Using GABA A Receptor modulators for the treatment of epileptic conditions

Abstract

This disclosure relates to GABA receptor modulators for treating epileptic conditions and compositions comprising a GABA receptor modulator. Also disclosed herein are methods of treating an epileptic condition in a subject by administering a GABA receptor modulator or composition as described herein. A A A ​​​

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 925,081, filed on October 23, 2019, and U.S. Provisional Application No. 62 / 950,674, filed on December 19, 2019, each of which is hereby incorporated by reference in its entirety.

[0003] Statement Regarding Federally Funded Research

[0004] This invention was made with government support under Award No. R43NS107051 awarded by the National Institute of Neurological Disorders and Stroke of the National Institute of Health. The government has certain rights in this invention.

[0005] Overview

[0006] Disclosed herein is a method of treating an epileptic condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (1a), formula (1b) or formula (1c) to treat the epileptic condition in the subject,

[0007]

[0008] Where X 1 , X 2 , X 3 , X 4 and X 5 are independently -C, -N, -S or -O, wherein X 1 , X 2 , X 3 , X 4 and X 5 At least two of them are -N,Y 1 and Y 2 are independently -C or -N, R 1 m m is 1, where R 1 is unsubstituted phenyl, phenyl substituted by C1-C4 hydrocarbon, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl group, R 2 n n is 1 or 2, where each R 2are independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted 5-membered or 6-membered heteroaryl group, Z 1 , Z 3 , Z 4 and Z 5 are independently -C, -N, -S or -O, A 1 and A 2 and A 3 are independently -C, -N or -C(C=O)-OR 7 or

[0009] Where R 7 is a hydrocarbon group, B 1 , B 2 , B 3 and B 4 are independently -C, -N or -O, R 21 S s is 1, 2, 3, or 4, and R 5 l l is 1 or 2, where each R 5 are independently C1-C4 alkynyl or halogen, R 6 k k is 1, 2, 3 or 4, where each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon or hydrogen, R 12 p p is 1 or 2, where each R 12 are independently substituted or unsubstituted C1-C4 hydrocarbon, I, Br, Cl or F, and R 13 q q is 1, 2, 3 or 4, where each R 13 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen. In some embodiments, the compound has the general formula (2), the general formula (3), the general formula (4), the general formula (5), the general formula (1c) or the general formula (7),

[0010]

[0011] In some embodiments, the compound has the formula (2a), the formula (3a), the formula (4a), the formula (5a), the formula (5b), the formula (1c), or the formula (7a),

[0012]

[0013] In some embodiments, R 1 m m is 1, and R 1 is: unsubstituted phenyl, substituted phenyl containing C1-C4 hydrocarbon group, F, Cl, Br, I, -CN as substituent, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as substituent, substituted biphenyl containing at least one -CN as substituent or -(C=O)-R 3 , where R 3 In some embodiments, the compound has the general formula (2a'), the general formula (3a'), the general formula (4a'), the general formula (5a'), the general formula (5b'), the general formula (VI) or the general formula (7a'),

[0014]

[0015] Where R 10 is a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group or hydrogen, R 11 is a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group or hydrogen, or R 12 p p is 1 and R 12 is I, Br, Cl or F. In some embodiments, the compound has the general formula (2a"), the general formula (3a"), the general formula (4a"), the general formula (5a"), the general formula (5b"), the general formula (VIa") or the general formula (7a"),

[0016]

[0017] Where R 7 is: unsubstituted C1-C6 hydrocarbon group, unsubstituted C3-C8 cycloalkyl group, unsubstituted C1-C6 alcohol, R 8 Yes: -O-CH2-R 4 , where R 4 is a substituted or unsubstituted 5-membered heteroaryl or an unsubstituted C1-C6 alcohol, R 9 is: unsubstituted C6 heteroaryl or halogen, or R 9 is an unsubstituted 6-membered heteroaryl group in formula (4a") or a halogen group in formula (5b"), R 10is a C1-C3 hydrocarbon group or hydrogen, R 11 is a substituted or unsubstituted aryl or heteroaryl group, R 14 is a substituted or unsubstituted aryl or heteroaryl group, R 12 is I, Cl, Br or F, or R 5 is C2 alkynyl or I. In some embodiments, the compound is α1, α2, α3 or α5 GABA A In some embodiments, the compound is a positive allosteric α2 or α3 GABA A Receptor modulator. In some embodiments, the subject is human. In some embodiments, the subject is a dog. In some embodiments, the subject is aged 0-17 years old. In some embodiments, the subject is aged 18-130 years old. In some embodiments, a therapeutically effective amount of a compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier. In some embodiments, the epilepsy condition is selected from the group consisting of: benign central temporal lobe epilepsy in children, benign occipital lobe epilepsy in children (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen's encephalitis, West syndrome, Dravet syndrome, progressive myoclonic epilepsy and Lennox-Gastaut syndrome (LGS).

[0018] Also disclosed herein is a method for treating epilepsy associated with sodium channel mutation in a subject, the method comprising administering a compound of formula (1a), formula (1b) or formula (1c) to the subject to treat epilepsy associated with sodium channel mutation,

[0019]

[0020] Where X 1 , X 2 , X 3 , X 4 and X 5 are independently -C, -N, -S or -O, wherein X 1 , X 2 , X 3 , X 4 and X 5 At least two of them are -N,Y 1 and Y 2are independently -C or -N, R 1 m m is 1, where R 1 is unsubstituted phenyl, phenyl substituted by C1-C4 hydrocarbon, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl group, R 2 n n is 1 or 2, where each R 2 are independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted 5-membered or 6-membered heteroaryl group, Z 1 , Z 3 , Z 4 and Z 5 are independently -C, -N, -S or -O, A 1 and A 2 and A 3 are independently -C, -N or -C(C=O)-OR 7 or

[0021] Where R 7 is a hydrocarbon group, B 1 , B 2 , B 3 and B 4 are independently -C, -N or -O, R 21 S s is 1, 2, 3, or 4, and R 5 l l is 1 or 2, where each R 5 are independently C1-C4 alkynyl or halogen, R 6 k k is 1, 2, 3 or 4, where each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon or hydrogen, R 12 p p is 1 or 2, where each R 12 are independently substituted or unsubstituted C1-C4 hydrocarbon, I, Br, Cl or F, and R 13 q q is 1, 2, 3 or 4, where each R 13are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen. In some embodiments, the compound has the general formula (2), the general formula (3), the general formula (4), the general formula (5), the general formula (1c) or the general formula (7),

[0022]

[0023] In some embodiments, the compound has the formula (2a), the formula (3a), the formula (4a), the formula (5a), the formula (5b), the formula (1c), or the formula (7a),

[0024]

[0025] In some embodiments, R 1 m m is 1, and R 1 is: unsubstituted phenyl, substituted phenyl containing C1-C4 hydrocarbon group, F, Cl, Br, I, -CN as substituent, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as substituent, substituted biphenyl containing at least one -CN as substituent or -(C=O)-R 3 , where R 3 In some embodiments, the compound has the general formula (2a'), the general formula (3a'), the general formula (4a'), the general formula (5a'), the general formula (5b'), the general formula (VI) or the general formula (7a'),

[0026]

[0027] Where R 10 is a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group or hydrogen, R 11 is a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group or hydrogen, or R 12 p p is 1 and R 12 is I, Br, Cl or F. In some embodiments, the compound has the general formula (2a"), the general formula (3a"), the general formula (4a"), the general formula (5a"), the general formula (5b"), the general formula (VIa") or the general formula (7a"),

[0028]

[0029] Where R 7 is: unsubstituted C1-C6 hydrocarbon group, unsubstituted C3-C8 cycloalkyl group, unsubstituted C1-C6 alcohol, R 8Yes: -O-CH2-R 4 , where R 4 is a substituted or unsubstituted 5-membered heteroaryl or an unsubstituted C1-C6 alcohol, R 9 is: unsubstituted C6 heteroaryl or halogen, or R 9 is an unsubstituted 6-membered heteroaryl group in formula (4a") or a halogen group in formula (5b"), R 10 is a C1-C3 hydrocarbon group or hydrogen, R 11 is a substituted or unsubstituted aryl or heteroaryl group, R 14 is a substituted or unsubstituted aryl or heteroaryl group, R 12 is I, Cl, Br or F, or R 5 is C2 alkynyl or I. In some embodiments, the compound is α1, α2, α3 or α5 GABA A In some embodiments, the compound is a positive allosteric α2 or α3 GABA A Receptor modulator. In some embodiments, the subject is human. In some embodiments, the subject is canine. In some embodiments, the subject is aged 0-17 years. In some embodiments, the subject is aged 18-130 years. In some embodiments, the therapeutically effective amount of the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier. In some embodiments, the sodium channel mutation comprises a mutation in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene.

[0030] Also disclosed herein is a method of treating Dravet syndrome in a subject, the method comprising administering to the subject an amount of a pharmaceutical composition to treat Dravet syndrome in the subject, the pharmaceutical composition comprising a compound selected from the group consisting of:

[0031] Its salts and polymorphs thereof. In some embodiments, the compound is:

[0032]

[0033] , a salt thereof or a polymorph thereof. In some embodiments, the amount is effective for treating Dravet syndrome when administered at a dosage of from about 0.003 mg / kg of the subject's body weight per day to about 10 mg / kg of the subject's body weight per day when administered to a subject (e.g., from about 0.003 mg / kg to about 100 mg / kg, from about 0.003 mg / kg to about 95 mg / kg, from about 0.003 mg / kg to about 90 mg / kg, from about 0.003 mg / kg to about 85 mg / kg, from about 0 .003 mg / kg to about 80 mg / kg, from about 0.003 mg / kg to about 75 mg / kg, from about 0.003 mg / kg to about 70 mg / kg, from about 0.003 mg / kg to about 65 mg / kg, from about 0.003 mg / kg to about 60 mg / kg, from about 0.003 mg / kg to about 55 mg / kg, from about 0.003 mg / kg to about 50 mg / kg, from about 0.003 mg / kg to about 45 mg / kg , from about 0.003 mg / kg to about 40 mg / kg, from about 0.003 mg / kg to about 35 mg / kg, from about 0.003 mg / kg to about 30 mg / kg, from about 0.003 mg / kg to about 25 mg / kg, from about 0.003 mg / kg to about 20 mg / kg, from about 0.003 mg / kg to about 15 mg / kg, from about 0.003 mg / kg to about 10 mg / kg, from about 0.003 mg / kg to about 9 mg / kg, from about 0.003 mg / kg to about 8 mg / kg, from about 0.003 mg / kg to about 7 mg / kg, from about 0.003 mg / kg to about 6 mg / kg, from about 0.003 mg / kg to about 5 mg / kg, from about 0.003 mg / kg to about 4 mg / kg, from about 0.003 mg / kg to about 3 mg / kg, from about 0.003 mg / kg to about 2 mg / kg, or from about 0.003 mg / kg to about 1 mg / kg). In some embodiments, the subject is a human. In some embodiments, the subject is a dog. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, diluent, or carrier. In some embodiments, the pharmaceutical composition comprises a carrier, wherein the carrier is methylcellulose. In some embodiments, the compound is Its polymorph or its salt. In some embodiments, the pharmaceutical composition comprises a salt of the compound. In some embodiments, the salt is a phosphate salt. In some embodiments, the salt is a sulfate salt. In some embodiments, the pharmaceutical composition comprises a polymorph of the compound. In some embodiments, the polymorph has a relative humidity of about 6.4 degrees ± 0.2 degrees, 7.5 degrees ± 0.2 degrees, 10.2 degrees ± 0.2 degrees, 12.7 degrees ± 0.2 degrees, 13.3 degrees ± 0.2 degrees, 14.5 degrees ± 0.2 degrees, 16.0 degrees ± 0.2 degrees, 17.1 degrees ± 0.2 degrees, 17.4 degrees ± 0.2 degrees, 17.9 degrees ± 0.2 degrees, 18.5 degrees ± 0.2 degrees, 19.1 degrees ± 0.2 degrees, 19.7 degrees ± 0.2 degrees, 20.3 degrees ± X-ray powder diffraction (XRPD) of characteristic peak positions of at least three of the values ​​in the group consisting of 0.2 degrees, 20.9 degrees ± 0.2 degrees, 21.5 degrees ± 0.2 degrees, 22.6 degrees ± 0.2 degrees, 23.7 degrees ± 0.2 degrees, 26.2 degrees ± 0.2 degrees, 26.7 degrees ± 0.2 degrees, 26.9 degrees ± 0.2 degrees, 27.5 degrees ± 0.2 degrees, 28.4 degrees ± 0.2 degrees, 30.2 degrees ± 0.2 degrees and 32.1 degrees ± 0.2 degrees 2θ: (a) X-ray wavelength parameters of Cu:K-α (b) an X-ray tube voltage setting of 40 kV and a current of 40 mA; (c) a scan range from about 3 degrees to about 40 degrees; (d) a sample rotation speed of about 15 rpm; and (e) a scan rate of 10 degrees per minute. In some embodiments, administration comprises oral administration. In some embodiments, administration is performed at least once a day. In some embodiments, administration of an amount effective for treating Dravet syndrome does not produce drowsiness or sedation in the subject.

[0034] Also disclosed herein is a method of treating an epileptic condition in a subject, the method comprising administering to the subject an amount of a compound of the formula:

[0035]

[0036] or a pharmaceutically acceptable salt or polymorph thereof, to treat an epileptic condition in a subject, wherein the amount comprises from about 0.003 mg / kg to about 10 mg / kg (i.e., from about 0.003 mg / kg to about 100 mg / kg, from about 0.003 mg / kg to about 95 mg / kg, from about 0.003 mg / kg to about 90 mg / kg, from about 0.003 mg / kg to about 85 mg / kg, from about 0.003 mg / kg to about 80 mg / kg , from about 0.003 mg / kg to about 75 mg / kg, from about 0.003 mg / kg to about 70 mg / kg, from about 0.003 mg / kg to about 65 mg / kg, from about 0.003 mg / kg to about 60 mg / kg, from about 0.003 mg / kg to about 55 mg / kg, from about 0.003 mg / kg to about 50 mg / kg, from about 0.003 mg / kg to about 45 mg / kg, from about 0.003 mg / kg to about to about 40 mg / kg, from about 0.003 mg / kg to about 35 mg / kg, from about 0.003 mg / kg to about 30 mg / kg, from about 0.003 mg / kg to about 25 mg / kg, from about 0.003 mg / kg to about 20 mg / kg, from about 0.003 mg / kg to about 15 mg / kg, from about 0.003 mg / kg to about 10 mg / kg, from about 0.003 mg / kg to about 9 mg / kg, from about 0. In some embodiments, the amount of clotrimazole is from about 0.003 mg / kg to about 8 mg / kg, from about 0.003 mg / kg to about 7 mg / kg, from about 0.003 mg / kg to about 6 mg / kg, from about 0.003 mg / kg to about 5 mg / kg, from about 0.003 mg / kg to about 4 mg / kg, from about 0.003 mg / kg to about 3 mg / kg, from about 0.003 mg / kg to about 2 mg / kg, or from about 0.003 mg / kg to about 1 mg / kg). In some embodiments, administration reduces the amount of epileptic seizures to an amount that is at least 20% less than the amount of epileptic seizures that occur based on administration of an equal dose of clobazam. In some embodiments, the amount includes a dose from about 0.08 mg / kg to about 2.5 mg / kg. In some embodiments, the compound is present in a shelf stable formulation. In some embodiments, the compound is formulated as a non-sleepy formulation. In some embodiments, the non-sleepy formulation comprises caffeine. In some embodiments, the compound, its pharmaceutically acceptable salt or polymorph thereof is a phosphate salt or a polymorph thereof. In some embodiments, the compound, its pharmaceutically acceptable salt or polymorph thereof is a sulfate salt or a polymorph thereof.

[0037] Described herein is a method of treating an epileptic condition in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (5a') or a salt or polymorph thereof,

[0038]

[0039] in

[0040] R 1 is unsubstituted phenyl, phenyl substituted by C1-C4 hydrocarbon, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl group, and

[0041] R 2 n n is 1 or 2, where each R 2 are independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted 5-membered or 6-membered heteroaryl group,

[0042] wherein the administration is in an amount effective to treat the epileptic condition in the subject, and wherein the amount comprises a dosage of from about 0.003 mg to about 1 mg of the compound or a salt or polymorph thereof per kg of the subject's body weight per day. A method of treating an epileptic condition in a subject is described herein, the method comprising administering to the subject a pharmaceutical composition comprising a compound having the structure

[0043]

[0044] or a salt or polymorph thereof, wherein administration is in an amount effective to treat an epileptic condition in a subject, and wherein the amount comprises a dose of from about 0.0003 mg to about 1 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the epileptic condition is generalized epilepsy or genetic epilepsy. In some embodiments, the epileptic condition is Dravet syndrome. In some embodiments, the epileptic condition is a focal seizure. In some embodiments, the epilepsy condition is selected from the group consisting of: benign central temporal epilepsy of childhood, benign occipital epilepsy of childhood (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen encephalitis, cerebral palsy, cerebral hypoxia, Down syndrome, hypoxic-ischemic encephalopathy (HIE), West syndrome, Dravet syndrome, focal seizures, progressive myoclonic epilepsy, focal seizures, or Lennox-Gastaut syndrome (LGS). In some embodiments, the compound or its salt or polymorph is a phosphate salt or a polymorph thereof. In some embodiments, the compound or its salt or polymorph is a sulfate salt or a polymorph thereof. In some embodiments, the compound or its salt or polymorph is a phosphate polymorph, and wherein the phosphate polymorph exhibits a relative humidity selected from the group consisting of about 6.4 degrees ± 0.2 degrees, 7.5 degrees ± 0.2 degrees, 10.2 degrees ± 0.2 degrees, 12.7 degrees ± 0.2 degrees, 13.3 degrees ± 0.2 degrees, 14.5 degrees ± 0.2 degrees, 16.0 degrees ± 0.2 degrees, 17.1 degrees ± 0.2 degrees, 17.4 degrees ± 0.2 degrees, 17.9 degrees ± 0.2 degrees, 18.5 degrees ± 0.2 degrees, 19.1 degrees ± 0.2 degrees, 19.7 degrees ± 0.2 degrees, 19.8 degrees ± 0.2 degrees, 19.9 ... 2θ degrees: (a) X-ray powder diffraction (XRPD) pattern of characteristic peak positions of at least three of the values ​​in the group consisting of 2θ of: 20.3 degrees ± 0.2 degrees, 20.9 degrees ± 0.2 degrees, 21.5 degrees ± 0.2 degrees, 22.6 degrees ± 0.2 degrees, 23.7 degrees ± 0.2 degrees, 26.2 degrees ± 0.2 degrees, 26.7 degrees ± 0.2 degrees, 26.9 degrees ± 0.2 degrees, 27.5 degrees ± 0.2 degrees, 28.4 degrees ± 0.2 degrees, 30.2 degrees ± 0.2 degrees and 32.1 degrees ± 0.2 degrees: (b) an X-ray tube voltage setting of 40 kV and a current of 40 mA; (c) a scanning range from about 3 degrees to about 40 degrees; (d) a sample rotation speed of about 15 rpm; and (e) a scanning rate of 10 degrees per minute. In some embodiments, the pharmaceutical composition is formulated for oral or transdermal administration. In some embodiments, the amount includes a dose of less than 0.3 mg of the compound or its salt or polymorph per kg of subject body weight per day. In some embodiments, the amount includes a dose of less than 0.1 mg of the compound or its salt or polymorph per kg of subject body weight per day. In some embodiments, the amount includes a dose of less than 0.03 mg of the compound or its salt or polymorph per kg of subject body weight per day. In some embodiments, the epileptic condition is Dravet syndrome. In some embodiments, the epileptic condition is focal epileptic seizures. In some embodiments, the compound or its salt or polymorph is not a phosphate or polymorph thereof, and is not a sulfate or polymorph thereof. In certain embodiments, the subject is a human subject. In some embodiments, the compound is formulated as a non-lethargic preparation. In some embodiments, the non-sedative formulation comprises caffeine. In some embodiments, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The novel features of the exemplary embodiments are set forth, in particular, in the appended claims. A better understanding of the features and advantages will be obtained by referring to the following detailed description and the accompanying drawings, which set forth illustrative embodiments utilizing the principles of the exemplary embodiments, wherein:

[0047] Figure 1 Depicted are the starting body temperatures of pre-treated female mice prior to the onset of temperature-induced seizures (mean (± SEM)). The mean body temperatures of female mice prior to the induction of heat-induced seizures ranged from about 34.5°C to about 35.5°C.

[0048] Figure 2 Depicted are the starting body temperatures (mean (± SEM)) of pre-treated male mice prior to the onset of temperature-induced seizures. The mean body temperatures of male mice prior to the induction of heat-induced seizures ranged from about 34.5°C to about 35.5°C.

[0049] Figure 3 Depicted are the average starting body temperatures (mean (± SEM)) of all pre-treated mice prior to the onset of temperature-induced seizures. The average body temperatures (mean (± SEM)) of mice prior to the induction of heat-induced seizures ranged from about 34.5°C to about 35.3°C.

[0050] Figure 4Depicted are the final body temperatures (mean (± SEM)) of female mice in the epileptic seizure study. The final body temperature increased to about 42°C (within a range of about 40.5°C to about 42.5°C), which is sufficient to induce epilepsy in the absence of clobazam or GABA. A Receptor modulator treatment induces heat-induced seizures in a mouse model.

[0051] Figure 5 Depicted are the terminal body temperatures (mean (± SEM)) of male mice in the epilepsy seizure study. The terminal body temperature increased to about 42°C (within a range from about 40.5°C to about 42.5°C), which is sufficient to induce heat-induced epileptic seizures in the mouse model in the absence of anti-epileptic treatment.

[0052] Figure 6 The average final body temperature of all mice in the epilepsy study is depicted (mean (± SEM)). The final body temperature increased to about 42°C (within a range from about 40.5°C to about 42.5°C), which is sufficient to induce heat-induced epileptic seizures in the mouse model in the absence of anti-epileptic treatment. Administration of vehicle resulted in the lowest total body temperature in mice.

[0053] Figure 7 Depicted are the total changes in body temperature of female mice during the seizure study (mean (± SEM)). The body temperature of female mice was increased between 5°C and 8°C to induce heat-induced seizures in the mouse model.

[0054] Figure 8 Depicted are the total changes in body temperature (mean (± SEM)) of male mice during the seizure study. The body temperature of male mice was increased between 5°C and 8°C to induce heat-induced seizures in the mouse model.

[0055] Fig. 9 Depicted is the average total change in body temperature for all mice during the seizure study (mean (± SEM)). The body temperature of mice increased between 5°C and 8°C to induce heat-induced seizures in the mouse model. Mice administered vehicle control had a total temperature increase of 5°C, which was lower than mice receiving other treatments.

[0056] Fig.10 Depicted are the changes in body temperature per minute for female mice during the seizure study (mean (± SEM)). The changes in body temperature per minute for female mice ranged from about 0.4°C / min to about 0.6°C / min.

[0057] Fig.11 Depicted are the changes in body temperature per minute for male mice during the seizure study (mean (± SEM)). The changes in body temperature per minute for male mice ranged from about 0.4°C / min to about 0.6°C / min.

[0058] Fig.12 The average change in body temperature per minute for all mice during the seizure study is depicted (mean (± SEM)). The change in body temperature per minute for mice ranged from about 0.4°C / min to about 0.6°C / min. Mice administered vehicle had the highest rate of temperature increase per minute (about 0.6°C / min), while mice administered 100 mg / kg of the exemplary GABA A Mice treated with receptor modulator Compound 2 had the lowest rate of temperature rise per minute (approximately 0.4°C / min).

[0059] Fig.13 An overview of the efficacy of each treatment in the epilepsy seizure study is depicted. Example GABA A Receptor modulators Compound 1 and Compound 2 were each effective in preventing heat-induced seizures in a mouse model. GABA A Administration of the receptor modulator Compound 2 prevented epileptic seizures in a dose-dependent manner.

[0060] Fig.14 Depicted is an exemplary GABA that is effective in treating epileptic conditions A Receptor modulators.

[0061] Details

[0062] definition

[0063] The term "GABA receptor" may be used according to its known meaning in the biochemical art; the term may refer to a receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A Ionotropic receptors are ligand-gated ion channels, and GABA B The GABA receptors (also called metabotropic receptors) are G protein-coupled receptors. A GABA receptors are the most common and important inhibitory receptors in the central nervous system. A The receptor consists of five subunits grouped into the following eight categories: α 1-6 , β 1-3 , γ 1-3 , δ, ε, π, θ, and ρ 1-3 . Most GABA A The receptor consists of two alpha subunits, two beta subunits and one gamma subunit. Compounds can bind to sites different from the endogenous ligand GABA. For example, benzodiazepines It can bind to the binding site located between the α subunit and the γ subunit. The compounds described herein can be GABA AAllosteric modulators of receptors. Different types of α subunits confer GABA A The α1 subunit, however, is a benzodiazepine The α2 subunit is responsible for, among other things, the anxiolytic function of the receptor, and the α3 subunit confers, among other things, the GABA A The muscle relaxant properties of the receptor.

[0064] The term "allosteric modulator" may be used in accordance with its known meaning in the fields of biochemistry and pharmacology; the term may refer to a substance that indirectly modulates the action of an agonist on a receptor. A positive allosteric modulator may induce amplification of the action of an agonist, while in the absence of an agonist, the positive allosteric modulator itself has no effect. An allosteric modulator may bind to a site that is different from the binding site of an agonist (allosteric).

[0065] The terms "subject", "patient" or "individual" as used herein can cover mammals and non-mammals. Mammals can be any member of the class mammalia, including but not limited to humans, non-human primates, such as chimpanzees, apes or other monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs (or canines) and cats (or felines); laboratory animals, including rodents, such as rats, mice and guinea pigs and similar animals. Non-mammals can include birds, fish, etc. In some embodiments, the subject can be a mammal. In some embodiments, the subject can be a human. In some cases, the human can be an adult. In some cases, the human can be a child. In some cases, the age of the human can be 0-17 years old. In some cases, the age of the human can be 18-130 years old. In some cases, the subject can be male. In some cases, the subject can be female. In some cases, the subject can be diagnosed as having or suspected of having a condition or disease. In some cases, the disease or condition can be epilepsy or a condition associated with epilepsy. The subject can be a patient. The subject can be an individual. In some cases, subject, patient, or individual may be used interchangeably.

[0066] As used herein, the terms "treat," "treating," "treatment," "ameliorate," or "ameliorating," and other grammatical equivalents, may include alleviating or reducing the symptoms of a disease or condition, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or halting symptoms of a disease or condition.

[0067] "Hydrocarbyl" may refer to a saturated straight or branched hydrocarbon having, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more carbon atoms, wherein a carbon-carbon bond may be unsaturated, and a CH2 portion may be exchanged for oxygen (ether bridge). Non-limiting examples of C1-C4 hydrocarbyl are methyl, ethyl, propyl, prop-2-enyl, n-butyl, 2-methylpropyl, tert-butyl, but-3-enyl, prop-2-ynyl and but-3-ynyl. Unless specifically stated otherwise in the specification, the hydrocarbyl group may be optionally substituted.

[0068] The term "alkynyl" may refer to an optionally substituted straight-chain hydrocarbon or optionally substituted branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl group may have from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples may include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and similar groups. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" may mean that the alkynyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition of the present invention may also encompass the occurrence of the term "alkynyl" in the absence of a numerical range that may be specified. In some embodiments, the alkynyl group may be C1-C6. 10 Alkynyl, C1-C9 alkynyl, C1-C8 alkynyl, C1-C7 alkynyl, C1-C6 alkynyl, C1-C5 alkynyl, C1-C4 alkynyl, C1-C3 alkynyl, C2-C 10 Alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl or C2 alkynyl.Unless otherwise specifically stated in the specification, the alkynyl group can be optionally replaced by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, halogenated alkyl, alkoxy (alkoxy), aryl, cycloalkyl, heterocyclic alkyl, heteroaryl etc. In some embodiments, alkynyl can be optionally replaced by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or NO2.In some embodiments, alkynyl can be optionally replaced by oxo, halogen, -CN, -CF3, -OH or -OMe.In some embodiments, alkynyl can be optionally replaced by halogen.

[0069] The term "aryl" may refer to a cyclic aromatic C5-C 10Hydrocarbons. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl and heteroaryl. The term "heteroaryl" may refer to an aryl compound in which at least one carbon atom is replaced by an oxygen atom, a nitrogen atom or a sulfur atom. Examples of heteroaryl groups may include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazine, quinoline, benzofuran and indole. Aryl or heteroaryl groups may be optionally substituted. Aromatic hydrocarbons may be neutral or charged. Aryl or heteroaryl groups as used herein may optionally include one or more additional substituent groups.

[0070] "Cycloalkyl" may refer to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl may be bonded through a non-aromatic ring atom), a bridged ring system, or a spiro ring system. Representative cycloalkyls may include, but are not limited to, cycloalkyls having from 3 to 15 carbon atoms (C3-C4). 15 Cycloalkyl), from 3 to 10 carbon atoms (C3-C 10 In some embodiments, the cycloalkyl group may be a 3- to 6-membered cycloalkyl group. In some embodiments, the cycloalkyl group may be a 5- to 6-membered cycloalkyl group. The monocyclic cycloalkyl group may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or polycyclic carbocyclic ring can include, for example, adamantyl, norbornyl, decahydronaphthalene, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane and bicyclo [3.3.2] decane and 7,7-dimethyl-bicyclo [2.2.1] heptyl. Partially saturated cycloalkyl can include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyl can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, halogenated alkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl can be optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or NO2. In some embodiments, cycloalkyl can be optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted by halogen.

[0071] "Halo" or "halogen" may refer to bromine (Br), chlorine (Cl), fluorine (F), or iodine (I). In some embodiments, the halogen may be Br, F, or Cl. In some embodiments, the halogen may be F.

[0072] The term "about" can mean within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation according to the practice in the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or biological processes, the term can mean within an order of magnitude, within 5 times, or within 2 times of a value. When describing a particular value in the present application and claims, unless otherwise stated, the term "about" means within an acceptable error range of the particular value that should be assumed.

[0073] situation

[0074] Disclosed herein are compounds useful for treating epileptic conditions. The compounds described herein (e.g., GABA A GABA receptor modulators) can be used to at least partially alleviate epileptic conditions. For example, administration of GABA A Receptor modulators can be effective in treating the onset of epileptic seizures associated with an epileptic condition. As used herein, the term epileptic condition can refer to a condition associated with an epileptic seizure. In some embodiments, treatment includes reducing or preventing the onset of epileptic seizures associated with an epileptic condition. In some embodiments, an epileptic seizure is accompanied by a convulsion. In some embodiments, an epileptic condition with an epileptic seizure is also accompanied by a convulsion. In some embodiments, an epileptic condition with an epileptic seizure may not be accompanied by a convulsion.

[0075] Seizures are often associated with many diseases or conditions. For example, seizures can be associated with happy puppet syndrome, arteriovenous malformations, brain abscesses, brain tumors, cavernomas, cerebral palsy, Down syndrome, eclampsia, epilepsy, encephalitis, fragile X syndrome, meningitis, multiple sclerosis, systemic lupus erythematosus, and tuberous sclerosis. In addition, seizures can be associated with adverse effects of certain drugs, including aminophylline, bupivicaine, bupropion, butyrophenone, excessive caffeine, chlorambucil, cyclosporine, clozapine, corticosteroids, diphenhydramine, enflurane, estrogen, fentanyl, insulin, lidocaine, maprotiline, meperidine, olanzapine, pentazocine, phenothiazine, prednisone, procaine, propofol, propoxyphene, quetiapine, risperidone, sevoflurane, theophylline, tramadol, tricyclic antidepressants, venlafaxine, isoniazid, lindane, metronidazole, nalidixic acid, penicillins, fluoroquinolones and carbapenems.

[0076] In some cases, the epileptic condition is epilepsy. Epilepsy is a common chronic neurological disorder characterized by recurring unprovoked seizures. These seizures are transient signs and / or symptoms due to abnormal, excessive or synchronized neuronal activity in the brain. There are many different epileptic conditions, each presenting a unique combination of its seizure type, typical age of onset, EEG findings, treatment, and prognosis. In some embodiments, the epileptic condition is generalized epilepsy. In some embodiments, the epileptic condition is hereditary epilepsy.

[0077] Other exemplary epileptic conditions include those that may occur with epileptic seizures, for example, benign central temporal lobe epilepsy of childhood, benign occipital lobe epilepsy of childhood (BOEC), autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), primary reading epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), symptomatic localization-related epilepsy, temporal lobe epilepsy (TLE), frontal lobe epilepsy, Rasmussen encephalitis, cerebral palsy, cerebral hypoxia, Down syndrome, hypoxic-ischemic encephalopathy (HIE), West syndrome, Dravet syndrome, progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS). Hereditary, congenital, and developmental conditions are often associated with epilepsy in younger patients. Tumors may be the cause in patients over 40 years of age. Head trauma and central nervous system infections can cause epilepsy at any age. In some cases, GABA may be administered AGABA receptor modulators are used to treat breakthrough seizures. As described herein, "breakthrough seizures" may refer to seizures that occur after an extended period of time without seizures. In some cases, breakthrough seizures may occur because the subject is not taking medication. In some cases, breakthrough seizures may occur due to resistance or intractability of seizures to existing therapeutic agents such as clobazam. Therefore, as described herein, GABA A Receptor modulators may be used as an alternative first-line treatment for breakthrough seizures.

[0078] In some embodiments, epileptic condition is focal epileptic seizure. Focal epileptic seizure can be simple focal epileptic seizure (aura). Simple focal epileptic seizure accompanied by motor symptoms can affect muscle activity, causing jerking movement of feet, face, arms or other parts of the body. Simple focal epileptic seizure may cause sensory symptoms that affect sensation, such as hearing problems, hallucinations and smell or other distortions. Simple focal epileptic seizure accompanied by autonomic symptoms can affect the part of the brain responsible for involuntary (involuntary) function. These epileptic seizures can cause changes in blood pressure, heart rhythm, or bowel function or bladder function. Some simple focal epileptic seizures may attack the part of the brain that triggers emotions or memories of previous experiences, causing fear, anxiety or the illusory feeling of having experienced something before. Focal epileptic seizure can be complex focal epileptic seizure. In some cases, complex focal epileptic seizures are preceded by simple focal epileptic seizures. In some cases, a subject experiencing a complex focal seizure may stare blankly into space, or experience automatisms (non-purposeful, repetitive movements such as lip movements, blinking, grunting, swallowing, or yelling).

[0079] In some cases, GABA as described herein is used to A The disease or condition treatable by a receptor modulator is epilepsy associated with a sodium channel mutation in a subject. ASuch a disease or condition that can be treated by a receptor modulator is Dravet syndrome. Dravet syndrome is a rare hereditary epileptic encephalopathy. In some cases, Dravet syndrome is associated with a sodium channel mutation. For example, Dravet syndrome may be associated with a mutation in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene. Such mutations of SCN1A may include missense mutations, nonsense mutations, frameshift mutations, splicing mutations, or in-frame deletions. For example, SCN1A mutations may include D79H, R101Q, R222X, I227S, R377X, R393C, R613X, R712X, R859C, R1596C, R1213X, R1648H, M1780T, A1783V, R1892X, or R1912X mutations.

[0080] Dravet syndrome may begin in infancy and persist throughout the life of the subject. Dravet syndrome may manifest as different seizure types, including myoclonic seizures, tonic-clonic seizures, absence seizures, atypical absence seizures, atonic seizures, focal cognitive seizures, or status epilepticus. GABA as described herein A Receptor modulators may be administered to a subject suffering from Dravet syndrome to at least partially alleviate the seizures associated with Dravet syndrome.

[0081] As described in the Examples of this application, GABA A Receptor modulators are effective in treating hyperthermia-induced seizures in the Scn1a+ / - knockout mouse model. + / - Knockout mouse models are well-recognized in the art as models for a variety of epileptic conditions, including Dravet syndrome. A Receptor modulators as a class have efficacy in treating or preventing seizures in a variety of epilepsy conditions as described herein.

[0082] Compound

[0083] Disclosed herein are compounds useful for treating epileptic conditions. In some cases, the compound useful for treating epileptic conditions can be GABA A In certain embodiments, the compound is a positive allosteric α2 and / or α3 GABA receptor modulator. A GABA receptor modulators that are specific for the α2 or α3 subunit while avoiding modulation of the α1 subunit A Receptor modulators may be useful in treating epileptic conditions as described herein without causing the drowsiness associated with α1 subunit modulation. AReceptor modulators can be formulated as non-sedating or non-hypnotic formulations. In some cases, non-hypnotic formulations may contain other components that may further counteract any sedative effects associated with administration, including stimulants (e.g., caffeine).

[0084] GABA A Receptor modulators and metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof may be included in exemplary embodiments and are expected to be effective in treating epileptic conditions as described herein.

[0085] GABA for epileptic conditions A The receptor modulator may be a compound of formula (1a), formula (1b) or formula (1c):

[0086]

[0087] in

[0088] -X 1 , X 2 , X 3 , X 4 and X 5 are independently -C, -N, -S or -O, wherein X 1 , X 2 , X 3 , X 4 and X 5 At least two of them are -N,

[0089] -Y 1 and Y 2 are independently -C or -N,

[0090] -R 1 m m is 1,

[0091] -R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted C6 heteroaryl group,

[0092] -R 2 n n is 1 or 2,

[0093] - Each R 2 As with any other R 2is independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, and in some cases -F or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl group,

[0094] -Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently -C, -N, -S or -O,

[0095] -A 1 and A 2 and A 3 are independently -C, -N or -C(C=O)-OR 7 ,or

[0096]

[0097] -R 7 is a hydrocarbon group,

[0098] -B 1 , B 2 , B 3 and B 4 are independently -C, -N or -O,

[0099] -R 21 S s is 1, 2, 3, or 4, and

[0100] - Each R 21 are independently hydrogen or a C1-C6 hydrocarbon group,

[0101] -R 5 l l is 1 or 2,

[0102] - Each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl,

[0103] -R 6 k k is 1, 2, 3 or 4, in some cases 1 or 2,

[0104] - Each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0105] In certain embodiments, compounds comprising formula (1a) are provided, wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently -C, -N, -S or -O, wherein X 1 , X 2 , X 3 , X 4 and X 5 At least two of them are -N,Y 1 and Y 2 are independently -C or -N, R 1 m m is 1, R 1 is a substituted or unsubstituted C6 aryl group or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted C6 heteroaryl group, R 2 n n is 1 or 2, each R 2 As with any other R 2 is independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, and in some cases -F or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl group.

[0106] In certain embodiments, compounds comprising the general formula (1b) are provided, wherein Z 3 , Z 4 and Z 5 are independently -C, -N, -S or -O, A 1 , A 2 and A 3 are independently -C, -N or -C(C=O)-OR 7 , where R 7 is a hydrocarbon group, R 5 l l is 1 or 2, each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl, R 6 k k is 1, 2, 3 or 4, in some cases 1 or 2, each R 6are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0107] In certain embodiments, compounds comprising the general formula (1c) are provided, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently -C, -N, -S or -O, R 5 l l is 1 or 2, each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl, R 6 k k is 1, 2, 3 or 4, in some cases 1 or 2, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0108] In certain embodiments, the compound comprises Formula (1a), Formula (1b), or Formula (1c), wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently -C, -N, wherein X 1 , X 2 , X 3 , X 4 and X 5 At least two of them are -N,Y 1 and Y 2 are independently -C or -N, R 1 m m is 1, R 1 is a substituted or unsubstituted C6 aryl group or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted C6 heteroaryl group, R 2 n n is 1 or 2, each R 2 As with any other R 2 is independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, and in some cases -F or -O-CH2-R 4 , where R 4is a substituted or unsubstituted C4 heteroaryl group, Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently -C, -N or -O, A 1 , A 2 and A 3 are independently -C, -N or -C(C=O)-OR 7 , where R 7 is a hydrocarbon group, R 5 l l is 1 or 2, each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl, R 6 k k is 1, 2, 3 or 4, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0109] In certain embodiments, compounds comprising formula (1a) are provided, wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently -C or -N, where X 1 , X 2 , X 3 , X 4 and X 5 At least two of them are -N,Y 1 and Y 2 are independently -C or -N, R 1 m m is 1, R 1 is a substituted or unsubstituted C6 aryl group or -(C=O)-R 3 , where R 3 is a substituted or unsubstituted C6 heteroaryl group, R 2 n n is 1 or 2, each R 2 As with any other R 2 is independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted C6 heteroaryl, halogen, and in some cases -F or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl group.

[0110] In certain embodiments, compounds comprising the general formula (1b) are provided, wherein Z 3 , Z 4 and Z 5 Independently of each other, -C or -N, A 1 , A 2 and A 3 are independently -C, -N or -C(C=O)-OR 7 , where R 7 is a hydrocarbon group, R 5 l l is 1 or 2, each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl, R 6 k k is 1, 2, 3 or 4, in some cases 1 or 2, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0111] In certain embodiments, compounds comprising the general formula (1c) are provided, wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are independently -C, -N or -O, R 5 l l is 1 or 2, each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl, R 6 k k is 1, 2, 3 or 4, in some cases 1 or 2, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0112] GABA for epileptic conditions A The receptor modulator can be a compound of formula (2), formula (3), formula (4), formula (5), formula (6) or formula (7)

[0113]

[0114] where Y 1 , Y 2 , Z 1 , Z 4 , Z 5 , R 1m m、R 1 , R 3 , R 2 n n、R 2 , R 4 , R 5 1 of 1, R 5 , R 6 k k, R 6 , A 1 , A 2 and A 3 has the same meaning as defined above.

[0115] In certain embodiments, the compound comprises Formula (2), Formula (3), Formula (4) or Formula (5), wherein Y 1 , Y 2 , R 1 m m、R 1 , R 3 , R 2 n n、R 2 and R 4 has the same meaning as defined above.

[0116] In certain embodiments, the compound comprises the general formula (6), wherein Z 1 , Z 4 , Z 5 , R 5 l l, R 5 , R 6 k k and R 6 has the same meaning as defined above.

[0117] In certain embodiments, the compound comprises the general formula (7), wherein Z 4 , Z 5 , R 5 l l, R 5 , R 6 k k, R 6 , A l , A 2 and A 3 has the same meaning as defined above.

[0118] GABA for epileptic conditions AThe receptor modulator can be a compound of formula (2a), formula (3a), formula (4a), formula (5a), formula (5b), formula (6a), formula (6b) or formula (7a)

[0119]

[0120] Where R 1 m m, R 1 , R 3 , R 2 n n、R 2 , R 4 , R 5 l l, R 5 , R 6 k k and R 6 has the same meaning as defined above.

[0121] In certain embodiments, the compound comprises Formula (2a), Formula (3a), Formula (4a), Formula (5a) or Formula (5b), wherein R 1 m m、R 1 , R 3 , R 2 n n、R 2 and R 4 has the same meaning as defined above.

[0122] In certain embodiments, the compound comprises Formula (6a) or Formula (6b), wherein R 5 l l, R 5 , R 6 k k and R 6 has the same meaning as defined above.

[0123] In certain embodiments, the compound comprises the general formula (7a), wherein R 5 l l, R 5 , R 6 k k and R 6 has the same meaning as defined above.

[0124] In certain embodiments, the compound comprises Formula 1a, Formula 1b, Formula 1c, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 2a, Formula 3a, Formula 4a, Formula 5a, Formula 5b, Formula 6a, Formula 6b, or Formula 7a, wherein R1 m m is 1 and R 1 is: unsubstituted phenyl, substituted phenyl comprising at least one -F as a substituent, unsubstituted biphenyl, substituted biphenyl comprising at least one -CN as a substituent, in some cases on a phenyl moiety not attached to a parent moiety; or substituted biphenyl comprising at least one -CN as a substituent, in some cases at least one -CN on the phenyl moiety not directly attached to a parent moiety, wherein in some cases one phenyl moiety additionally comprises at least one -F as a substituent, in some cases each phenyl moiety additionally comprises at least one -F as a substituent, or -(C=O)-R 3 , where R 3 is pyridine, and R 5 l l is 1 and R 5 It is Cl, Br, F or C2 alkynyl.

[0125] In certain embodiments, the compound comprises Formula 1a, Formula 2, Formula 3, Formula 4, Formula 5, Formula 2a, Formula 3a, Formula 4a, Formula 5a, or Formula 5b, wherein R 1 m m is 1 and R 1 is: unsubstituted phenyl, substituted phenyl comprising at least one -F as a substituent, unsubstituted biphenyl, substituted biphenyl comprising at least one -CN as a substituent, in some cases on a phenyl moiety not attached to a parent moiety; or substituted biphenyl comprising at least one -CN as a substituent, in some cases at least one -CN on the phenyl moiety not directly attached to a parent moiety, wherein in some cases one phenyl moiety additionally comprises at least one -F as a substituent, in some cases each phenyl moiety additionally comprises at least one -F as a substituent, or -(C=O)-R 3 , where R 3 It's pyridine.

[0126] In certain embodiments, the compound comprises Formula 1b, Formula 7, or Formula 7a, wherein R 5 l l is 1 and R 5 It is Cl, Br, F or C2 alkynyl.

[0127] In certain embodiments, the compound comprises Formula 1c, Formula 6, Formula 6a, or Formula 6b, wherein R 5 l l is 1 and R 5 It is Cl, Br, F or C2 alkynyl.

[0128] In certain embodiments, the compound comprises Formula 1a, Formula 1b, Formula 1c, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 2a, Formula 3a, Formula 4a, Formula 5a, Formula 5b, Formula 6a, Formula 6b, or Formula 7a, wherein R 2 n n is 1 or 2, and in the case where n is 2, each R 2 are independently unsubstituted C3-C8 cycloalkyl, in some cases C4 cycloalkyl, unsubstituted C1-C6 alkyl, in some cases tert-butyl or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl group, in some cases R 4 is a substituted or unsubstituted triazole, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, a halogen, in some cases -F; in the case where n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl, in some cases pyridine, and R 6 k k is 1 or 4, and in the case where k is 1, R 6 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and when k is 4, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0129] In certain embodiments, the compound comprises Formula 1a, Formula 1b, Formula 1c, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 2a, Formula 3a, Formula 4a, Formula 5a, Formula 5b, Formula 6a, Formula 6b, or Formula 7a, wherein R 2 n n is 1 or 2, and in the case where n is 2, each R 2 are independently unsubstituted C3-C8 cycloalkyl, in some cases C4 cycloalkyl, unsubstituted C1-C6 alkyl, in some cases tert-butyl or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl group, in some cases R 4 is a substituted or unsubstituted triazole, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, a halogen, in some cases -F; in the case where n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl, in some cases pyridine, and R6 k k is 1 or 4, and in the case where k is 1, R 6 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and when k is 4, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0130] In certain embodiments, the compound comprises Formula 1a, Formula 2, Formula 3, Formula 4, Formula 5, Formula 2a, Formula 3a, Formula 4a, Formula 5a, or Formula 5b, wherein R 2 n n is 1 or 2, and in the case where n is 2, each R 2 are independently unsubstituted C3-C8 cycloalkyl, in some cases C4 cycloalkyl, unsubstituted C1-C6 alkyl, in some cases tert-butyl or -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl group, in some cases R 4 is a substituted or unsubstituted triazole, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, a halogen, in some cases -F; in the case where n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl, and in some cases pyridine.

[0131] In certain embodiments, the compound comprises Formula 1b, Formula 7, or Formula 7a, wherein R 6 k k is 1 or 4, and in the case where k is 1, R 6 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group; when k is 4, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0132] In certain embodiments, the compound comprises Formula 1c, Formula 6, Formula 6a, or Formula 6b, wherein R 6 k k is 1 or 4, and in the case where k is 1, R 6 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group; when k is 4, each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen.

[0133] In certain embodiments, the compound comprises Formula 1a, Formula 1b, Formula 1c, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6, Formula 7, Formula 2a, Formula 3a, Formula 4a, Formula 5a, Formula 5b, Formula 6a, Formula 6b, or Formula 7a, wherein R 2 n n is 2 and an R 2 is an unsubstituted C3-C8 cycloalkyl, in some cases a C4 cycloalkyl or an unsubstituted C1-C6 alkyl, in some cases a tert-butyl group, and the other R 2 Yes-O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or an R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and the other R 2 is a halogen, in some cases -F, and R 6 k k is 4, and the two R 6 is oxygen, the other R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon or hydrogen.

[0134] In certain embodiments, the compound comprises Formula 1a, Formula 2, Formula 3, Formula 4, Formula 5, Formula 2a, Formula 3a, Formula 4a, Formula 5a, or Formula 5b, wherein R 2 n n is 2 and an R 2 is an unsubstituted C3-C8 cycloalkyl, in some cases a C4 cycloalkyl, or an unsubstituted C1-C6 alkyl, in some cases a tert-butyl, and the other R 2 It is O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or an R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and the other R 2 is a halogen, and in some cases is -F.

[0135] In certain embodiments, the compound comprises Formula 1b, Formula 7, or Formula 7a, wherein R 6 k k is 4, and the two R 6 is oxygen, the other R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon or hydrogen.

[0136] In certain embodiments, the compound comprises Formula 1c, Formula 6, Formula 6a, or Formula 6b, wherein R 6 k k is 4, and the two R 6 is oxygen, the other R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbon or hydrogen.

[0137] GABA for epileptic conditions A The receptor modulator can be a compound of formula (2a'), formula (3a'), formula (4a'), formula (5a'), formula (5b'), formula (6a'), formula (6b') or formula (7a')

[0138]

[0139] Where R 1 , R 3 , R 2 n n、R 2 , R 4 , R 5 , R 6 k k and R 6 has the same meaning as defined above.

[0140] In certain embodiments, the compound comprises Formula (2a'), Formula (3a'), Formula (4a'), Formula (5a'), or Formula (5b'), wherein R 1 , R 3 , R 2 n n、R 2 and R 4 has the same meaning as defined above.

[0141] In certain embodiments, the compound comprises Formula (6a') or Formula (6b'), wherein R 6 k k and R 6 has the same meaning as defined above.

[0142] In certain embodiments, the compound comprises the general formula (7a'), wherein R 6 k k and R 6 has the same meaning as defined above.

[0143] In certain embodiments, the compound comprises Formula (2a'), Formula (3a'), Formula (4a'), Formula (5a'), Formula (5b'), Formula (6a'), Formula (6b'), or Formula (7a'), wherein R 1 In the case of formula (2a'), it is a substituted or unsubstituted C6 aryl group, in some cases it is an unsubstituted phenyl group, a substituted phenyl group containing at least one -F as a substituent, in the case of formula (3a'), formula (5a') or formula (5b'), it is a substituted or unsubstituted biphenyl group, in some cases it is an unsubstituted biphenyl group, a substituted biphenyl group containing at least one -CN as a substituent, in some cases on a phenyl moiety not connected to the parent moiety, wherein in some cases one phenyl moiety further contains at least one -F as a substituent, in some cases each phenyl moiety further contains at least one -F as a substituent, or in the case of formula (4a'), it is -(C=O)-R 3 , where R 3 is a substituted or unsubstituted C6 heteroaryl, in some cases wherein R 3 is pyridine, R 5 In the case of formula (6a') or formula (6b'), it is Cl, Br or F, and in the case of formula (7a'), it is C2 alkynyl, wherein R 2 n and R 6 k has the same meaning as defined above.

[0144] In certain embodiments, the compound comprises Formula (2a'), Formula (3a'), Formula (4a'), Formula (5a'), or Formula (5b'), wherein R 1 In the case of formula (2a'), it is a substituted or unsubstituted C6 aryl group, in some cases it is an unsubstituted phenyl group, a substituted phenyl group containing at least one -F as a substituent, in the case of formula (3a'), formula (5a') or formula (5b'), it is a substituted or unsubstituted biphenyl group, in some cases it is an unsubstituted biphenyl group, a substituted biphenyl group containing at least one -CN as a substituent, in some cases on a phenyl moiety not connected to the parent moiety, wherein in some cases one phenyl moiety further contains at least one -F as a substituent, in some cases each phenyl moiety further contains at least one -F as a substituent, or in the case of formula (4a'), it is -(C=O)-R 3 , where R 3 is a substituted or unsubstituted C6 heteroaryl, in some cases wherein R 3 is pyridine, where R 2 n has the same meaning as defined above.

[0145] In certain embodiments, the compound comprises Formula (6a') or Formula (6b'), wherein R 5 is Cl, Br or F, where R 6 k has the same meaning as defined above.

[0146] In certain embodiments, the compound comprises the general formula (7a'), wherein R 5 is a C2 alkynyl group, wherein R 6 k has the same meaning as defined above.

[0147] GABA for epileptic conditions A The receptor modulator can be a compound of formula (2a"), formula (3a"), formula (4a"), formula (5a"), formula (5b"), formula (6a") or formula (7a")

[0148]

[0149] Where R 7 is an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group, an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and in some cases R 7 In the case of formula (2a"), it is an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group, or an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group, or R 7 In the case of formula (5a") or formula (5b"), it is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 8 Yes-O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, in some cases R 8 In the case of formula (2a"), it is -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or R 8 In the case of formula (3a"), it is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 9 is unsubstituted C6 heteroaryl, in some cases pyridine or halogen, in some cases -F, R 9In the case of formula (4a"), it is an unsubstituted C6 heteroaryl group, in some cases pyridine, or R 9 In the case of formula (5b"), it is halogen, in some cases -F, R 10 is a C1-C3 hydrocarbon group or hydrogen, R 11 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, in some cases R 11 In the case of formula (6a"), R is a substituted or unsubstituted aryl group, in some cases a phenyl group, 11 In the case of formula (7a"), R is a substituted or unsubstituted heteroaryl group, in some cases pyridine, a substituted or unsubstituted aryl group, in some cases phenyl group, 5 In the case of formula (6a"), it is Cl, Br or F, and in the case of formula (7a"), it is a C2 alkynyl group.

[0150] In certain embodiments, the compound comprises Formula (2a"), Formula (3a"), Formula (4a"), Formula (5a"), or Formula (5b"), wherein R 7 is an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group, an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group, an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and in some cases R 7 In the case of formula (2a"), it is an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group, or an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group, or R 7 In the case of formula (5a") or formula (5b"), it is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 8 Yes-O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, in some cases R 8 In the case of formula (2a"), it is -O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or R 8 In the case of formula (3a"), it is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 9 is unsubstituted C6 heteroaryl, in some cases pyridine or halogen, in some cases -F, R 9In the case of formula (4a"), it is an unsubstituted C6 heteroaryl group, in some cases pyridine, or R 9 In the case of formula (5b") it is halogen, in some cases it is -F.

[0151] In certain embodiments, compounds useful for treating epileptic conditions comprise the general formula (6a"), wherein R 10 is a C1-C3 hydrocarbon group or hydrogen, R 11 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, in some cases R 11 In the case of formula (6a"), R is a substituted or unsubstituted aryl group, in some cases a phenyl group, 11 In the case of formula (7a"), R is a substituted or unsubstituted heteroaryl group, in some cases pyridine, 5 is Cl, Br or F.

[0152] In certain embodiments, the compound comprises the general formula (7a"), wherein R 11 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, in some cases R 11 In the case of formula (6a"), R is a substituted or unsubstituted aryl group, in some cases a phenyl group, 11 In the case of formula (7a"), R is a substituted or unsubstituted heteroaryl group, in some cases pyridine, 5 It is a C2 alkynyl group.

[0153] In certain embodiments, the compound comprises Formula (2a"), Formula (3a"), Formula (4a"), Formula (5a"), or Formula (5b"), wherein in the case of Formula (2a"), R 1 is unsubstituted phenyl, substituted phenyl containing at least one -F as a substituent, R 7 is an unsubstituted C1-C6 hydrocarbon group, in some cases tert-butyl, or an unsubstituted C3-C8 cycloalkyl group, in some cases C4 cycloalkyl group, and R 8 Yes-O-CH2-R 4 , where R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole; in the case of formula (3a"), R 1 is an unsubstituted biphenyl group, a substituted biphenyl group comprising at least one -CN as a substituent, in some cases on a phenyl moiety not attached to the parent moiety, wherein in some cases one phenyl moiety additionally comprises at least one -F as a substituent, in some cases each phenyl moiety additionally comprises at least one -F as a substituent, R 8is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, in the case of formula (4a"), R 1 Yes -(C=O)-R 3 , where R 3 is an unsubstituted C6 heteroaryl group, in some cases R 3 is pyridine, and R 9 is an unsubstituted C6 heteroaryl group, in some cases pyridine; in the case of formula (5a"), R 1 is an unsubstituted biphenyl group, a substituted biphenyl group comprising at least one -CN as a substituent, in some cases on a phenyl moiety not attached to the parent moiety, wherein in some cases one phenyl moiety additionally comprises at least one -F as a substituent, in some cases each phenyl moiety additionally comprises at least one -F as a substituent, R 7 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol; in the case of formula (5b"), R 1 is an unsubstituted biphenyl group, a substituted biphenyl group comprising at least one -CN as a substituent, in some cases on a phenyl moiety not attached to the parent moiety, wherein in some cases one phenyl moiety additionally comprises at least one -F as a substituent, in some cases each phenyl moiety additionally comprises at least one -F as a substituent, R 7 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 9 is a halogen, in some cases F.

[0154] GABA for epileptic conditions A The receptor modulator may be a compound of the general formula (8):

[0155]

[0156] in

[0157] -Z 4 and Z 5 are independently -C, -N, -S or -O,

[0158] -A 1 and A 2 are independently -C, -N or -C(C=O)-OR 7 , where R 7 is a hydrocarbon group,

[0159] -B 1 , B 2 , B 3 and B 4 are independently -C, -N or -O,

[0160] -R5 l l is 1 or 2,

[0161] - Each R 5 are independently C1-C4 alkynyl or halogen, in some cases -Cl,

[0162] -R 6 k k is 1, 2, 3 or 4, in some cases 1 or 2,

[0163] - Each R 6 are independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbon, oxygen or hydrogen,

[0164] -R 21 S s is 1, 2, 3, or 4, or

[0165] - Each R 21 are independently hydrogen or a C1-C6 hydrocarbon group.

[0166] In certain embodiments, the compound is selected from Fig.14 Compounds depicted in, such as L-838417; TPA023 (MK-0777); TPA123; MRK-409 (MK-0343); NS11394; Ocinaplon (DOV-273547); TPA023B; TP003; N-desmethylclobazam 1, 2, 3, 4 and 5; Hz-166; MP-III-080; KRM-II-81; PF-06372865; SL65.1498; AZD7325; AZD6280; L-838417 and CTP-354.

[0167] In some cases, the compound is selected from the group consisting of:

[0168]

[0169] or a salt, prodrug, polymorph, solvate, ester, stereoisomer or derivative thereof.

[0170] In some cases, the compound may be or a salt, prodrug, polymorph, solvate, ester, stereoisomer or derivative thereof.

[0171] As shown in the Examples below, exemplary GABA A Receptor modulators Compound 1 and Compound 2 are effective in preventing heat-induced epileptic seizures. The structures of Compound 1 and Compound 2 are described below:

[0172]

[0173] Compound 1

[0174]

[0175] Compound 2.

[0176] As described herein, it is expected that GABA A Receptor modulators such as Compound 1 and Compound 2 have a A Modulation of these receptors is effective in treating epileptic conditions.

[0177] This article also discloses GABA A A pharmaceutically acceptable salt form of a receptor modulator. The salt may comprise a counterion selected from the group consisting of acetate, benzoate, bitartrate, aspartate, formate, bromide, chloride, iodide, fumarate, citrate, maleate, nitrate, salicylate, succinate, sulfate, phosphate, benzenesulfonate, hippurate, naphthoate, naphthylsulfonate, sulfosalicylate, toluenesulfonate, octanoate, oleate, pamoate, stearate, propionate, caproate, decanoate, aspartate, bitartrate, salicylate, naphthylsulfonate or sulfite, and any combination thereof.

[0178] This article also discloses GABA A Polymorphs of receptor modulators. The polymorphs may include the GABA described herein A Free base polymorph of a receptor modulator, or GABA A A salt polymorph of a receptor modulator, or GABA as described herein A In some cases, the polymorphs may have improved solubility, improved oral bioavailability, more consistent oral bioavailability, improved stability, improved manufacturability, and corresponding improved formulations. Such polymorphs may be prepared by crystallizing or co-crystallizing GABA in a crystallization solvent. A The receptor modulators are prepared as free bases or salts in solvents for crystallization such as ethyl acetate, methyl ethyl ketone, 2-methyl butanone, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetone, water, tetrahydrofuran (THF), 2-methyl-THF, isopropyl acetate (IPAC), acetonitrile or dichloromethane.

[0179] The preparation of a polymorph can be confirmed by collecting diffraction patterns of crystals or co-crystals. In some cases, X-ray powder diffraction (XRPD) can be used to collect diffraction patterns. Exemplary XRPD parameters are provided below:

[0180]

[0181] In some exemplary cases, a polymorph of Compound 1 can be administered, such as a polymorph of Compound 1 having an XRPD pattern having an XRPD pattern selected from the group consisting of about 6.4 degrees ± 0.2 degrees, 7.5 degrees ± 0.2 degrees, 10.2 degrees ± 0.2 degrees, 12.7 degrees ± 0.2 degrees, 13.3 degrees ± 0.2 degrees, 14.5 degrees ± 0.2 degrees, 16.0 degrees ± 0.2 degrees, 17.1 degrees ± 0.2 degrees, 17.4 degrees ± 0.2 degrees, 17.9 degrees ± 0.2 degrees, 18.5 degrees ± 0.2 degrees, 19.1 degrees ± 0.2 degrees, 19.7 degrees ± 0.2 degrees, 20. .3 degrees ± 0.2 degrees, 20.9 degrees ± 0.2 degrees, 21.5 degrees ± 0.2 degrees, 22.6 degrees ± 0.2 degrees, 23.7 degrees ± 0.2 degrees, 26.2 degrees ± 0.2 degrees, 26.7 degrees ± 0.2 degrees, 26.9 degrees ± 0.2 degrees, 27.5 degrees ± 0.2 degrees, 28.4 degrees ± 0.2 degrees, 30.2 degrees ± 0.2 degrees and 32.1 degrees ± 0.2 degrees 2θ, about 5.4 degrees ± 0.2 degrees, 10.8 degrees ± 0.2 degrees, 12.3 degrees ± 0.2 degrees, 12.6 degrees ± 0.2 degrees, 13.5 degrees ± 0.2 degrees, 14.8 degrees ± 0.2 degrees, 15.9 degrees ± 0.2 degrees, 16.3 degrees ± 0.2 degrees, 16.4 degrees ± 0.2 degrees, 17.3 degrees ± 0.2 degrees, 17.8 degrees ± 0.2 degrees, 19.3 degrees ± 0.2 degrees, 20.4 degrees ± 0.2 degrees, 21.5 degrees ± 0.2 degrees, 21.7 degrees ± 0.2 degrees, 22.7 degrees ± 0.2 degrees, 23.4 degrees ± 0.2 degrees, 24.4 degrees ± 0.2 degrees, 24.7 degrees ± 0.2 degrees, 25.0 degrees ± 0.2 degrees, 26.1 degrees ± 0.2 degrees, 26.6 degrees ± 0.2 degrees, 27.0 degrees ± 0.2 degrees, 27.2 degrees ± 0.2 degrees, 27.5 degrees ± 0.2 degrees, 28.4 degrees ± 0.2 degrees, 28.7 degrees ± 0.2 degrees, 29.0 degrees ± 0.2 degrees, The characteristic peak positions are as follows: 29.6 degrees ± 0.2 degrees, 30.2 degrees ± 0.2 degrees and 32.3 degrees ± 0.2 degrees 2θ, at least three of the values ​​in the group consisting of about 7.0 degrees ± 0.2 degrees, 12.4 degrees ± 0.2 degrees, 12.6 degrees ± 0.2 degrees, 13.0 degrees ± 0.2 degrees, 14.1 degrees ± 0.2 degrees, 15.4 degrees ± 0.2 degrees, 15.7 degrees ± 0.2 degrees, 16.3 degrees ± 0.2 degrees, 17.5 degrees ± 0.2 degrees, 18.3 degrees ± 0.2 degrees, 19.0 degrees ± 0.2 degrees, 21.0 degrees ± 0.2 degrees, 22.3 degrees ± 0.2 degrees, 23.0 degrees ± 0.2 degrees and 24.9 degrees ± 0.2 degrees 2θ.

[0182] Pharmaceutical composition

[0183] Also disclosed herein are compositions comprising GABA as described herein.A In some embodiments, the pharmaceutical composition may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more GABA receptor modulators disclosed herein. A Receptor modulators.

[0184] In some cases, a pharmaceutical composition may include a GABA as described herein. A A receptor modulator and at least one of an excipient, a diluent, or a carrier. In some cases, the GABA described herein A The receptor modulator may be dissolved or suspended in a diluent or carrier.

[0185] In some embodiments, the pharmaceutical composition may include an excipient. The excipient may be an excipient described in the American Pharmaceutical Association Handbook of Pharmaceutical Excipients (1986).

[0186] Non-limiting examples of suitable excipients may include buffers, preservatives, stabilizers, binders, compacting agents, lubricants, chelating agents, dispersion enhancers, disintegrants, flavoring agents, sweeteners, coloring agents.

[0187] In some embodiments, excipient can be a buffer. The non-limiting examples of suitable buffer can include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate and calcium bicarbonate. As buffer, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide and other calcium salts or their combinations can be used in the pharmaceutical composition.

[0188] In some embodiments, the excipient may include a preservative. Non-limiting examples of suitable preservatives may include antioxidants, such as alpha-tocopherol and ascorbate, and antibacterial agents such as parabens, chlorobutanol and phenol. Antioxidants may also include, but are not limited to, EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium sulfite, p-aminobenzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol and N-acetyl cysteine. In some cases, the preservative can include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, Na-toluenesulfonyl-Phe-chloromethyl ketone, Na-toluenesulfonyl-Lys-chloromethyl ketone, aprotinin, phenylmethylsulfonyl fluoride, diisopropyl fluorophosphate, kinase inhibitors, phosphatase inhibitors, caspase inhibitors, granzyme inhibitors, cell adhesion inhibitors, cell division inhibitors, cell cycle inhibitors, lipid signaling inhibitors, protease inhibitors, reducing agents, alkylating agents, antibacterial agents, oxidase inhibitors or other inhibitors.

[0189] In some embodiments, the pharmaceutical composition can include a binder as an excipient. Non-limiting examples of suitable binders can include starch, pregelatinized starch, gelatin, polyvinyl pyrrolidone, cellulose, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylamide, polyvinyloxazolidinone, polyvinyl alcohol, C12-C18 fatty acid alcohol, polyethylene glycol, polyol, sugar, oligosaccharide and combinations thereof.

[0190] Binders that can be used in the pharmaceutical composition can be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural gums and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinyl pyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.

[0191] In some embodiments, pharmaceutical composition can include lubricant as excipient.The non-limiting examples of suitable lubricant can include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, polyoxyethylene monostearate, talcum powder, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil.The lubricant that can be used for pharmaceutical composition can be selected from metal stearate (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid ester (such as sodium stearyl fumarate), fatty acid (such as stearic acid), fatty alcohol, behenic acid glyceride, mineral oil, paraffin, hydrogenated vegetable oil, leucine, polyethylene glycol (PEG), metal lauryl sulfate (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talcum powder or its combination.

[0192] In some embodiments, the pharmaceutical composition may include a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants may include starch, alginic acid, polyvinyl pyrrolidone, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[0193] In some embodiments, the pharmaceutical composition can include disintegrants as excipients. In some embodiments, disintegrants can be non-effervescent disintegrants. The limiting examples of suitable non-effervescent disintegrants can include starches such as corn starch, potato starch, its pregelatinized and modified starches, sweeteners, clays such as bentonite, microcrystalline cellulose, alginate, sodium starch glycolate, gums such as agar, guar gum, locust bean gum, karaya gum, pectin and tragacanth. In some embodiments, disintegrants can be effervescent disintegrants. The limiting examples of suitable effervescent disintegrants can include sodium bicarbonate combined with citric acid, and sodium bicarbonate combined with tartaric acid.

[0194] In some embodiments, the excipient may include a flavoring agent. The flavoring agent incorporated into the outer layer may be selected from synthetic flavor oils and flavoring aromatic compounds; natural oils; extracts from plants, leaves, flowers and fruits; and combinations thereof. In some embodiments, the flavoring agent may be selected from the group consisting of: cinnamon oil; wintergreen oil; peppermint oil; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oils such as lemon oil, orange oil, grape oil and grapefruit oil; and fruit flavors including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple and apricot.

[0195] In some embodiments, the excipient may include a sweetener. Non-limiting examples of suitable sweeteners may include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts, such as sodium salt; dipeptide sweeteners, such as aspartame; dihydrochalcone compounds; glycyrrhizin; Stevia Rebaudiana (stevioside); chlorinated derivatives of sucrose, such as sucralose; and sugar alcohols, such as sorbitol, mannitol, xylitol, and the like.

[0196] In some cases, the pharmaceutical composition may include a colorant. Non-limiting examples of suitable colorants may include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext.D&C). Colorants may be used as dyes or their corresponding lakes.

[0197] In some cases, the pharmaceutical composition may include a diluent. Non-limiting examples of diluents may include water, glycerol, methanol, ethanol and other similar biocompatible diluents. In some cases, the diluent may be an aqueous acid such as acetic acid, citric acid, maleic acid, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or the like. In some cases, the diluent may be used to adjust the pH of the compound to a pH such as physiological pH to produce a salt as described above. In other cases, the diluent may be selected from the group including: alkali metal carbonates such as calcium carbonate; alkali metal phosphates such as calcium phosphate; alkali metal sulfates such as calcium sulfate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, palm stearin, lactitol, kaolin (caoline), lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and / or its anhydrate, hydrate and / or pharmaceutically acceptable derivative or combination thereof.

[0198] In other embodiments, the pharmaceutical composition may include a surfactant. The surfactant may be selected from, but is not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene olefin ethers, sorbitan fatty acid esters, polyethylene glycol (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, amino acids such as L-leucine, sugar esters of fatty acids, glycerides of fatty acids, or combinations thereof.

[0199] Pharmaceutical compositions disclosed herein can be formulated into various forms and applied in many different ways. Pharmaceutical compositions can be administered orally, rectally or parenterally with preparations, and the preparations include conventionally acceptable carriers, adjuvants and vehicles required. The term "parenteral" as used herein can include subcutaneous, intravenous, intramuscular or intrasternal injection and infusion techniques. Application can include injection or infusion, including intra-arterial, intracardiac, intracerebroventricular, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous, suction, transdermal, transmucosal, sublingual, buccal and local (including epidermis, dermis, enema, eye drops, ear drops, intranasal, vaginal) administration. In some exemplary embodiments, route of administration can be via injection, such as intramuscular injection, intravenous injection, subcutaneous injection or intraperitoneal injection.

[0200] Solid dosage forms for oral administration can include capsules, tablets, caplets, pills, lozenges, pastilles, powders and granules. Capsules can include a core material comprising a nutritional protein or composition and a shell wall that encapsulates the core material. In some embodiments, the core material can include at least one of a solid, a liquid and an emulsion. In some embodiments, the shell wall material can include at least one of a soft gelatin, a hard gelatin and a polymer. Suitable polymers may include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, and sodium carboxymethyl cellulose; acrylic polymers and copolymers such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (e.g., those copolymers sold under the trade name "Eudragit"); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (purified shellac). In some embodiments, at least one polymer may function as a taste masking agent.

[0201] Tablets, pills and the like can be compressed, compressed multiple times, layered multiple times and / or coated. Coating can be single or multiple. In some embodiments, coating material can include at least one of sugar, polysaccharide and glycoprotein extracted from at least one of plants, fungi and microorganisms. Non-limiting examples can include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextran, maltodextrin, cyclodextrin, inulin, pectin, mannan, gum arabic, locust bean gum, mesquite gum, guar gum, karaya gum, gum ghatti, tragacanth, funori, carrageenan, agar, alginate, chitosan or gellan gum. In some embodiments, coating material can include protein. In some embodiments, coating material can include at least one of fat and / or oil. In some embodiments, at least one of fat and / or oil can be high temperature molten. In some embodiments, at least one of fat and / or oil can be hydrogenated or partially hydrogenated. In some embodiments, at least one of fat and / or oil can be derived from plant. In some embodiments, at least one of fat and / or oil can include at least one of glyceride, free fatty acid and fatty acid ester. In some embodiments, coating material can include at least one edible wax. Edible wax can be derived from animal, insect or plant. Non-limiting examples can include beeswax, lanolin, bayberry wax, carnauba wax and rice bran wax. Tablets and pills can be prepared with enteric coating in addition.

[0202] Liquid preparations can include syrups (e.g., oral preparations), intravenous preparations, intranasal preparations, ophthalmic preparations (e.g., for treating eye infections), ear preparations (e.g., for treating ear infections), ointments, creams, aerosols, etc. In some cases, a combination of multiple preparations can be used. In some embodiments, tablets, pills, etc. can be formulated for extended release profiles. In some embodiments, the composition can be formulated to increase storage stability when stored in a closed container under standard ambient conditions.

[0203] Dosing and administration

[0204] In one aspect, described herein is a method of treating an epileptic condition in a subject, the method comprising administering to the subject a GABA as described herein. A A receptor modulator compound or a pharmaceutical composition comprising the same. In some cases, GABA A Receptor modulators, salts thereof, or GABA receptor modulators described herein AThe pharmaceutical composition of the receptor modulator or its salt can be administered at a dosage of from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 0.2 mg to about 1000 mg, from about 0.3 mg to about 1000 mg, from about 0.4 mg to about 1000 mg, from about 0.5 mg to about 1000 mg, from about 0.6 mg to about 1000 mg, from about 0.7 mg to about 1000 mg, from about 0.8 mg to about 1000 mg, from about 0.9 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 2 mg to about 1000 mg, from about 3 mg to about 1000 mg. From about 40 mg to about 1000 mg, from about 5 mg to about 1000 mg, from about 6 mg to about 1000 mg, from about 7 mg to about 1000 mg, from about 8 mg to about 1000 mg, from about 9 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 35 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 45 mg to about 1000 mg, from about 5 0 mg to about 1000 mg, from about 55 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 65 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 75 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 85 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 95 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 150 mg to about 1000 mg, from about 200 mg to about 1000 mg, from about 250 mg to about 1000 mg, from about 300 mg to about 1000 mg. g to about 1000 mg, from about 350 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 450 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 550 mg to about 1000 mg, from about 600 mg to about 1000 mg, from about 650 mg to about 1000 mg, from about 700 mg to about 1000 mg, from about 750 mg to about 1000 mg, from about 800 mg to about 1000 mg, from about 850 mg to about 1000 mg, from about 900 mg to about 1000 mg, or from about 950 mg to about 1000 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 1 mg to 5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 1 mg to 3 mg. In some embodiments, GABA AThe receptor modulator or salt thereof is administered at a dose of 1.5 mg to 2.5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 1.9 mg to 2.1 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 1.8 mg to 2.2 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.5 mg to 5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.5 mg to 4 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.1 mg to 10 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.01 mg to 10 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.01 mg to 5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.1 mg to 20 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.1 mg to 15 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 1 mg to 8 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.5 mg to 10 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 0.25 mg to 5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 2 mg to 5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 2 mg to 10 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 3 mg to 5 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 2 mg to 4 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 6 mg to 7 mg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of 5 mg to 15 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 10 mg to 20 mg.

[0205] In some cases, GABA A Receptor modulators, salts thereof, or GABA receptor modulators described herein AThe pharmaceutical composition of a receptor modulator or a salt thereof can be administered at a dose of at least about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg g, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48 mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73 mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 9 8mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 11 9mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 133mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139mg, 1 40mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg,161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186mg, 187mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg, 199mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, In some cases, GABA, A Receptor modulators, salts thereof, or GABA receptor modulators described herein AThe pharmaceutical composition of a receptor modulator or a salt thereof can be administered at a dose of up to about 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg g, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48 mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73 mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 9 8mg, 99mg, 100mg, 101mg, 102mg, 103mg, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg, 117mg, 118mg, 11 9mg, 120mg, 121mg, 122mg, 123mg, 124mg, 125mg, 126mg, 127mg, 128mg, 129mg, 130mg, 131mg, 132mg, 133mg, 134mg, 135mg, 136mg, 137mg, 138mg, 139mg, 1 40mg, 141mg, 142mg, 143mg, 144mg, 145mg, 146mg, 147mg, 148mg, 149mg, 150mg, 151mg, 152mg, 153mg, 154mg, 155mg, 156mg, 157mg, 158mg, 159mg, 160mg,161mg, 162mg, 163mg, 164mg, 165mg, 166mg, 167mg, 168mg, 169mg, 170mg, 171mg, 172mg, 173mg, 174mg, 175mg, 176mg, 177mg, 178mg, 179mg, 180mg, 181mg, 182mg, 183mg, 184mg, 185mg, 186mg, 187mg, 188mg, 189mg, 190mg, 191mg, 192mg, 193mg, 194mg, 195mg, 196mg, 197mg, 198mg, 199mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, In some cases, GABA, A The receptor modulator or salt thereof is administered at a dose of about 0.5 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 1 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 1.5 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 2 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 2.5 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 3 mg. In some cases, GABAA The receptor modulator or salt thereof is administered at a dose of about 3.5 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 4 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 4.5 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 5 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 10 mg. In some cases, GABA A The receptor modulator or salt thereof is administered at a dose of about 15 mg.

[0206] In some embodiments, the GABA described A The GABA receptor modulator or salt thereof is administered daily. A The receptor modulator or salt thereof is administered once daily. In some embodiments, the GABA A The GABA receptor modulator or salt thereof is administered twice daily. A The receptor modulator or salt thereof is administered three times a day. In some embodiments, the GABA A The receptor modulator or salt thereof is administered 1 to 4 times per day. In some embodiments, the GABA A The receptor modulator or a salt thereof is administered once a week.

[0207] In some cases, GABA A Receptor modulators, salts thereof, or GABA receptor modulators described herein A The pharmaceutical composition of a receptor modulator or a salt thereof can be administered at a dose relative to the subject's body weight. A Receptor modulators, salts thereof, or GABA receptor modulators described herein A The pharmaceutical composition of a receptor modulator or a salt thereof can be administered at a dose of at least 0.0003 mg / kg. In some cases, GABA A Receptor modulators, salts thereof, or GABA receptor modulators described herein AThe pharmaceutical composition of the receptor modulator or its salt can be administered at a dose of from about 0.003 mg / kg to about 100 mg / kg, from about 0.003 mg / kg to about 95 mg / kg, from about 0.003 mg / kg to about 90 mg / kg, from about 0.003 mg / kg to about 85 mg / kg, from about 0.003 mg / kg to about 80 mg / kg, from about 0.003 mg / kg to about 75 mg / kg, from about 0.003 mg / kg to about 70 mg / kg, from about 0.003 mg / kg to about 65 mg / kg, from about 0.003 mg / kg to about 60 mg / kg, from about 0.003 mg / kg to about 55 mg / kg, from about 0.003 mg / kg to about 50 mg / kg, from about 0.003 mg / kg to about 45 mg / kg, from about 0.003 mg / kg to about 40 mg / kg, From about 0.003 mg / kg to about 35 mg / kg, from about 0.003 mg / kg to about 30 mg / kg, from about 0.003 mg / kg to about 25 mg / kg, from about 0.003 mg / kg to about 20 mg / kg, from about 0.003 mg / kg to about 15 mg / kg, from about 0.003 mg / kg to about 10 mg / kg, from about 0.003 mg / kg to about 9 mg / kg, from about 0.003 mg / kg to about 8 mg / kg, from about 0.003 mg / kg to about 7 mg / kg, from about 0.003 mg / kg to about 6 mg / kg, from about 0.003 mg / kg to about 5 mg / kg, from about 0.003 mg / kg to about 4 mg / kg, from about 0.003 mg / kg to about 3 mg / kg, from about 0.003 mg / kg to about 2 mg / kg, or from about 0.003 mg / kg to about 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.003 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.0003 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.0005 mg / kg to 0.5 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.001 mg / kg to 0.5 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.001 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.001 mg / kg to 1 mg / kg. In some embodiments, GABAA The receptor modulator or salt thereof is administered at a dose of from 0.001 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.0003 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.003 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.003 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.003 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.003 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.003 mg / kg to 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.01 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.01 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.01 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.01 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.01 mg / kg to 0.05 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.01 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.01 mg / kg to 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.03 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.03 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.03 mg / kg to 1 mg / kg. In some embodiments, GABA AThe receptor modulator or salt thereof is administered at a dose of from 0.03 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.03 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.05 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.05 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.05 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.05 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.05 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.1 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.1 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.1 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.1 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.1 mg / kg to 0.5 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of from 0.1 mg / kg to 0.05 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.01 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.02 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.04 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.05 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.06 mg / kg. In some embodiments, GABAA The receptor modulator or salt thereof is administered at about 0.07 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.08 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.09 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.1 mg / kg.

[0208] In some cases, GABA A Receptor modulators, salts thereof, or GABA receptor modulators described herein AThe pharmaceutical composition of the receptor modulator or its salt can be administered at a dose of less than 0.0005 mg / kg, less than 0.001 mg / kg, less than 0.002 mg / kg, less than 0.003 mg / kg, less than 0.004 mg / kg, less than 0.005 mg / kg, less than 0.006 mg / kg, less than 0.007 mg / kg, less than 0.008 mg / kg, less than 0.009 mg / kg, less than 0.01 mg / kg, less than 0.02 mg / kg, less than 0.03 mg / kg, less than 0.04 mg / kg, less than 0.05 mg / kg, less than 0.06 mg / kg, less than 0.07 mg / kg, less than 0.08 mg / kg. / kg, less than 0.09mg / kg, less than 0.1mg / kg, less than 0.11mg / kg, less than 0.12mg / kg, less than 0.13mg / kg, less than 0.14mg / kg, less than 0.15mg / kg, less than 0.16mg / kg, less than 0.17mg / kg, less than 0.18mg / kg, less than 0.19mg / kg, less than 0.2mg / kg, less than 0.21mg / kg, less than 0.22mg / kg, less than 0.23mg / kg, less than 0.24mg / kg, less than 0.25mg / kg, less than 0.26mg / kg, less than 0.27mg / kg, less than 0.28mg / kg, less than 0.29 mg / kg, less than 0.3mg / kg, less than 0.31mg / kg, less than 0.32mg / kg, less than 0.33mg / kg, less than 0.34mg / kg, less than 0.35mg / kg, less than 0.36mg / kg, less than 0.37mg / kg, less than 0.38mg / kg, less than 0.39mg / kg, less than 0.4mg / kg, less than 0.41mg / kg, less than 0.42mg / kg, less than 0.43mg / kg, less than 0.44mg / kg, less than 0.45mg / kg, less than 0.46mg / kg, less than 0.47mg / kg, less than 0.48mg / kg, less than 0.49mg / kg, less than 0. 5mg / kg, less than 0.51mg / kg, less than 0.52mg / kg, less than 0.53mg / kg, less than 0.54mg / kg, less than 0.55mg / kg, less than 0.56mg / kg, less than 0.57mg / kg, less than 0.58mg / kg, less than 0.59mg / kg, less than 0.6mg / kg, less than 0.61mg / kg, less than 0.62mg / kg, less than 0.63mg / kg, less than 0.64mg / kg, less than 0.65mg / kg, less than 0.66mg / kg, less than 0.67mg / kg, less than 0.68mg / kg, less than 0.69mg / kg, less than 0.7mg / kg, less than 0.71mg / kg, less than 0.72mg / kg, less than 0.73mg / kg, less than 0.74mg / kg, less than 0.75mg / kg, less than 0.76mg / kg, less than 0.77mg / kg, less than 0.78mg / kg, less than 0.79mg / kg, less than 0.8mg / kg, less than 0.81mg / kg, less than 0.82mg / kg, less than 0.83mg / kg, less than 0.84mg / kg, less than 0.85mg / kg, less than 0.86mg / kg, less than 0.87mg / kg, less than 0.88mg / kg, less than 0.89mg / kg, less than 0.9mg / kg, less than 0.91mg / kg, less than 0.92mg / kg, less than 0.93mg / kg, less than 0.94mg / kg, less than 0.95mg / kg, less than 0.96mg / kg, less than 0.97mg / kg, less than 0.98mg / kg, less than 0.99mg / kg, less than 1mg / kg, less than 2mg / kg, less than 2.1mg / kg, less than 2.2mg / kg, less than 2.3mg / kg, less than 2.4mg / kg, less than 2.5mg / kg, less than 2.6mg / kg, less than 2.7mg / kg, less than 2.8mg / kg, less than 2.9mg / kg, less than 3mg / kg, less than 3.1mg / kg, less than 3.2mg / kg, less than 3.3mg / kg g / kg, less than 3.4mg / kg, less than 3.5mg / kg, less than 3.6mg / kg, less than 3.7mg / kg, less than 3.8mg / kg, less than 3.9mg / kg, less than 4mg / kg, less than 4.1mg / kg, less than 4.2mg / kg, less than 4.3mg / kg, less than 4.4mg / kg, less than 4.5mg / kg, less than 4.6mg / kg, less than 4.7mg / kg, less than 4.8mg / kg, less than 4.9mg / kg, less than 5mg / kg, less than 5.1mg / kg, less than 5.2mg / kg, less than 5.3mg / kg, less than 5.4mg / kg, less than 5.5mg / kg, less than 5.6 mg / kg, less than 5.7mg / kg, less than 5.8mg / kg, less than 5.9mg / kg, less than 6mg / kg, less than 6.1mg / kg, less than 6.2mg / kg, less than 6.3mg / kg, less than 6.4mg / kg, less than 6.5mg / kg, less than 6.6mg / kg, less than 6.7mg / kg, less than 6.8mg / kg, less than 6.9mg / kg, less than 7mg / kg, less than 7.1mg / kg, less than 7.2mg / kg, less than 7.3mg / kg, less than 7.4mg / kg, less than 7.5mg / kg, less than 7.6mg / kg, less than 7.7mg / kg, less than 7.8mg / kg, less than 7.9mg / kg, less than 8mg / kg, less than 8.1mg / kg, less than 8.2mg / kg, less than 8.3mg / kg, less than 8.4mg / kg, less than 8.5mg / kg, less than 8.6mg / kg, less than 8.7mg / kg, less than 8.8mg / kg, less than 8.9mg / kg, less than 9mg / kg, less than 9.1mg / kg, less than 9.2mg / kg, less than 9.3mg / kg, less than 9.4mg / kg, less than 9.5mg / kg, less than 9.6mg / kg, less than 9.7mg / kg, less than 9.8mg / kg, less than 9.9mg / kg, less than 10mg / kg, less than 11mg / kg, less than 12mg / kg, less than 13mg / kg, less than 14mg / kg, less than 15mg / kg, less than 16mg / kg, less than 17mg / kg, less than 18mg / kg, less than 19mg / kg In some embodiments, the GABA. A The receptor modulator or salt thereof is administered at a dose of less than 1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of less than 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of less than 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of less than 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or salt thereof is administered at a dose of less than 0.01 mg / kg.

[0209] In some embodiments, GABA A Receptor modulators, salts thereof, or GABA receptor modulators described herein AThe pharmaceutical composition of the GABA receptor modulator or its salt can be administered as a liquid formulation. A The receptor modulator or salt thereof is administered at a concentration of from 0.01 mg / ml to 100 mg / ml. In some embodiments, the GABA A The receptor modulator or salt thereof is administered at from 0.001 mg / ml to 10 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.1 mg / ml to 10 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.001 mg / ml to 10 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.001 mg / ml to 1 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.001 mg / ml to 0.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.5 mg / ml to 5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 1 mg / ml to 2 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.5 mg / ml to 2 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.2 mg / ml to 1 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.2 mg / ml to 0.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.2 mg / ml to 0.4 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.1 mg / ml to 0.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.1 mg / ml to 0.3 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at from 0.05 mg / ml to 0.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.1 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.25 mg / ml. In some embodiments, GABA AThe receptor modulator or salt thereof is administered at about 0.3 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 0.75 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 1 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 1.25 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 1.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 2 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 2.5 mg / ml. In some embodiments, GABA A The receptor modulator or salt thereof is administered at about 5 mg / ml. In some embodiments, GABA A Receptor modulators or their salts are administered at about 10 mg / ml. In some embodiments, 0.01 ml to 500 ml of liquid preparations are administered daily. In some embodiments, 0.05 ml to 250 ml of liquid preparations are administered daily. In some embodiments, 0.05 ml to 50 ml of liquid preparations are administered daily. In some embodiments, 0.1 ml to 25 ml of liquid preparations are administered daily. In some embodiments, 1 ml to 250 ml of liquid preparations are administered daily. In some embodiments, 1 ml to 200 ml of liquid preparations are administered daily. In some embodiments, 50 ml to 200 ml of liquid preparations are administered daily. In some embodiments, 25 ml to 100 ml of liquid preparations are administered daily. In some embodiments, 5 ml to 50 ml of liquid preparations are administered daily. In some embodiments, 1 ml to 20 ml of liquid preparations are administered daily. In some embodiments, 1 ml to 5 ml of liquid preparations are administered daily.

[0210] In some embodiments, described herein is a method of treating an epileptic condition in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound having the structure

[0211] or a salt or polymorph thereof, wherein the administration is in an amount effective to treat an epileptic condition in a subject. In some embodiments, an amount effective to treat an epileptic condition comprises a dosage of from about 0.0003 mg to about 1 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the amount comprises a dosage of less than 0.3 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the amount comprises a dosage of less than 0.1 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day. In some embodiments, the amount comprises a dosage of less than 0.03 mg of the compound, or a salt or polymorph thereof, per kg of subject body weight per day.

[0212] Those skilled in the art can extrapolate a dose effective in one animal model to an equivalent dose in another model. For example, a dose shown to be effective in a mouse model can be divided by an allometric scaling factor (i.e., 12) to generate a human equivalent dose.

[0213] GABA A Administration of a receptor modulator, salt, or composition can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times per day. In some cases, GABA A Administration of a receptor modulator, salt, or composition can be performed at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 times per week. In some cases, GABA AAdministration of a receptor modulator, salt or composition can be performed at least once, twice, three times, four times, five times, six times, seven times, eight times, nine times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times, 21 times, 22 times, 23 times, 24 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times, 32 times, 33 times, 34 times, 35 times, 36 times, 37 times, 38 times, 39 times, 40 times, 41 times, 42 times, 43 times, 44 times, 45 times, 46 times, 47 times, 48 ​​times, 49 times, 50 times, 51 times, 52 times, 53 times, 54 times, 55 times, 56 times, 57 times, 58 times, 59 times, 60 times, 61 times, 62 times, 63 times, 64 times, 65 times, 4, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90. In some embodiments, GABA A The receptor modulator or its salt is administered to the subject for a period of time. The period of time can be from 1 day to more than 30 years. In some embodiments, the period of time is from 1 day to 20 years, from 1 week to 10 years, from 1 month to 5 years, from 1 month to 1 year, from 1 week to 1 year, or any number or range therebetween.

[0214] The present invention is further illustrated by the following examples, from which further embodiments and advantages can be derived. These examples are intended to illustrate the present invention, but not to limit its scope.

[0215] Example 1 - Formulation

[0216] Exemplary GABA A Receptor modulators were formulated prior to administration. Each modulator was combined with Tylose MH300 (0.5% w / v), Tween 80 (1% final volume) and 0.9% bacteriostatic saline (to final volume). The resulting suspension was then sonicated at 37°C for at least 10 minutes.

[0217] A control solution of 0.5% Tylose MH 300 (w / v) and 1% Tween 80 (v / v) in 0.9% bacteriostatic saline was also prepared.

[0218] Example 2 - Study Design

[0219] animal

[0220] Reasons for species selection: Scn1a + / - Knockout mice ([129xB]F1.Scn1a + / -) is a DS model object with a high translational value.

[0221] Population: 112 (56 males and 56 females) First generation Scn1a + / - Heterozygous knockout mice ([129xB]F1.Scn1a + / - ).

[0222] Spare animals: 112 wild-type littermates. A portion of the spare animals was used to determine the exemplary GABA A PK profiles of receptor modulators.

[0223] Strain / Health Status: Scn1a + / - Heterozygous knockout mice ([129xB]F1.Scn1a + / - )

[0224] Breeders: Acquire Scn1a + / - Breeding male mice (129S-Scn1a + / - , n=12), and C57BL / 6J females (n=24) were used as breeding trios.

[0225] Age / Weight: Scn1a between P14 and P16 + / - Heterozygous knockout mice were randomly assigned to treatment groups.

[0226] Receiving: Upon arrival, breeding female C57BL / 6J mice were given a physical examination to ensure they were healthy. + / - Breeding male mice (129S-Scn1a + / - , n=12) were isolated for 2 weeks until cleared by PCR test.

[0227] Adaptation: No adaptation is required. + / - After heterozygous knockout, weaned mice were included in the study and received treatment.

[0228] Allocation to Groups: After weaning, the required number of animals were randomly assigned to treatment groups (by sex).

[0229] Identification: Scn1a obtained from breeding groups of three + / - Heterozygous knockout mice were numbered in each cage at P7-10 via toe clipping. Cage cards indicate the number of animals in each cage. Wild-type littermates not designated for PK testing were euthanized. Scn1a only + / - Heterozygous knockout mice ([129xB]F1.Scn1a + / -) were included in the study of hyperthermia-induced seizures.

[0230] Environmental conditions

[0231] From arrival, animals were housed in an SPF barrier rodent unit. Animal room conditions were set up as follows:

[0232] Temperature: 20℃-26℃(68℉-79℉)

[0233] Relative humidity: 50±20%,

[0234] Light / dark cycle: 12h / 12h; light on at 07:00,

[0235] Ventilation: Filtered, non-recirculated air at approximately 10 to 15 cycles / hour.

[0236] The corresponding instruments and equipment are checked and calibrated at regular intervals. Temperature and relative humidity are continuously recorded (recording device equipped with alarm system).

[0237] The animal rooms were disinfected prior to the arrival of the animals and cleaned regularly thereafter.

[0238] Feeding

[0239] Scn1a + / - Breeding male mice (129S-Scn1a + / - ) and C57BL / 6J females were each housed 4 per cage upon arrival in autoclaved polycarbonate cages equipped with a stainless steel lid with a microfilter top and a perforated holder containing 1 / 4-corncob bedding.

[0240] One breeding male and two females were set up to breed groups of three. + / - Heterozygous knockout mice ([129xB]F1.Scn1a + / - and wild-type) were kept with their dams (C57BL / 6J females) until they were enrolled in the study. + / - After littermates were included in the study, wild-type littermates were euthanized.

[0241] Example 3 - Treatment of Hypothermia-Induced Epileptic Seizures

[0242] Treatment Group

[0243] Rationale for Dose Level Selection—Dose levels were selected based on the results of previous studies.

[0244] Scn1a between P14 and P16 + / -Heterozygous knockout mice were randomly assigned to treatment groups (n=7 males, 7 females / treatment group). + / - knockout mouse model as it is an art-recognized animal model for epileptic conditions including Dravet syndrome. The treatment is GABA A Receptor modulator 1 ("Compound 1", as phosphate salt at 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg), GABA A Receptor modulator 2 ("Compound 2" at 3 mg / kg, 10 mg / kg, 30 mg / kg, 100 mg / kg), vehicle, or clobazam ("CBZ") (10 mg / kg; positive control).

[0245] Duration

[0246] For this study, dose formulations were administered individually.

[0247] Application

[0248] GABA A Receptor modulators were administered intraperitoneally (ip) using a 0.5 ml or 1 ml plastic syringe equipped with a 27 gauge or 30 gauge 0.5" long beveled needle.

[0249] Animals received 10 mL of formulation per kg body weight (as measured on the day of the experiment).

[0250] The formulation was adjusted to delivery conditions (37°C temperature) and maintained at delivery conditions throughout the procedure.

[0251] The formulation was mixed just before administration by inverting its container 2-3 times.

[0252] To verify the dose concentration, mice were dosed with the test article or control and placed into individual home cages. The temperature probe was gently inserted into the rectum of the mouse and secured by tying the probe's wire to the mouse's tail with the tag end on the dorsal side of the mouse. For each group, the probe was inserted as follows:

[0253] a. For mice administered CBZ, five (5) minutes elapsed before the probe was inserted to allow for a 20-30 min pre-treatment time when hyperthermia was achieved.

[0254] b. For mice administered Compound 1, thirty-five (35) minutes elapsed before the probe was inserted to allow for a 50-60 min pre-treatment time when a hyperthermic state was achieved.

[0255] c. For mice administered Compound 2, five (5) minutes elapsed before the probe was inserted to allow for a 20-30 min pre-treatment time while the hyperthermic state was achieved.

[0256] Each mouse was allowed to acclimate to the temperature probe for five (5) minutes, and then baseline temperature was recorded. Figure 1-Figure 3 Depicted are the starting temperatures of female mice, male mice, and the average starting temperature of all mice before induction of heat-induced seizures.

[0257] The core body temperature of the mice was raised approximately 0.5°C every 2 min by keeping the mice on a heating pad until the first tonic-clonic seizure with loss of posture was observed or until a body temperature of 42.5°C was reached. Figure 4-Figure 6 Depicted are the final core body temperatures of female mice, male mice, and the average final core body temperature of all mice after warming. Figure 7-Figure 9 The graph shows the total temperature change for female mice, male mice, and the average for all mice; Figure 10-12 The mean temperature change per minute for female mice, male mice, and the average for all mice are depicted. The body temperature of the mice was maintained at 42.5°C for 3 min. If no seizures occurred, the mice were considered to be seizure-free.

[0258] Tables 1-9 below depict the results of administration of control, CBZ, Compound 1, and Compound 2, and their ability to protect against epileptic seizures as a function of dose.

[0259] Table 1 - Control Vehicle (30 Minutes Pre-treatment)

[0260]

[0261]

[0262] Table 2: 10 mg / kg clobazam (30 minutes pre-treatment)

[0263]

[0264]

[0265] Table 3 - 0.1 mg / kg Compound 1 (60 minutes pre-treatment)

[0266]

[0267] Table 4: 0.3 mg / kg Compound 1 (60 minutes pre-treatment)

[0268]

[0269] Table 5-1.0 mg / kg Compound 1 (60 minutes pre-treatment)

[0270]

[0271]

[0272] Table 6: 3 mg / kg Compound 2 (30 minutes pre-treatment)

[0273]

[0274]

[0275] Table 7: 10 mg / kg Compound 2 (30 minutes pre-treatment)

[0276]

[0277] Table 8: 30 mg / kg Compound 2 (30 minutes pre-treatment)

[0278]

[0279]

[0280] Table 9: 100 mg / kg Compound 2 (30 minutes pre-treatment)

[0281]

[0282] A summary of the data is presented in Tables 10 and Fig.13 middle.

[0283] Table 10: Summary of seizure data

[0284]

[0285] As shown in Table 10, GABA A The receptor modulators Compound 1 and Compound 2 reduced the amount of seizures in the animal model relative to vehicle administration. In addition, Compound 1 and Compound 2 performed at least as well as the clobazam positive control. Given that clobazam is a first-line treatment for epileptic seizures, GABA A Receptor modulators are promising therapeutic agents for the treatment of epileptic seizures. In fact, the data showed that Compound 2 treated epileptic seizures in a dose-dependent manner, with a 100 mg / kg dose completely preventing epileptic seizures in each animal (n=8).

[0286] In fact, administration of from about 0.1 mg / kg to about 100 mg / kg of Compound 1 or Compound 2 was shown to be effective in preventing epileptic seizures in a mouse model. One of ordinary skill in the art will be able to extrapolate this effective amount to other animals. For example, using a human analogue factor of 12, the human equivalent dose would be about 0.008 mg / kg to about 10 mg / kg.

[0287] Those skilled in the art will appreciate that the effectiveness of Compound 1 and Compound 2 in treating epileptic seizures in an animal model induced by hyperthermia is not limited to specific compounds. Rather, one of ordinary skill in the art would reasonably expect that GABA A Receptor modulators as a class will be effective in treating epileptic seizures in a manner comparable to the efficacy observed with Compound 1 and Compound 2. Furthermore, the skilled artisan will appreciate that efficacy will not be limited to preventing Scn1a + / - knockout mice. Rather, the animal model is a well-established animal model for a variety of epileptic conditions, including Dravet syndrome. Therefore, a skilled artisan would reasonably expect that the entire class of GABA A Receptor modulators would be effective in treating epileptic conditions by preventing epileptic seizures.

[0288] Therefore, the results showed that GABA A Receptor modulators as a class generally have potential for treating epileptic conditions, as demonstrated in a mouse model of heat-induced seizures.

[0289] Example 4 - Pharmacokinetic Determination

[0290] To determine the pharmacokinetic parameters of compound 1 and compound 2, P14-P16 mice (n=7 groups) were -1 ·gender -1 Time point -1 ) will be administered Compound 1 and Compound 2, and terminal blood samples will be collected at the following time points:

[0291] a. Compound 1: 30min, 1h, 2h, 4h, 8h, 12h, 24h,

[0292] b. Compound 2: 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h.

[0293] Blood collection: Immediately prior to blood collection, mice will be euthanized by CO2 inhalation. Blood will be collected via cardiac puncture using a 27-gauge needle and transferred to a 500 μL K3EDTA tube and immediately placed on wet ice. Samples will be centrifuged at 2900 g for 10 minutes under refrigerated conditions (set to maintain +4°C) within 2 hours of collection. Plasma will be transferred to a separate tube within 2 hours and stored at -20°C.

[0294] Dose formulation concentration verification

[0295] 0.3 mL aliquots of each formulation will be collected from the mid-dose concentration location and stored in sealed vials wrapped in parafilm at 2°C-4°C or lower until the end of the study.

[0296] A calibration curve consisting of at least 6 calibration standards will be constructed using the LC / UV method.

[0297] The concentration of test compound in dose formulation samples will be determined by LC / UV method.

[0298] Determination of plasma levels of test items

[0299] The LC-MS / MS method for the quantitative determination of the test compounds in the biological matrix will be developed under non-GLP compliance.

[0300] For LC-MS / MS methods, a calibration curve with at least 6 non-zero calibration standards (STD) will be constructed.

[0301] Determination of research samples

[0302] Study samples will be measured in batches using LC-MS / MS after appropriate preparation. Typically, if the number of samples is 48 or less, one set of calibration curves and two sets of QC samples consisting of low, medium, and high concentrations will be used. If the number of samples is more than 48, two sets of calibration curves and two sets of QC samples will be used.

[0303] Typically, one reagent blank, one plasma blank, and, if applicable, two plasma blanks containing only the internal standard will be run.

[0304] Samples in the same matrix for different PK projects will be quantified in the same analytical run.

[0305] Acceptance criteria for analytical batches

[0306] Linearity: STDs of ≥75% were back-calculated to within ±20% of their nominal values ​​in biological fluids (for LLOQ ±25%) and within 25% of their nominal values ​​in tissue homogenates and fecal samples (for LLOQ 30%).

[0307] Accuracy: ≥67% of all QC samples were back-calculated to within ±20% of their nominal values ​​for biological fluids and within 25% of their nominal values ​​for tissue and fecal samples.

[0308] Specificity: The average calculated concentration of the analyte in the single blank matrix should be less than 0.5 times the LLOQ.

[0309] Pharmacokinetic analysis

[0310] Analysis of pharmacokinetic data will be performed for each dose level, gender, and sampling occasion.

[0311] Typically, the following toxicokinetic parameters will be calculated / measured, if possible: C0, C 最大 , T 最大 , T 1 / 2 , AUC 0-t , AUC 0-inf , MRT 0-t , MRT 0-inf , Cl and Vss.

[0312] Values ​​below the lower limit of quantitation will be reported in a separate table as BLQ and will be considered zero for descriptive statistics and integrated into statistical calculations. BLQ will be reported when the mean of the individual concentrations is below the limit of quantitation.

[0313] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, those skilled in the art will now appreciate that many variations, changes and substitutions may be employed in practicing the present invention. It is intended that the following claims define the scope of the present invention, and thus encompass methods and structures and their equivalents within the scope of these claims.

[0314] Example 5 - Evaluation of the acute anticonvulsant efficacy of Compound 1 in mouse and rat models of acute epileptic seizures

[0315] method:

[0316] The anticonvulsant efficacy of Compound 1 was tested in an acute 6 Hz seizure model at 32 mA and 44 mA intensities in CF-1 mice. The dose-related efficacy of Compound 1 was evaluated in the 6 Hz seizure test after acute administration at a single time point and compared with the efficacy of the positive control diazepam (DZP) (tested 0.5 hours after drug administration). The formulation vehicle (VEH) was used as a negative control.

[0317] After oral administration of the compound, mice were challenged at appropriate time points with 32 mA or 44 mA current delivered through corneal electrodes for 3 seconds to induce typical epileptic seizures. 6 Hz seizures are characterized by an initial momentary vertigo, followed immediately by forelimb clonus, vibrissa twitching, and straub tail 1. Animals that did not exhibit all of these behaviors in the immediate (5-10 seconds) time period after stimulation were considered "protected" (N = number of protected / F = number of tested).

[0318] Compound 1 was administered 3 hours later and the anticonvulsant efficacy of compound 1 was tested. The compound was administered at 3 doses (0.01 mg / kg, 0.03 mg / kg and 0.1 mg / kg; n=8 male CF-1 mice / dose group) in a volume of 0.01 mL / g. The test was conducted over a 1-2 day process, with animals in each test group randomly receiving a single dose of the study compound or vehicle. For each day of testing, animals were tested in groups of 20-30 mice / stage, and treatment was randomized in all groups and test days. The compound dose (ED50) and 95% confidence interval required to produce the desired endpoint in 50% of the animals were calculated by a computer program based on the Probit method 6. Groups of vehicle-treated and DZP-treated (1 mg / kg, PO) mice will also be tested in parallel at the previously determined DZP peak effect time (0.5 hours); all tests were performed by researchers blind to the treatment condition. A statistically significant increase in the number of protected mice compared to the number of protected mice of the negative control (P≤0.05) was considered to be efficacy. A summary of the results is provided in Table 11.

[0319] Table 11: Dosage and efficacy of Compound 1 relative to vehicle in a 6 Hz seizure study in 32 mA mice

[0320]

Claims

1. Use of a compound for the manufacture of a medicament for treating Dravet syndrome in a subject, wherein the compound is 。 2. The use according to claim 1, wherein the compound is α1, α2, α3 or α5 GABA A Receptor modulators.

3. The use according to claim 2, wherein the compound is a positive allosteric α2 or α3 GABA A Receptor modulators.

4. The use according to claim 1, wherein the subject is a human.

5. The use according to claim 1, wherein the therapeutically effective amount of the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier.

6. Use of a compound for the manufacture of a medicament for treating Dravet syndrome in a subject, the medicament comprising a pharmaceutical composition comprising the compound, the compound being or a salt thereof, wherein the pharmaceutical composition is in an amount effective to treat the Dravet syndrome in the subject.

7. Use of a compound for the manufacture of a medicament for treating Dravet syndrome in a subject, the medicament comprising a pharmaceutical composition comprising the compound, the compound being , or a salt thereof, wherein the pharmaceutical composition is in an amount effective for treating the Dravet syndrome in the subject, and wherein the amount comprises a dose of from 0.0003 mg to 1 mg of the compound or its salt per kg body weight of the subject per day.

8. The use according to claim 6 or 7, wherein the compound or its salt is a phosphate.

9. The use according to claim 6 or 7, wherein the compound or its salt is a sulfate.

10. The use according to claim 6 or 7, wherein the pharmaceutical composition is formulated for oral or transdermal administration.

11. The use according to claim 6 or 7, wherein the amount comprises a dosage of less than 0.3 mg of the compound or salt thereof per kg of body weight of the subject per day.

12. The use according to claim 6 or 7, wherein the amount comprises a dosage of less than 0.1 mg of the compound or salt thereof per kg of body weight of the subject per day.

13. The use according to claim 6 or 7, wherein the amount comprises a dosage of less than 0.03 mg of the compound or salt thereof per kg of body weight of the subject per day.

14. The use according to claim 6 or 7, wherein the compound or its salt is not a phosphate and is not a sulfate.

15. The use according to claim 10, wherein the pharmaceutical composition comprises caffeine.

16. The use according to claim 6 or 7, wherein the subject is a human.

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