, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(hydroxymethyl)phenyl)pyridin-2-yl)carbamate, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyclopropylphenyl)pyridin-2-yl)carbamate, (S)—N-(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-5-(hydroxymethyl)pyridin-2-yl)acetamide, (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-(difluoromethyl)pyridin-4-yl)benzonitrile, (S)-1-(2-(difluoromethyl)-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethoxy)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(3-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(5-chloro-2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(2-fluoro-3-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(2,3-difluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-(4-(pyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine, (S)-1-(4-(2-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine, (S)-1-(4-(3-methoxypyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(3-fluoropyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-methylpyridin-4-yl)benzonitrile, (S)-1-(2-cyclopropyl-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(2-(difluoromethyl)-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-[3,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methyl-[3,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-cyano-[3,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[3,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-chloro-[3,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methoxy-[3,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2'-chloro-5-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2'-(difluoromethyl)-5-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2'-(difluoromethyl)-[3,4'-bipyridine]-5-carbonitrile, (S)-1-((5-chloro-2'-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',5-dimethyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-methoxy-2'-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2',6-dimethyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-chloro-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((6-chloro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-2,4-dimethyl-1-(4-(quinolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine, (S)-2,4-dimethyl-1-(2-(trifluoromethyl)-4-(7-(trifluoromethyl)quinolin-4-yl)phenoxy)pentan-2-amine, (S)-1-(4-(7-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(5,7-difluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(6-fluoroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(2-cyclopropyl-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, 1-(2-chloro-6-fluoro-4-(quinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(7-fluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5,7-difluoroquinolin-4-yl)nicotinonitrile, (S)-1-((3-chloro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-methoxy-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)nicotinonitrile, (S)-2,4-dimethyl-1-((2-methyl-6-(quinolin-4-yl)pyridin-3-yl)oxy)pentan-2-amine, (S)-2,4-dimethyl-1-((4-methyl-6-(quinolin-4-yl)pyridin-3-yl)oxy)pentan-2-amine, (S)-1-((2-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(1,6-naphthyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,6-naphthyridin-4-yl)benzonitrile, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(1,5-naphthyridin-4-yl)benzonitrile, (S)-1-(4-(7-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)quinoline-7-carbonitrile, (S)-2,4-dimethyl-1-(2-methyl-4-(2-methylpyridin-4-yl)phenoxy)pentan-2-amine, (S)-1-(2-fluoro-4-(2-methylpyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(4-(2-fluoropyridin-4-yl)-2-methylphenoxy)-2,4-dimethylpentan-2-amine, (S)-1-(2-fluoro-4-(2-fluoropyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(2-fluoropyridin-4-yl)benzonitrile, (S)-1-((2'-fluoro-5-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-4-(6-((2-amino-2,4-dimethylpentyl)oxy)-5-methylpyridin-3-yl)quinoline-7-carbonitrile, (S)-1-((5-fluoro-2'-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-fluoro-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-4-(6-((2-amino-2,4-dimethylpentyl)oxy)-5-fluoropyridin-3-yl)quinoline-7-carbonitrile, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-3-fluoropyridin-2-yl)carbamate, (S)-6-((2-amino-2,4-dimethylpentyl)oxy)-2'-methyl-[3,4'-bipyridine]-5-carbonitrile, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(7-methylquinolin-4-yl)benzonitrile, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(3-fluoro-2-methylpyridin-4-yl)benzonitrile, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(quinolin-4-yl)benzonitrile, (S)-2-((2-amino-2,4-dimethylpentyl)oxy)-5-(5-fluoro-2-methylpyridin-4-yl)benzonitrile, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-cyanophenyl)-5-fluoropyridin-2-yl)carbamate, (S)-1-((6-fluoro-2',4-dimethyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, Methyl (5-((3-isobutylazetidin-3-yl)methoxy)-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-2-((2-amino-4-methylpentyl)oxy)-5-(6-methylpyridazin-4-yl)benzonitrile, (S)-1-(2-(isoxazol-5-yl)-4-(quinolin-4-yl)phenoxy)-4-methylpentan-2-amine, (S)-4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(trifluoromethyl)phenyl)-2-methylnicotinic acid, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(dimethylamino)methyl)phenyl)pyridin-2-yl)carbamate, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)-3-(methylsulfonyl)phenyl)pyridin-2-yl)carbamate, (S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(methylsulfonyl)phenoxy)pentan-2-amine, (S)-2,4-dimethyl-1-(2-(methylsulfonyl)-4-(quinolin-4-yl)phenoxy)pentan-2-amine, (S)-1-(2-(difluoromethyl)-4-(6-fluoroquinolin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(difluoromethyl)-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((4-(difluoromethyl)-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',4-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2'-(difluoromethyl)-4-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-(2-cyclopropyl-4-(2-(difluoromethyl)pyridin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, ((S)-1-((4-(difluoromethyl)-6-(6-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-6-(6-(trifluoromethoxy)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(7-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(6-fluoroquinolin-4-yl)-2-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-(difluoromethyl)-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-(difluoromethyl)-6-(6-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-2'-ethyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2'-chloro-4-(difluoromethyl)-3'-fluoro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2'-chloro-4-(difluoromethyl)-5'-fluoro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-((2'-methyl-4-(trifluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)pentan-2-amine, (S)-2,4-dimethyl-1-((6-(quinolin-4-yl)-4-(trifluoromethyl)pyridin-3-yl)oxy)pentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2'-chloro-4-(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-5'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-3'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-6-(2-methylpyrimidin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-(2-(difluoromethyl)-4-(2-methylpyrimidin-4-yl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-5-((2-amino-2,4-dimethylpentyl)oxy)-3'-fluoro-6-methyl-[2,4'-bipyridine]-2'-amine, (S)-1-((2'-chloro-3'-fluoro-6-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-5'-fluoro-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2'-chloro-5'-fluoro-6-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-3'-fluoro-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2'-chloro-6-(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2'-chloro-6-(difluoromethyl)-3'-fluoro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(difluoromethyl)-3'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, ((S)-1-((6-chloro-2'-(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-(difluoromethyl)-6-(6-methylpyridazin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2-(difluoromethyl)-6-(6-methylpyridazin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-2,4-dimethyl-1-((2'-methyl-4-(trifluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)pentan-2-amine, (R)-2,4-dimethyl-1-((6-(quinolin-4-yl)-4-(trifluoromethyl)pyridin-3-yl)oxy)pentan-2-amine, (R)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-(trifluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (R)-1-((2'-chloro-4-(difluoromethyl)-3'-fluoro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((2'-chloro-4-(difluoromethyl)-5'-fluoro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((2'-chloro-4-(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((4-(difluoromethyl)-2'-ethyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((4-(difluoromethyl)-5'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((4-(difluoromethyl)-3'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((2',4-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(4-(difluoromethyl)-5-((2-hydroxy-2,4-dimethylpentyl)oxy)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((4-(difluoromethyl)-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-ol, (S)-Methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (R)-Methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-Methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (R)-Methyl(5-((2-amino-2-(fluoromethyl)-4-methylpentyl)oxy)-4-(difluoromethyl)-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine, (S)-1-((2',4-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine, (R)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine, (R)-1-((2',4-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine, (S)-1-((4-(difluoromethyl)-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine, (R)-1-((4-(difluoromethyl)-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2-(fluoromethyl)-4-methylpentan-2-amine, (S)—N-(4-(4-((2-amino-4-methylpentyl)oxy)-3-fluorophenyl)pyridin-2-yl)acetamide, (S)-1-((3-chloro-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-chloro-5-(6-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-chloro-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2'-chloro-5-(difluoromethyl)-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(difluoromethyl)-2'-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(7-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4'-bipyridin]-2'-yl)carbamate, (S)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',5-bis(difluoromethyl)-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(6-fluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(7-(trifluoromethyl)quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(difluoromethyl)-2',3'-dimethyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(7-methylquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-methoxy-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((2'-(difluoromethyl)-4-methoxy-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-methyl(4-(4-((2-amino-2,4-dimethylpentyl)oxy)naphthalen-1-yl)pyridin-2-yl)carbamate, (S)-2,4-dimethyl-1-((4-(quinolin-4-yl)naphthalen-1-yl)oxy)pentan-2-amine, (S)-methyl(4-(5-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-2-yl)pyridin-2-yl)carbamate, (S)-methyl(4-(2-((2-amino-2,4-dimethylpentyl)oxy)pyrimidin-5-yl)pyridin-2-yl)carbamate, (S)-2,4-dimethyl-1-((2',4,6-trimethyl-[2,4'-bipyridin]-5-yl)oxy)pentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)4,6-dimethyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-2,4-dimethyl-1-(4-(quinazolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine, (S)-1-(4-(3,6-dihydro-2H-pyran-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-(4-(2-methylquinolin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine, (S)-1-(4-(6-chloroquinolin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-((5-(quinolin-4-yl)-3-(trifluoromethyl)pyridin-2-yl)oxy)pentan-2-amine, (S)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(trifluoromethyl)-[3,4'-bipyridin]-2'-yl)carbamate, (S)-2,4-dimethyl-1-((2'-methyl-5-(trifluoromethyl)-[3,4'-bipyridin]-6-yl)oxy)pentan-2-amine, (S)-1-((5-(6-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(6-fluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(5,7-difluoroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(7-chloroquinolin-4-yl)-3-methylpyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(5,7-difluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',4-dimethyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(6-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(6-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(7-chloroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(7-fluoroquinolin-4-yl)-4-methylpyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-6-(5,7-difluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-6-(6-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-6-(quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-4-chloro-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((4-chloro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-6-(6-chloroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',4-dichloro-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-6-(7-fluoroquinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-6-(7-(trifluoromethyl)quinolin-4-yl)pyridin-3-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-2',3'-dimethyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((5-(difluoromethyl)-2'-methyl-[3,4'-bipyridin]-6-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-Methyl(6-((2-amino-2,4-dimethylpentyl)oxy)-5-(difluoromethyl)-[3,4'-bipyridin]-2'-yl)carbamate, (R)-1-((3-(difluoromethyl)-5-(quinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((3-(difluoromethyl)-5-(5,7-difluoroquinolin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (R)-1-((5-(7-chloroquinolin-4-yl)-3-(difluoromethyl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, N-(4'-((2-amino-2,4-dimethylpentyl)oxy)-3'-methyl-[1,1'-biphenyl]-3-yl)acetamide, (S)-1-(4-(2-(difluoromethyl)pyridin-4-yl)-2-(trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-(4-(2-methylpyridin-4-yl)-2-(trifluoromethyl)phenoxy)pentan-2-amine, (S)-Methyl(5-((2-amino-2,4-dimethylpentyl)oxy)-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate, (S)-1-((4-(difluoromethyl)-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-2,4-dimethyl-1-((2'-methyl-4-(trifluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)pentan-2-amine, (S)-1-((4-(difluoromethyl)-3'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((6-(difluoromethyl)-3'-fluoro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((3-(difluoromethyl)-5-(2-methylpyrimidin-4-yl)pyridin-2-yl)oxy)-2,4-dimethylpentan-2-amine, (S)-1-((4-chloro-2'-methyl-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine, and pharma- ceutically acceptable salts thereof.

[0040] A preferred AAK1 inhibitor is (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine: [ka] (herein referred to as “Compound 1”) or a pharma- ceutically acceptable salt thereof. A particular salt of Compound 1 is ((S)-1-((2′,6-bis(difluoromethyl)-[2,4′-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate.

[0041] The AAK1 inhibitors disclosed herein may exist in various solid (e.g., crystalline) forms. A particular solid form of ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate, referred to herein as Form I, is described in U.S. Patent Application No. 18 / 114,104, filed February 24, 2023, and U.S. Provisional Patent Application No. 63 / 315,507, filed March 1, 2022. Crystalline Form I has an average molecular weight of about 4.81, 5.99, 7.44, 7.89, 11.66, 14.85, 15.77, 19.19, 20.0 ... , 20.86, 21.65, 23.96, 24.48, or 24.73 degrees 2θ (measured, for example, using a Bruker X-ray diffractometer equipped with a LYNXEYE detector (copper Kα radiation)). When referring to XPRD peaks herein, the term "about" means ±0.2 degrees 2θ. Crystalline Form I has a melting point of about 184° C. as determined by differential scanning calorimetry (DSC) (melting endotherm). When referring to temperature, the terms "substantially" and "about" mean ±2° C.

[0042] The AAK1 inhibitors disclosed herein can be prepared by methods known in the art, e.g., U.S. Patent No. 9,902,722; Hartz, RA, supra; Luo G., et al., J Med Chem. 2022 Mar24; 65(6): 4534-4564; and Luo G, et al., J Med Chem. 2022 Mar24; 65(6): 4457-4480.

[0043] Pharmaceutical Compositions The pharmaceutical formulations may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, topical, intravenous, or intradermal injection or infusion). Such formulations may be prepared by any method known in the pharmaceutical art, for example, by combining the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection is preferred.

[0044] Pharmaceutical formulations suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil emulsions.

[0045] For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral non-toxic pharma- ceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier, for example, an edible carbohydrate, such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents can also be present.

[0046] Capsules are manufactured by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants, such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, can be added to the powder mixture before the filling operation. Disintegrants or solubilizers, such as agar-agar, calcium carbonate, or sodium carbonate, can also be added to improve the availability of the medicament when the capsule is ingested.

[0047] Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding lubricants and disintegrating agents, and pressing into tablets. Powder mixtures are prepared by mixing suitable comminuted compounds with diluents or bases as described above, and optionally with binders such as carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders (e.g. paraffin), resorption enhancers such as quaternary salts, and / or absorbents (e.g. betonite, kaolin, or dicalcium phosphate). The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage, or solutions of cellulosic or polymeric materials, and forcing through a sieve. Instead of granulating, the powder mixture may be passed through a tablet machine, resulting in imperfectly formed slugs being broken into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc, or mineral oil to prevent sticking to the tablet forming dies. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with free-flowing inert carriers and compressed directly into tablets without the granulation or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a sugar or polymeric coating, and a polish coating of wax may be provided, and dyes may be added to these coatings to distinguish different unit dosages.

[0048] Oral liquid preparations such as solution, syrup, elixir, etc. may be prepared in dosage unit form so that a given amount contains a predetermined amount of compound.Syrup may be prepared by dissolving compound in a suitably seasoned aqueous solution, while elixir may be prepared by using non-toxic excipients.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners may be added.

[0049] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. Formulations may also be prepared to provide extended or sustained release, for example by coating or embedding particulate matter in polymers, waxes, and the like.

[0050] The compounds of formula (I) and their pharma- ceutically acceptable salts can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0051] The compound of formula (I) and its pharma- ceutically acceptable salts may also be delivered by using monoclonal antibodies as individual carriers to which the compound molecules are bound. The compound may also be bound to a soluble polymer as a targetable drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide polylysine substituted with palytoyl residues. In addition, the compound may be bound to a group of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0052] Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to be in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research 1986, 3(6), 318.

[0053] Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0054] Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or enemas.

[0055] Pharmaceutical formulations adapted for nasal administration where the carrier is a solid include coarse powders having a particle size, for example in the range 20 to 500 microns, which are administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Formulations where the carrier is a liquid, suitable for administration as a nasal spray or drops, include aqueous or oily solutions of the active ingredient.

[0056] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or inhalers.

[0057] Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

[0058] Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0059] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may contain other agents conventional in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0060] Treatment method The present invention relates, in part, to methods of treating, managing, and preventing spasticity in a patient. Spasticity is defined as a velocity-dependent increase in tonic stretch reflexes with excess of movement due to hyperexcitability of the stretch reflex. Characteristics and qualities of spasticity include increased tone (enhanced response to muscle stretch and reduced modulation of the stretch reflex); spasms, which are involuntary, repetitive, sustained movements that usually involve multiple muscle groups and joints; and clonus, an involuntary contraction in a rhythmic pattern in response to sudden stretching of a muscle. Chang, supra. Most cases of spasticity can be subdivided into spinal or cerebral spasticity. Spinal spasticity results from removal or destruction of supraspinal regulation, leading to increased excitability of motor neurons, whereas cerebral spasticity results from loss of descending inhibition.

[0061] Certain embodiments of the present invention include a method for treating, managing, or preventing spasticity in a patient, the method comprising inhibiting AAK1 in the patient. In a preferred embodiment, AAK1 inhibition is achieved by administering an effective amount of an AAK1 inhibitor to the patient. Preferred AAK1 inhibitors penetrate the central nervous system and are disclosed herein. A particularly preferred AAK1 inhibitor is (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine, or a pharmaceutically acceptable salt thereof.

[0062] Certain embodiments of the present invention include a method for preventing spasticity in a patient who needs spasticity prevention, comprising administering a prophylactically effective amount of AAK1 inhibitor to the patient.The patient who needs such prevention includes the patient who suffers from spinal cord injury (SCI), cerebral palsy, stroke, amyotrophic lateral sclerosis or multiple sclerosis (MS).

[0063] Certain embodiments of the present invention include a method for treating spasticity in a patient in need of such treatment, comprising administering a therapeutically effective amount of an AAK1 inhibitor to the patient.The patient in need of such treatment includes those suffering from SCI, cerebral palsy, stroke, amyotrophic lateral sclerosis or MS.

[0064] In certain embodiments, AAK1 inhibitor is administered in combination with another therapeutic agent (not necessarily simultaneously or in the same pharmaceutical formulation) that is commonly used to treat spasticity.Examples of such therapeutic agents include centrally acting drugs such as baclofen, clonidine and tizanidine, anticonvulsants such as benzodiazepines and gabapentin, and peripherally acting drugs such as dantrolene.

[0065] The AAK1 inhibitor may be administered to a subject in one or more doses. In some embodiments, the AAK1 inhibitor is administered in an amount of about 10 mg to 1000 mg per dose, for example, about 10 mg to 20 mg, about 20 mg to 25 mg, about 25 mg to 50 mg, about 50 mg to 75 mg, about 75 mg to 100 mg, about 100 mg to 125 mg, about 125 mg to 150 mg, about 150 mg to 175 mg, about 175 mg to 200 mg, about 200 mg to 225 mg, about 225 mg to 250 mg, about 250 mg to 300 mg, about 300 mg to 350 mg, about 350 mg to 400 mg, about 400 mg to 450 mg, about 450 mg to 500 mg, about 500 mg to 750 mg, or about 750 mg to 1000 mg per dose. In some embodiments, the AAK1 inhibitor is administered to the subject in one or more single dose(s) of about 40 mg. In some embodiments, the AAK1 inhibitor is administered to the subject in one or more single dose(s) of about 200 mg.

[0066] In some embodiments, the amount of the AAK1 inhibitor per dose is determined based on body weight. For example, in some embodiments, the AAK1 inhibitor is administered at a dose of about 0.5 mg / kg to 100 mg / kg, for example, about 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 2 mg / kg to 3 mg / kg, about 3 mg / kg to 5 mg / kg, about 5 mg / kg to 7 mg / kg, about 7 mg / kg to about 10 mg / kg, about 10 mg / kg to 15 mg / kg, about 15 mg / kg to 20 mg / kg, about 2 mg / kg to 30 mg / kg, about 3 mg / kg to 5 ... The compound is administered in an amount of about 0 mg / kg to 25 mg / kg, about 25 mg / kg to 30 mg / kg, about 30 mg / kg to 40 mg / kg, about 40 mg / kg to 50 mg / kg, about 50 mg / kg to 60 mg / kg, about 60 mg / kg to 70 mg / kg, about 70 mg / kg to 80 mg / kg, about 80 mg / kg to 90 mg / kg, or about 90 mg / kg to 100 mg / kg, or about 100 mg / kg or more.

[0067] Those of skill in the art will readily appreciate that dosage levels can vary as a function of a number of different factors, including, but not limited to, the particular AAK1 inhibitor administered, the severity of the symptoms, the age and / or body size of the subject, and the subject's susceptibility to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[0068] In some embodiments, multiple doses of the AAK1 inhibitor are administered. The frequency of administration of the AAK1 inhibitor can vary depending on any of a variety of factors, such as the severity of symptoms. For example, in some embodiments, the AAK1 inhibitor is administered once a month, twice a month, three times a month, every other week (qow), once a week (qw), twice a week (biw), three times a week (tid), four times a week, five times a week, six times a week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid). As mentioned above, in some embodiments, the AAK1 inhibitor is administered continuously.

[0069] The duration of administration may vary depending on any of a variety of factors known to those of skill in the art (e.g., patient response, route of administration, dosage form). For example, the AAK1 inhibitor may be administered for about 1 day to 1 week, about 2 weeks to 4 weeks, about 1 month to 2 months, about 2 months to 4 months, about 4 months to 6 months, about 6 months to 8 months, about 8 months to 1 year, about 1 year to 2 years, or longer.

[0070] Embodiments of the present invention provide methods and compositions for administering AAK1 inhibitors to a patient (e.g., a human) using any available method and route suitable for drug delivery, including in vivo and ex vivo methods, and systemic and local routes of administration.

[0071] The routes of administration include oral, intranasal, intramuscular, intratracheal, subcutaneous, intradermal, topical application, intravenous, rectal, nasal, and other enteral and parenteral routes of administration. If desired, the routes of administration can be combined or adjusted depending on the drug and / or the desired effect. The active agent can be administered in a single dose or multiple doses using conventional methods and routes suitable for conventional drug delivery, including systemic or local routes. In general, the routes of administration contemplated by the present disclosure include, but are not limited to, enteral, parenteral, or inhalation routes.

[0072] Parenteral administration routes other than inhalation administration include, but are not limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal and intravenous routes.Parenteral administration can be carried out to achieve systemic or local delivery of AAK1 inhibitor.When systemic delivery is desired, administration typically includes invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations.

[0073] The AAK1 inhibitor can also be delivered to a subject by enteral administration. Enteral administration routes include, but are not limited to, oral and rectal delivery.

[0074] Methods of administration through the skin or mucous membrane include, but are not limited to, topical application of appropriate pharmaceutical preparations, transdermal transmission, injection, and epidermal administration.For transdermal transmission, absorption enhancers or iontophoresis are suitable methods.Iontophoretic transmission can be achieved using commercially available patches that deliver the product continuously for periods of several days or more via electrical pulses to unbroken skin.

[0075] In some embodiments, the pharmaceutical composition is administered orally, intravenously, subcutaneously, epidurally, intracerebroventricularly, intramuscularly, intraperitoneally, or via inhalation. In some embodiments, the pharmaceutical composition is administered orally.

[0076] A preferred method of administration of Compound 1 is orally once daily at a dose of about 3 mg / kg to 30 mg / kg. In one method, Compound 1 is administered to a human patient initially at a loading dose of 100 mg, followed by a maintenance dose of 10 mg. In another method, Compound 1 is administered to a human patient initially at a loading dose of 200 mg, followed by a maintenance dose of 20 mg.

[0077] Working Example Aspects of certain embodiments of the present invention are illustrated by the following examples.

[0078] Tablet dosage form Tablets containing 10 mg, 20 mg, and 50 mg of Compound 1 as the dihydrogen phosphate salt were prepared in batches of 20,000 using the ingredients listed below: [Table 1] 1 1 mg of Compound 1 corresponds to 0.7973 mg of the corresponding free base. 2 The amount of Compound 1 is adjusted according to the supplier's certificate of analysis, potency based on assay (wt%, HPLC). The proportions of silicified microcrystalline cellulose and dibasic calcium phosphate anhydrous are adjusted accordingly. 3OpaDry II White is dispersed in purified water at 15% solids and coated onto tablet cores. A 50% excess coating is provided to compensate for losses during film coating and to ensure a consistent coating weight per tablet. The purified water is removed during manufacturing.

[0079] The following steps were followed to prepare a solid oral dosage form of Compound 1: 1. The amount of Compound 1 is adjusted according to the supplier's Certificate of Analysis, potency based on assay (wt%, HPLC). 2. Compound 1, silicified microcrystalline cellulose, dibasic calcium phosphate anhydrous, and croscarmellose sodium are passed through a sieve into a bin blender and mixed. Note: The ratio of silicified microcrystalline cellulose and dibasic calcium phosphate anhydrous is adjusted according to the potency of Compound 1 determined in step 1. 3. Sift the talc and colloidal silicon dioxide into the step 2 blend and mix. 4. Add hydrogenated vegetable oil through a sieve to the blend from step 3 and mix. 5. Compress the blend from step 4. 6. The tablet cores of step 5 are then coated with an aqueous dispersion of OpaDry II White, exhibiting approximately a 4% weight gain. 7. The coated tablets from step 6 are packaged in HDPE bottles sealed with child resistant caps.

[0080] Experimental autoimmune encephalomyelitis (EAE) model The effect of Compound 1 on spasticity was evaluated in a myelin oligodendrocyte glycoprotein (MOG)-induced mouse model of experimental autoimmune encephalomyelitis (EAE), a central nervous system (CNS) autoimmune demyelinating disease that shares many of the clinical and pathological features of multiple sclerosis. Gilgun-Sherki Y., et al., Neurosciences Research 47:201-207,2003.

[0081] Test Article Preparation: Test articles were prepared according to the instructions set forth below.

[0082] Vehicle preparation: 0.5% (w / w) (hydroxypropyl) methylcellulose and 0.1% (w / w) Tween® 80 in water, pH 3.0±0.2, dose volume of 5 ml / kg (Group 1): 1) Weight 0.5 g (hydroxypropyl) methylcellulose; 2) Add 100 μL Tween® 80; 3) Add DDW to obtain 90 mL of solution; 4) Stir well to obtain a clear solution; 5) Adjust PH to 3.0±0.2 with phosphoric acid; 6) Add DDW to obtain 100 mL of solution; 7) Store at 4° C.; Mice weighing approximately 20 g are administered 0.1 mL of vehicle via PO. Vehicle should be prepared weekly and stored at 4° C. Vehicle should be brought to room temperature prior to compound 1 formulation.

[0083] Preparation of FTY720: 3 mg / kg dose level, 0.6 mg / ml concentration, and 5 ml / kg dose volume (Group 2): 1) Take 25 mg of fingolimod (FTY720) and dissolve in 41.7 ml of distilled water to obtain a concentration of 0.6 mg / ml; 2) Divide into 1.8 ml aliquots and store at -20°C; 3) Thaw an aliquot of working solution before each dosing. Note: For animals weighing approximately 20 g, administer 0.1 ml PO; QD.

[0084] Preparation of Compound 1 (10 mg / kg): salt form (containing 79.7% of the free base) at a dose level of 12.55 mg / kg, a concentration of 2 mg / ml of free base (2.51 mg / ml), and a dose volume of 5 ml / kg (Group 3): 1) weigh out 5 mg of Compound 1; 2) dissolve in 2 mL of vehicle; 3) vortex and sonicate to achieve a uniform suspension; 4) use solution within 24 hours of preparation. Note: Mice weighing 20 g are dosed with 0.1 mL of Compound 1 via PO.

[0085] Preparation of Compound 1 (3 mg / kg): salt form at a dose level of 3.76 mg / kg, a concentration of 0.6 mg / ml of the free base (0.752 mg / ml), and a dose volume of 5 ml / kg (Group 4): 1) take 0.6 ml of solution of Compound 1 at a concentration of 2.51 mg / ml; 2) add 1.4 ml of vehicle to obtain a concentration of 0.752 mg / ml; 3) stir well. NOTE: Mice weighing approximately 20 g are dosed with 0.1 mL of Compound 1 via PO.

[0086] Preparation of Tizanidine: 1 mg / kg dose level, 0.2 mg / ml concentration, and 5 ml / kg dose volume (Group 5): 1) weigh out 6 mg of tizanidine; 2) dissolve in 30 mL of saline; 3) stir well until completely dissolved. Note: Administer 0.1 ml of tizanidine IP to animals weighing approximately 20 g.

[0087] MOG (antigenic item): MOG solution is freshly prepared prior to the inoculation session by dissolving RP-HPLC-purified lyophilized powder in phosphate-buffered saline (PBS) to obtain a solution with a final injection concentration of 2 mg / ml (25 mg dissolved in 12.5 ml PBS). This concentration is appropriate for the selected dose and dose volume of 200 μg MOG in 100 μl PBS.

[0088] CFA (sensitizing item): Complete Freund's adjuvant (CFA) suspension containing heat-killed mycobacterium tuberculosis H37 Ra at a concentration of 3 mg / ml is used as the feed.

[0089] MOG / CFA Emulsion (Antigenicity / Sensitization Section): Equal volumes of MOG and CFA are mixed prior to inoculation on study day 0. For example, 100 μl of MOG solution (200 μg) is emulsified with 100 μl of CFA suspension (300 μg of heat-killed mycobacterium tuberculosis H37 Ra). The solution is mixed thoroughly by using two syringes connected by a Luer fitting until a stable emulsion is reached. A total dose volume of 200 μl is administered SC to each animal.

[0090] Pertussis Toxin (Immunostimulatory Item): Prior to the immune stimulatory injections performed on study day 0, a Pertussis Toxin (PT) stock solution was freshly prepared by dissolving the commercial PT sample in 500 μL of sterile (water for injection) distilled water (vial contains 50 μg) to achieve a stock concentration of 100 μg / ml. Prior to each injection on study days 0 and 2, the PT stock solution (100 μg / ml) was diluted with phosphate buffered saline (PBS) to obtain a final injection concentration of 2 μg / ml (dilution x 50), which is appropriate for the selected dose and volume dose. 0.5 ml of PT at a concentration of 100 μg / ml was taken and diluted with 24.5 ml of PBS to obtain a solution at a concentration of 2 μg / ml in a total volume of 25 ml. Each mouse was injected with 0.15 ml IP (approximately 300 ng / mouse). After each PT injection, the day vial was discarded. The diluted stock solution (100 µg / ml) is refrigerated at 2-8 °C and reused for the second PT injection on study day 2, except that the solution should not be used if more than 48 h has elapsed since preparation. It should be vortexed thoroughly immediately before each PT injection session.

[0091] Phosphate Buffered Saline (additional item): PBS serves as the MOG and PT diluent and is used as provided.

[0092] Water for Injection (supplement): Water for Injection (DW) serves as the PT diluent (stock concentration 100 μg / ml) and is used as provided.

[0093] Study design and results. This study used 60 female young adult (10-11 weeks old at the start of the study) C57BL / 6J mice supplied by Envigo RMS (Israel), Ltd. The animals were divided into five experimental groups. [Table 2]

[0094] Each group received a dose volume of 5 ml / kg, and the regimen was performed daily, QD, from study days 0 to 22. On study day 21, half of the animals in each group were treated and electrophysiological and electromyographic (EMG) studies were performed 2 hours after administration. On study day 22, the same was performed on the other half of the animals in each group.

[0095] Figure 1 provides a representation of this study. After baseline measurements, the MOG mouse model received a single subcutaneous (SC) injection of MOG emulsified in complete Freund's adjuvant (CFA) on study day 0, followed by an intraperitoneal (IP) boost with pertussis toxin (PT) once on the day of EAE induction (study day 0) and again 48 hours later (study day 2). As shown in Figure 1, body weight (BW) and clinical scores for EAE were monitored at baseline and daily thereafter from days 8 to 21. Mechanical allodynia was tested using the Von Frey test at baseline and at various time points on day 9. To assess spasticity, transcranial motor evoked potentials (tcMEPs) were tested at baseline, as well as on days 9 and 21-22 (half of the animals each day). All animals were administered treatment starting on day 0 through day 22. Animals in group 1 were treated orally (PO) with vehicle. Animals in group 2 were treated with fingolimod (FTY720, positive control) at a dose level of 3 mg / kg PO. Animals in groups 3 and 4 were treated with test article compound 1 at dose levels of 10 mg / kg or 3 mg / kg PO, respectively. Animals in group 5 were treated with tizanidine at a dose level of 1 mg / kg IP.

[0096] Body Weight Measurements: Group 1 animals treated with vehicle showed a gradual decrease in BW compared to baseline levels throughout the study.

[0097] Animals treated with FTY720 3 mg / kg (group 2) showed a statistically significantly higher mean BW expressed as a percentage from baseline on days 11-17 compared to vehicle-treated mice (group 1): 99.34 ± 3.60% vs. 82.06 ± 2.35% for vehicle; day 16; p < 0.0001, using one-way ANOVA followed by Dunnett's post-hoc test.

[0098] Treatment with tizanidine 1 mg / kg (group 5) resulted in a higher mean BW compared to the vehicle-treated group, but this was found to be statistically significant only on day 16: 91.31 ± 1.59% versus 82.06 ± 2.35% for vehicle; p < 0.05, using one-way ANOVA followed by Dunnett's post-hoc test.

[0099] The BW of animals following treatment with Compound 1 at 10 mg / kg or 3 mg / kg (Groups 3 and 4, respectively) was not significantly different from the vehicle group throughout the study.

[0100] EAE clinical scores and AUC: Group 1 animals treated with vehicle showed a gradual increase in clinical scores throughout the study, reaching a maximum score of 3.91±0.28 points on the 17th day.

[0101] Animals treated with FTY720 3 mg / kg (group 2) showed statistically significantly lower clinical scores on days 11-21 compared to vehicle-treated animals (group 1), reaching a maximum score of 2.18 ± 0.50 points on days 20 and 21: 1.27 ± 0.43 points compared to 3.45 ± 0.25 points for vehicle; p < 0.0001, using one-way ANOVA followed by Dunnett's post-hoc test.

[0102] Differences between animals treated with FTY720 (group 2) and vehicle (group 1) were also shown using calculation of the area under the curve (AUC) of the clinical score: 12.45 ± 3.18 points versus 29.96 ± 3.41 for vehicle; p < 0.001 using one-way ANOVA followed by Dunnett's post-hoc test.

[0103] Treatment with either Compound 1 or tizanidine did not result in a significant decrease in clinical scores compared to vehicle.

[0104] Mechanical allodynia assessment (Von Frey test): Animals were tested for mechanical allodynia using the Von Frey test at baseline and then at 0.5 hours (Group 5 only), 1.5 hours, 3.5 hours (all groups), and 5.5 hours (Groups 1-4 only) post-dose on day 9.

[0105] As shown in Figure 2, vehicle-treated animals (Group 1) exhibited significantly lower withdrawal thresholds compared to baseline levels at all time points. Animals treated with FTY720 3 mg / kg (Group 2) exhibited statistically significantly higher withdrawal thresholds compared to the vehicle-treated group at 1.5 hours post-dose: 1.40 ± 0.10 g vs. 0.89 ± 0.11 g for vehicle; p < 0.01 using one-way ANOVA followed by Dunnett's post-hoc test. The effect was not significant at 3.5 and 5.5 hours post-dose.

[0106] Treatment with the high dose of Compound 1, 10 mg / kg (Group 3), resulted in statistically significantly higher withdrawal force thresholds compared to the vehicle-treated group at all time points post-dose (1.5, 3.5, and 5.5 hours): 1.48±0.10 g vs. 0.89±0.11 g for vehicle at 1.5 hours post-dose, 1.36±0.09 g vs. 0.78±0.06 g for vehicle at 3.5 hours post-dose, and 1.52±0.13 g vs. 0.82±0.08 g for vehicle at 5.5 hours post-dose, p<0.01, p<0.5, p<0.001 (respectively), using one-way ANOVA followed by Dunnett's post-hoc test.

[0107] Treatment with a low dose of Compound 1 (3 mg / kg: Group 4) also resulted in higher withdrawal force thresholds at all time points post-administration compared to the vehicle-treated group.

[0108] Treatment with tizanidine 1 mg / kg (Group 5) resulted in higher withdrawal force thresholds at all time points post-dosing (0.5, 1.5, and 3.5 hours), however, only the 3.5 hour time point was found to be statistically significant compared to the vehicle group: 1.32±0.15 g vs. 0.78±0.06 g for vehicle; p<0.05 using one-way ANOVA followed by Dunnett's post-hoc test.

[0109] Electrophysiological testing: Animals underwent electrophysiological testing at baseline and on study days 10 and 21. EMG, latency, latency to main event, duration, peak-to-peak (P2P) amplitude, and number of subpeaks were recorded.

[0110] As shown in FIG. 3, animals treated with 3 mg / kg FTY720 (Group 2) or both doses of Compound 1 (Groups 3 and 4) had a statistically significantly lower fibrillation rate on day 21 compared to vehicle: 1.11±4.69Hz in vehicle-treated animals vs. 0.41±0.89Hz in Group 2, 1.22±0.57Hz in Group 3, and 0.38±0.38Hz in Group 4; p<0.05 or p<0.01 using one-way ANOVA followed by Dunnett's post-hoc test.

[0111] Animals treated with 3 mg / kg FTY720 (group 2) or both doses of Compound 1 (groups 3 and 4) had statistically significantly shorter latencies on day 10 compared to vehicle: 5.16 ± 0.16 ms (group 2), 5.54 ± 0.22 ms (group 3), 5.31 ± 0.21 ms (group 4) versus 6.94 ± 0.59 ms for vehicle (group 1); p<0.01 and p<0.05 (respectively) using one-way ANOVA followed by Dunnett's post-hoc test.

[0112] As shown in Figure 4, animals in all test groups showed statistically significant lower latencies (ms) to reach the main event compared to the vehicle group on day 10: 10.05 ± 2.59 ms for vehicle vs. 5.16 ± 0.16 ms for FTY720, 5.55 ± 0.22 ms for compound 1 at 10 mg / kg, 5.32 ± 0.22 ms for compound 1 at 3 mg / kg, and 5.64 ± 0.19 ms for tizanidine; p < 0.05, using one-way ANOVA followed by Dunnett's post-hoc test. Signal duration was increased in all groups compared to baseline levels. No significant differences were found between groups.

[0113] As shown in Figure 5, P2P amplitudes measured in vehicle-treated animals gradually decreased compared to baseline levels throughout the study. Treatment with all test items resulted in statistically significantly higher P2P amplitudes compared to vehicle on day 10, which then decreased on day 21: 13472.18 ± 1099.82 μV for FTY720 versus 7681.17 ± 1505.12 μV for vehicle, 11613.75 ± 1154.41 μV for Compound 1 at 10 mg / kg, 11321.67 ± 1321.68 μV for Compound 1 at 3 mg / kg, and 13488.71 ± 1234.10 μV for Tizanidine; p<0.05 using one-way ANOVA followed by Dunnett's post-hoc test.

[0114] A gradual increase in the number of subpeaks was observed in all groups throughout the study. Treatment with all test items resulted in fewer subpeaks compared to the vehicle group on days 10 and 21. However, only treatment with FTY720 resulted in a statistically significant decrease in the number of subpeaks compared to vehicle on day 21: 1.61±0.51 vs. 4.93±1.72 for vehicle; p<0.05 using one-way ANOVA followed by Dunnett's post-hoc test.

[0115] Under the conditions of this study and limited to in vivo data, treatment with Compound 1 at 10 mg / kg administered once daily was effective in significantly reducing the sensitivity of the animals to mechanical stimuli. Compound 1 at 3 mg / kg administered once daily reduced the sensitivity of the animals to mechanical stimuli. Furthermore, treatment with Compound 1 at both dose levels was effective in significantly reducing fibrillation rate as measured using EMG, was effective in significantly reducing latency, latency to event, and was effective in increasing P2P amplitude as measured by transcranial evoked potentials. Compound 1 also reduced the duration and number of sub-potentials at both dose levels when compared to vehicle-treated animals.

[0116] Spinal cord injury The efficacy of Compound 1 was measured in a rat model of spasticity induced by complete spinal cord transection. A model of complete spinal cord transectomy at the 8th thoracic (T8) vertebral level was used to induce muscle spasticity. Five weeks after spinal cord injury (SCI), rats were orally (PO) treated with Compound 1 (3, 10, or 30 mg / kg), baclofen (4.5 mg / kg), tizanidine (3 mg / kg), or vehicle alone (0.9% NaCl, Compound 1 vehicle), and the degree of spasticity response was measured using velocity-dependent depression (RDD) of the Hoffman reflex (H-reflex) and seizure induction.

[0117] Materials and Methods: 165 rats were subjected to complete transection of the spinal cord at the T8 vertebral level; 1 died during the surgical procedure; 2 died during the postoperative recovery period; 11 exhibited self-injurious behavior and were euthanized. 151 SCI rats were kept until the end of the 5th week after injury. 140 rats underwent PO administration of test compounds and EMG analysis.

[0118] One hour after surgery, rats were awakened with an intramuscular (IM) injection of atipamezole (1 mg / kg; Antisedan, Orion Pharma, Espoo, Finland) and given 5 ml of warm NaCl (0.9%, 37°C) subcutaneously. Rats were kept in a warm room (38°C) until awakening and for at least another 2 hours. Buprenorphine (0.05 mg / kg; Vetergesic, Sogeval, Laval, France) was given subcutaneously (SC) immediately after awakening and every 8 hours for 48 hours. Over the following days, bladders were emptied manually (twice daily) until urinary function was restored, temperature and hydration were checked, and clinical signs of pain or infection were observed.

[0119] Rats were securely restrained to immobilize the head. In the upright position, the gavage needle was passed along the side of the mouth. The needle was advanced along the palate into the esophagus and into the stomach. After the needle had been passed to the correct length, compound was slowly injected. Rats were randomly assigned to one of the following test groups: [Table 3]

[0120] Neuroelectromyography was performed on the right hind limb before and 1, 2, 3, 4, 5, and 6 hours after PO administration.

[0121] Thermoregulation: The chest and hind limbs of the rats were fixed with adhesive tape onto a heating pad. Body temperature was maintained at 37.5 ± 0.5 °C, as temperature can affect neuromuscular transmission and the propagation of action potentials along muscle fibers.

[0122] Electrode implantation: Four monopolar 29-gauge (12 mm length) subdermal Teflon needle electrodes (AD Instruments, Paris, France) were used for electrical stimulation and recording. A ground electrode was placed under the skin at the base of the tail.

[0123] Electromyographic (EMG) signals were amplified (100x), bandpass filtered (300 Hz–5 kHz; AM Systems Amplifier, Everett, Washington; model 1700), and sampled at 13.5 kHz (Digidata 1440A, Molecular Devices). The tibial nerve was stimulated by using square pulses of increasing stimulation intensity (0.2 mA, 0.2 Hz, 0.2 mA increments starting at 0.2 ms; AM Systems Stimulator, model 2100) to obtain recruitment curves.

[0124] RDD of the H-reflex: To induce sedation, an intraperitoneal injection of ketamine (100 mg / kg, Imalgen®) was used to suppress locomotor activity and increase muscle tone. The rat's chest and hind limbs were fixed with adhesive tape on a heating pad. The following series of measurements were repeated throughout the experiment: 1. Determination of Hmax and Mmax: The tibial nerve was stimulated at 0.2 Hz for 0.2 ms with increasing current intensity (1-6 mA, in 0.1 mA increments) until Mmax stabilized. 2. RDD measurements: The intensities required to obtain the maximum H-reflex were used in trains of 13 stimuli at 0.2, 1, 2, and 5 Hz with a 2 minute interval between each train of stimuli. The total train of measurements lasted approximately 15 minutes. 3. Determination of the level of RDD: At the different frequencies, responses to the first three stimuli necessary for depression to occur were discarded and all responses were expressed as a percentage of the mean response at 0.2 Hz in the same series of measurements.

[0125] Muscle spasms: In awake chronic SCI rats, muscle spasms were induced by stimulation of the tibial nerve while electromyographic (EMG) recordings from the flexor digitorum brevis (FDB) muscle were performed. Nine days prior to the experiment, spastic spinal rats were handled and individually restrained in plexiglass tubes and gradually habituated to having their paralyzed lower limbs immobilized with tape. 1. Determination of Hmax and Mmax: The tibial nerve was stimulated at 0.2 Hz for 0.2 ms with increasing current intensity (1-6 mA, in 0.2 mA increments) until Mmax stabilized. 2. Supramaximal single-pulse stimulation to induce muscle twitches was fixed throughout the experiment (2x or 3x the M-wave threshold intensity) and was elicited five times with an interstimulus interval of 60 s. EMG was corrected and averaged over a 2000 ms post-stimulus interval to quantify twitches (Clampfit 8.0, Axon Instruments).

[0126] Data analysis: H-reflex RDD and area under the curve (AUC) were determined as measures of spasticity and analyzed at each time point and frequency using Mann-Whitney test or Kruskal Wallis one-way analysis of variance (ANOVA) test followed by Dunn's multiple comparison test. P<0.05 was considered significant. Significant differences were marked with an asterisk (*) according to the respective P value: values ​​were expressed as mean ± standard error of the mean (SEM) in all graphs. All statistical analyses were performed using GraphPad Prism 7 (San Diego, California, USA).

[0127] Modulation of the RDD of the H-reflex. The Hoffman reflex was used to assess the excitability of primary (type Ia) afferent-mediated motor neurons in rats suffering from spasticity. Electromyograms typically show two responses: an early M-wave (Figure 6B) due to direct activation of motor axons (Figure 6A-1), and a delayed H-wave (Figure 6B) resulting from monosynaptic activation of motor neurons by afferents (6A-2).

[0128] Velocity-dependent depression (RDD), a measure of the change in amplitude of the H-reflex to successive stimuli, is attenuated in SCI rats. To assess whether spastic symptoms, such as RDD weakness, were suppressed after a single PO administration of Compound 1 (3, 10, 30 mg / kg), baclofen (4.5 mg / kg), or tizanidine (3 mg / kg), the amplitude of the H-reflex was measured before and 1, 2, 3, 4, 5, and 6 hours after administration. The mean relative amplitude of the H-reflex was significantly decreased in SCI rats treated with Compound 1 at 10 mg and 30 mg, in SCI rats treated with baclofen at 4.5 mg / kg, and in SCI rats treated with tizanidine at 3 mg / kg (P<0.05, P<0.01, P<0.001, P<0.0001, Kruskal-Wallis, Dunn post-hoc test).

[0129] To determine the level of RDD at different frequencies, responses to the first three stimuli required for depression to occur were discarded and all responses were expressed as a percentage of the mean response at 0.2 Hz in the same series of measurements. The amplitude of the H-wave is attenuated by repeated activation at frequencies higher than 0.2 Hz, with a maximal decrease at 5 Hz in intact rats. RDD is gradually decreased in animals with SCI, and this effect is a reliable correlate of the development of spasticity. In the present study, RDD was significantly decreased 5 weeks after complete transection of the spinal cord in rats (P<0.0001, unpaired t-test). No differences were observed in the mean relative amplitude of the H-reflex among the seven test groups for each frequency before PO administration of the compound (P>0.05, unpaired t-test).

[0130] As shown in Figure 7, a single PO dose of 10 mg / kg Compound 1 demonstrated an onset of action of 1 hour (P<0.05 at 1 Hz) and a duration of action of at least 6 hours (P<0.05 at 1 Hz). At 30 mg / kg, Compound 1 demonstrated an onset of action of 1 hour (P<0.01 at 1 Hz, P<0.001 at 2 Hz, and P<0.05 at 5 Hz) and a duration of action of at least 6 hours (P<0.05 at 1 Hz, P<0.01 at 2 Hz). Compound 1 did not appear to affect spasticity when administered at a dose of 3 mg / kg.

[0131] In comparison, baclofen (4.5 mg / kg) had an onset of action of 1 hour (P<0.05 at 1 Hz, P<0.01 at 2 Hz, P<0.05 at 5 Hz), a maximum effect of 5 hours (P<0.001 at 1 Hz, P<0.0001 at 2 Hz, P<0.01 at 5 Hz), and a duration of action of at least 6 hours (P<0.01 at 1 Hz, P<0.01 at 2 Hz). Tizanidine (3 mg / kg) had an onset of action and maximum effect of 2 hours (P<0.01 at 1 Hz, P<0.001 at 2 Hz, P<0.05 at 5 Hz), and a duration of action of at least 6 hours (P<0.05 at 2 Hz, P<0.01 at 5 Hz).

[0132] Modulation of muscle spasms. Acute (1 week after injury) stimulation of the tibial nerve in injured rats elicited few reflexes in the FDB muscle, regardless of the intensity of stimulation (Figure 8A). In contrast, stimulation of the tibial nerve in chronic (5 weeks after injury) SCI rats produced more (P<0.0001; Mann-Whitney test, Figure 8C) sustained muscle contractions (Figure 8B). This effect is a reliable correlate of the development of spasticity. In spastic rats, spasms were induced via the FDB muscle after electrical stimulation of the tibial nerve. The response was usually characterized by a sustained muscle contraction lasting several seconds (Figure 8B).

[0133] Muscle spasms (AUC) were significantly reduced in SCI rats (n=10) administered Compound 1 at all doses tested (P<0.05, P<0.01, P<0.001; Kruskal-Wallis, Dunn post-hoc test). Muscle spasms were also reduced in SCI rats administered Baclofen (4.5 mg / kg) and Tizanidine (3 mg / kg). This effect was specific to long-term tonic activity, without altering any of the parameters characterizing the M-wave and H-wave (p>0.05; Kruskal-Wallis, Dunn post-hoc test). Figure 9 shows the effect of the compound 3 hours after administration.

[0134] After a single PO dose, compound 1 (3, 10, 30 mg / kg) showed an onset of action of 1 hour (P<0.05, P<0.01), 1 hour (P<0.01), 1 hour (P<0.01), and 4 hours (P<0.01), respectively, and a duration of action of 5 hours (P<0.05), 3 hours (P<0.05), and 5 hours (P<0.05), respectively. In comparison, baclofen (4.5 mg / kg) showed an onset of action of 1 hour (P<0.05), a maximum effect of 2 hours (P<0.01), and a duration of action of at least 6 hours (P<0.01). Tizanidine (3 mg / kg) showed an onset of action of 2 hours (P<0.01), a maximum effect of 3 hours (P<0.001), and a duration of action of at least 6 hours (P<0.01).

[0135] In conclusion, complete thoracic spinal cord transection in adult rats induces spasticity, as evidenced by the weakness of the H-reflex RDD and the appearance of muscle spasms. The relevance of this model is confirmed by the efficacy obtained with baclofen (4.5 mg / kg, a GABA B receptor activator) and tizanidine (3 mg / kg, a central alpha-2-adrenergic receptor agonist), both of which are currently used in patients. In this rat model of spasticity, orally administered compound 1 showed anticonvulsant therapeutic effects at doses of 10 and 30 mg / kg. This efficacy was demonstrated in the two parameters that define spasticity, namely stretch reflex hyperexcitability and spasms. Among the compounds evaluated in this model, compound 1 was the first to show therapeutic effects by oral administration.

[0136] While the invention has been described in conjunction with a detailed description thereof, it should be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0137] Each reference disclosed herein is incorporated herein in its entirety.

Claims

1. 1. A method for treating or preventing spasticity, comprising inhibiting adaptor associated kinase 1 (AAK1) in a patient in need of such treatment or prevention.

2. A method for treating or preventing spasticity, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an AAK1 inhibitor.

3. 3. The method of claim 1 or 2, wherein the patient is suffering from spinal cord injury, cerebral palsy, stroke, amyotrophic lateral sclerosis, or multiple sclerosis.

4. The AAK1 inhibitor has formula (I): 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein A is, 【Chemistry 2】 is selected from During the ceremony, 【Chemistry 3】 indicates the point of attachment to B, B is, 【Chemistry 4】 wherein "*" is selected from R ５ indicates the point of attachment to ring A; R １ is hydrogen, amino, -CO ２ H, difluoromethyl, ethyl, halo, hydroxymethyl, methoxy, methyl, -NHC(O)CH ３ , -NHCO ２ CH ３ , trifluoromethoxy, and trifluoromethyl; R ２ is hydrogen, cyano, -CH ２ selected from OH, halo, and methyl; R ３ is hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, methylsulfonyl, trifluoromethoxy, trifluoromethyl, -CH ２ N (CH ３ ) ２ and a 5-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R ４ is selected from hydrogen, halo, and methyl; R ５ teeth, 【Chemistry 5】 is selected from R ６ is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl; R ７ The method of claim 2 , wherein is methyl.

5. The AAK1 inhibitor has the formula (II): 【Chemistry 6】 or a pharma- ceutically acceptable salt thereof, wherein A is, 【Chemistry 7】 is selected from 【Chemistry 8】 indicates the point of attachment to B, B is selected from phenyl and pyridinyl; R １ is hydrogen, difluoromethyl, halo, methoxy, methyl, -NHC(O)CH ３ , -NHCO ２ CH ３ and trifluoromethyl; R ２ is hydrogen, -CH ２ OH, and halo; R ３ is selected from hydrogen, cyano, cyclopropyl, difluoromethyl, halo, hydroxymethyl, methoxy, methyl, trifluoromethoxy, trifluoromethyl, and a 5-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur; R ４ is selected from hydrogen, halo, and methyl; R ６ The method of claim 4, wherein is selected from hydrogen, ethyl, fluoromethyl, difluoromethyl, methyl, and trifluoromethyl.

6. A, 【Chemistry 9】 The method according to claim 5, wherein

7. B, 【Chemistry 10】 The method according to claim 5, wherein

8. R ５ but, 【Chemistry 11】 The method according to claim 5, wherein

9. A method for treating or preventing spasticity, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of an adaptor associated kinase 1 (AAK1) inhibitor, wherein the AAK1 inhibitor is (S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridine]-5-yl)oxy)-2,4-dimethylpentan-2-amine, 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof.

10. 10. The method of claim 9, wherein the AAK1 inhibitor is ((S)-1-((2',6-bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-aminium dihydrogen phosphate.

11. The method of claim 10, wherein the AAK1 inhibitor has a melting point of 184±2° C.

12. 10. The method of claim 9, wherein the patient is suffering from spinal cord injury, cerebral palsy, stroke, amyotrophic lateral sclerosis, or multiple sclerosis.

13. The method of claim 9 , wherein the AAK1 inhibitor is administered orally.

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