Treatment of epileptic conditions with GABAA receptor modulators

Abstract

Disclosed herein are treatment of epileptic conditions with GABAA receptor modulators. Disclosed herein are GABAA receptor modulators and compositions comprising GABAA receptor modulators for the treatment of epileptic conditions. Also disclosed herein are methods of treating an epileptic condition in a subject by administering a GABAA receptor modulator or composition as described herein.

Description

[0001] This application is a divisional application of the application with the filing date of October 23, 2020, application number 202080086778.2, and invention title "Treatment of Epileptic Conditions with GABA A Receptor Modulators".

[0002] Cross - References

[0003] 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.

[0004] Overview

[0005] Disclosed herein are methods for 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,

[0006]

[0007] wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently - C, - N, - S, or - O, wherein at least two of X 1 , X 2 , X 3 , X 4 and X 5 are - N, Y 1 and Y 2 are independently - C or - N, m of R 1 m is 1, wherein R 1 is unsubstituted phenyl, phenyl substituted with a C1 - C4 hydrocarbyl, F, Cl, Br, I, - CN, substituted or unsubstituted biphenyl, or -(C = O)-R 3 , wherein R 3 is substituted or unsubstituted aryl or a 5 - to 6 - membered heteroaryl, n of R 2 n is 1 or 2, wherein each R 2 is independently substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted C1 - C6 hydrocarbyl, substituted or unsubstituted C1 - C6 alcohol, substituted or unsubstituted 6 - membered heteroaryl, halogen, or - O - CH2 - R 4 , wherein R 4is a substituted or unsubstituted 5- or 6-membered heteroaryl, 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)-O-R 7 or

[0008] wherein 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 s is 1, 2, 3 or 4, and R 5 l 's l is 1 or 2, wherein each R 5 is independently a C1-C4 alkynyl or a halogen, R 6 k 's k is 1, 2, 3 or 4, wherein each R 6 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbon group or hydrogen, R 12 p 's p is 1 or 2, wherein each R 12 is independently a substituted or unsubstituted C1-C4 hydrocarbon group, I, Br, Cl or F, and R 13 q 's q is 1, 2, 3 or 4, wherein each R 13 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbon group, oxygen or hydrogen. In some embodiments, the compound has the general formula (2), general formula (3), general formula (4), general formula (5), general formula (1c) or general formula (7),

[0009]

[0010] In some embodiments, the compound has the general formula (2a), general formula (3a), general formula (4a), general formula (5a), general formula (5b), general formula (1c) or general formula (7a),

[0011]

[0012] In some embodiments, R 1 mm is 1, and wherein R 1 is: unsubstituted phenyl, substituted phenyl containing C1-C4 hydrocarbyl, F, Cl, Br, I, -CN as substituents, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as a substituent, substituted biphenyl containing at least one -CN as a substituent or -(C=O)-R 3 wherein R 3 is pyridine. In some embodiments, the compound has the general formula (2a'), general formula (3a'), general formula (4a'), general formula (5a'), general formula (5b'), general formula (VI) or general formula (7a'),

[0013]

[0014] wherein R 10 is substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbyl or hydrogen, R 11 is substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbyl 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''), general formula (3a''), general formula (4a''), general formula (5a''), general formula (5b''), general formula (VIa'') or general formula (7a''),

[0015]

[0016] wherein R 7 is: unsubstituted C1-C6 hydrocarbyl, unsubstituted C3-C8 cycloalkyl, unsubstituted C1-C6 alcohol, R 8 is: -O-CH2-R 4 wherein R 4 is substituted or unsubstituted 5-membered heteroaryl or unsubstituted C1-C6 alcohol, R 9 is: unsubstituted C6 heteroaryl or halogen, or R 9 is unsubstituted 6-membered heteroaryl in formula (4a'') or halogen in formula (5b''), R 10 is C1-C3 hydrocarbyl or hydrogen, R 11 is substituted or unsubstituted aryl or heteroaryl, R 14 is substituted or unsubstituted aryl or heteroaryl, 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 AReceptor modulators. In some embodiments, the compound is a positive allosteric α2 or α3 GABA A Receptor modulators. In some embodiments, the subject is human. In some embodiments, the subject is canine. In some embodiments, the age of the subject is from 0 to 17 years. In some embodiments, the age of the subject is from 18 to 130 years. In some embodiments, a therapeutically effective amount of the compound is present in a pharmaceutical composition that comprises a pharmaceutically acceptable excipient, diluent, or carrier. In some embodiments, the epileptic condition is selected from the group consisting of: childhood absence epilepsy, childhood benign occipital epilepsy (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).

[0017] Also disclosed herein is a method of treating epilepsy in a subject associated with a sodium channel mutation, the method comprising administering to the subject a compound of formula (1a), formula (1b), or formula (1c) to treat epilepsy associated with a sodium channel mutation,

[0018]

[0019] wherein X 1 、X 2 、X 3 、X 4 and X 5 are independently -C, -N, -S or -O, wherein at least two of X 1 、X 2 、X 3 、X 4 and X 5 are -N, Y 1 and Y 2 are independently -C or -N, m of R 1 m is 1, wherein R 1 is unsubstituted phenyl, phenyl substituted with C1-C4 hydrocarbyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl, or -(C═O)-R 3 wherein R 3is a substituted or unsubstituted aryl or 5- to 6-membered heteroaryl, R 2 n wherein n is 1 or 2, and each R 2 is independently a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C1-C6 hydrocarbon group, a substituted or unsubstituted C1-C6 alcohol, a substituted or unsubstituted 6-membered heteroaryl, a halogen, or -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted 5- or 6-membered heteroaryl, 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)-O-R 7 or

[0020] wherein R 7 is a hydrocarbon group, B 1 、B 2 、B 3 and B 4 are independently -C, -N, or -O, R 21 S wherein s is 1, 2, 3, or 4, and R 5 l wherein l is 1 or 2, and each R 5 is independently a C1-C4 alkynyl or a halogen, R 6 k wherein k is 1, 2, 3, or 4, and each R 6 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbon group, or hydrogen, R 12 p wherein p is 1 or 2, and each R 12 is independently a substituted or unsubstituted C1-C4 hydrocarbon group, I, Br, Cl, or F, and R 13 q wherein q is 1, 2, 3, or 4, and each R 13 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbon group, oxygen, or hydrogen. In some embodiments, the compound has the general formula (2), general formula (3), general formula (4), general formula (5), general formula (1c), or general formula (7),

[0021]

[0022] In some embodiments, the compound has the general formula (2a), general formula (3a), general formula (4a), general formula (5a), general formula (5b), general formula (1c) or general formula (7a),

[0023]

[0024] In some embodiments, for R 1 m m is 1, and wherein R 1 is: unsubstituted phenyl, substituted phenyl containing C1-C4 hydrocarbyl, F, Cl, Br, I, -CN as substituents, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as a substituent, substituted biphenyl containing at least one -CN as a substituent or -(C=O)-R 3 wherein R 3 is pyridine. In some embodiments, the compound has the general formula (2a'), general formula (3a'), general formula (4a'), general formula (5a'), general formula (5b'), general formula (VI) or general formula (7a'),

[0025]

[0026] wherein R 10 is substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbyl or hydrogen, R 11 is substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbyl or hydrogen, or for 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''), general formula (3a''), general formula (4a''), general formula (5a''), general formula (5b''), general formula (VIa'') or general formula (7a''),

[0027]

[0028] wherein R 7 is: unsubstituted C1-C6 hydrocarbyl, unsubstituted C3-C8 cycloalkyl, unsubstituted C1-C6 alcohol, R 8 is: -O-CH2-R 4 wherein R 4 is substituted or unsubstituted 5-membered heteroaryl or unsubstituted C1-C6 alcohol, R 9 is: unsubstituted C6 heteroaryl or halogen, or R 9is an unsubstituted 6-membered heteroaryl in formula (4a”) or is a halogen in formula (5b”), R 10 is a C1-C3 hydrocarbyl or hydrogen, R 11 is a substituted or unsubstituted aryl or heteroaryl, R 14 is a substituted or unsubstituted aryl or heteroaryl, R 12 is I, Cl, Br or F, or R 5 is a C2 alkynyl or I. In some embodiments, the compound is an α1, α2, α3 or α5 GABA A receptor modulator. 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 age of the subject is from 0 to 17 years. In some embodiments, the age of the subject is from 18 to 130 years. In some embodiments, a 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.

[0029] 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 the Dravet syndrome in the subject, the pharmaceutical composition comprising a compound selected from the group consisting of:

[0030]

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

[0032]

[0033] , its salts or its polymorphs. In some embodiments, the amount is effective for treating Dravet syndrome when administered at the following doses: from about 0.003 mg / kg of subject body weight per day to about 10 mg / kg of subject body weight 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 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 polymorphs or salts thereof. In some embodiments, the pharmaceutical composition comprises a salt of the compound. In some embodiments, the salt is a phosphate. In some embodiments, the salt is a sulfate. In some embodiments, the pharmaceutical composition comprises a polymorph of the compound. In some embodiments, the polymorph has characteristic peak positions in X-ray powder diffraction (XRPD) containing at least three values 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 when measured using: (a) X-ray wavelength parameter of Cu:K-α (b) X-ray tube voltage setting of 40 kV and current of 40 mA; (c) scan range from about 3 degrees to about 40 degrees; (d) sample rotation speed of about 15 rpm; and (e) scan rate of 10 degrees per minute. In some embodiments, administration includes oral administration. In some embodiments, administration is performed at least once daily. In some embodiments, administration of an amount effective to treat Dravet syndrome does not produce drowsiness or sedation in the subject.

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

[0035]

[0036] or a pharmaceutically acceptable salt or polymorph thereof, to treat a subject having a seizure disorder, wherein the amount comprises a dose 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 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 administration reduces the amount of seizures to an amount that is at least 20% less than the amount of seizures that occur based on administration of an equivalent dose of clobazam. In some embodiments, the amount comprises 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-sedating formulation. In some embodiments, the non-sedating formulation comprises caffeine. In some embodiments, the compound, its pharmaceutically acceptable salt or polymorph is a phosphate or a polymorph thereof. In some embodiments, the compound, its pharmaceutically acceptable salt or polymorph is a sulfate or a polymorph thereof.

[0037] The present invention describes a method for treating a subject having a seizure disorder, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (5a’), or a salt or polymorph thereof,

[0038]

[0039] wherein

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

[0041] R 2 n has an n of 1 or 2, wherein each R 2 is independently a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 hydrocarbyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen or -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted 5- or 6-membered heteroaryl,

[0042] wherein the administration is in an amount effective to treat the subject's seizure disorder, and wherein the amount comprises a dose of from about 0.003 mg to about 1 mg of the compound or its salt or polymorph per kg of the subject's body weight per day. The present invention describes a method for treating a subject having a seizure disorder, the method comprising administering to the subject a pharmaceutical composition comprising a compound having the following structure

[0043]

[0044] or a salt or polymorph thereof, wherein the administration is in an amount effective to treat a subject's epilepsy condition, 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 the subject's body weight per day. In some embodiments, the epilepsy condition is generalized epilepsy or genetic epilepsy. In some embodiments, the epilepsy condition is Dravet syndrome. In some embodiments, the epilepsy condition is focal seizure. In some embodiments, the epilepsy condition is selected from the group consisting of: childhood absence 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 seizure, progressive myoclonic epilepsy, focal seizure or Lennox-Gastaut syndrome (LGS). In some embodiments, the compound or a salt or polymorph thereof is a phosphate or a polymorph thereof. In some embodiments, the compound or a salt or polymorph thereof is a sulfate or a polymorph thereof. In some embodiments, the compound or a salt or polymorph thereof is a phosphate polymorph, and wherein the phosphate polymorph exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values 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: (a) X-ray wavelength parameter of Cu:K-α (b) X-ray tube voltage set at 40 kV and current of 40 mA; (c) scanning range from about 3 degrees to about 40 degrees; (d) sample rotation speed of about 15 rpm; and (e) 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 comprises 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 comprises 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 comprises 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 seizure. In some embodiments, the compound or its salt or polymorph is not a phosphate or its polymorph, and is not a sulfate or its polymorph. In certain embodiments, the subject is a human subject. In some embodiments, the compound is formulated as a non-sedating formulation. In some embodiments, the non-sedating formulation comprises caffeine. In some embodiments, the subject is human. Brief Description of the Drawings

[0045] The novel features of the exemplary embodiments are set forth, particularly in the appended claims. A better understanding of the features and advantages will be obtained by reference to the following detailed description and the drawings, which set forth illustrative embodiments that utilize the principles of the exemplary embodiments, in which:

[0046] Figure 1 Depicts the starting body temperature (mean (±SEM)) of pre-treated female mice before the onset of temperature-induced seizures. The mean body temperature of female mice before the induction of heat-induced seizures is in the range from about 34.5 °C to about 35.5 °C.

[0047] Figure 2 Depicts the starting body temperature (mean (±SEM)) of pre-treated male mice before the onset of temperature-induced seizures. The mean body temperature of male mice before the induction of heat-induced seizures is in the range from about 34.5 °C to about 35.5 °C.

[0048] Figure 3 Depicts the mean starting body temperature (mean (±SEM)) of all pre-treated mice before the onset of temperature-induced seizures. The mean body temperature (mean (±SEM)) of mice before the induction of heat-induced seizures is in the range from about 34.5 °C to about 35.3 °C.

[0049] Figure 4Depicts the final body temperature (mean (±SEM)) of female mice in the seizure study. The final body temperature increased to approximately 42 °C (in the range from approximately 40.5 °C to approximately 42.5 °C), which was sufficient to induce heat-induced seizures in a mouse model without clobazam or GABA A receptor modulator treatment.

[0050] Figure 5 Depicts the final body temperature (mean (±SEM)) of male mice in the seizure study. The final body temperature increased to approximately 42 °C (in the range from approximately 40.5 °C to approximately 42.5 °C), which was sufficient to induce heat-induced seizures in a mouse model without anti-seizure treatment.

[0051] Figure 6 Depicts the mean final body temperature (mean (±SEM)) of all mice in the seizure study. The final body temperature increased to approximately 42 °C (in the range from approximately 40.5 °C to approximately 42.5 °C), which was sufficient to induce heat-induced seizures in a mouse model without anti-seizure treatment. Administration of the vehicle resulted in the lowest overall body temperature in the mice.

[0052] Figure 7 Depicts the total change in body temperature (mean (±SEM)) of female mice during the seizure study. The body temperature of female mice increased between 5 °C and 8 °C in order to induce heat-induced seizures in the mouse model.

[0053] Figure 8 Depicts the total change in body temperature (mean (±SEM)) of male mice during the seizure study. The body temperature of male mice increased between 5 °C and 8 °C in order to induce heat-induced seizures in the mouse model.

[0054] Figure 9 Depicts the mean total change in body temperature (mean (±SEM)) of all mice during the seizure study. The body temperature of the mice increased between 5 °C and 8 °C in order to induce heat-induced seizures in the mouse model. Mice administered the vehicle control had a total temperature increase of 5 °C, which was lower than that of mice receiving other treatments.

[0055] Figure 10 Depicts the change in body temperature per minute (mean (±SEM)) of female mice during the seizure study. The change in body temperature per minute of female mice was in the range from approximately 0.4 °C / min to approximately 0.6 °C / min.

[0056] Figure 11 Depicts the change in body temperature per minute (mean (±SEM)) of male mice during the seizure study. The change in body temperature per minute of male mice was in the range from approximately 0.4 °C / min to approximately 0.6 °C / min.

[0057] Figure 12 Depicts the average change in body temperature per minute (mean (±SEM)) of all mice during the seizure study. The change in body temperature per minute of the mice ranges from about 0.4 °C / min to about 0.6 °C / min. The mice administered the vehicle had the highest rate of temperature increase per minute (about 0.6 °C / min), while the mice administered the exemplary GABA A receptor modulator compound 2 had the lowest rate of temperature increase per minute (about 0.4 °C / min).

[0058] Figure 13 Depicts an overview of the efficacy of each treatment in the seizure study. The exemplary GABA A receptor modulator compounds 1 and 2 were each effective in preventing heat-induced seizures in a mouse model. GABA A The administration of the GABA receptor modulator compound 2 prevented seizures in a dose-dependent manner.

[0059] Figure 14 Depicts exemplary GABA A receptor modulators that are effective in treating seizure conditions.

[0060] Details

[0061] Defines

[0062] The term "GABA receptor" can be used in its meaning as known in the field of biochemistry; the term can refer to receptors for the inhibitory neurotransmitter γ-aminobutyric acid (GABA). GABA A receptors (ionotropic receptors) are ligand-gated ion channels, and GABA B receptors (also known as metabotropic receptors) are G protein-coupled receptors. GABA A receptors are the most common and important inhibitory receptors in the central nervous system. GABA A receptors include 5 subunits, which are grouped into the following 8 classes: α 1-6 、β 1-3 、γ 1-3 、δ, ε, π, θ and ρ 1-3 . Most GABA A receptors include two α subunits, two β subunits and one γ subunit. Compounds such as benzodiazepines can bind to sites different from the endogenous ligand GABA. For example, benzodiazepines can bind to a 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 different properties on the GABA A receptor. However, among other functions, the α1 subunit is responsible for the sedative effects of benzodiazepines , the α2 subunit is associated with the anxiolytic function of the receptor among other functions, and the α3 subunit confers the muscle relaxant properties of the GABA A receptor among other functions.

[0063] The term "allosteric modulator" can be used in its known meaning in the fields of biochemistry and pharmacology; the term can refer to a substance that indirectly modulates the agonist action on a receptor. A positive allosteric modulator can induce amplification of the agonist action, and in the absence of an agonist, a positive allosteric modulator has no effect by itself. An allosteric modulator can bind to a site different from the agonist binding site (allosterically).

[0064] As used herein, the terms "subject", "patient" or "individual" can encompass 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 cows, 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 the like. 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 between 0 - 17 years old. In some cases, the age of the human can be between 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 with or suspected of having a condition or disease. In some cases, the disease or condition can be epilepsy or a condition related to epilepsy. The subject can be a patient. The subject can be an individual. In some cases, the terms subject, patient or individual can be used interchangeably.

[0065] As used herein, the terms "treat", "treating", "treatment", "ameliorate" or "ameliorating" and other grammatical equivalents can include reducing or lessening the symptoms of a disease or condition, inhibiting a disease or condition, e.g., preventing the development of a disease or condition, alleviating a disease or condition, causing the regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0066] "Hydrocarbyl" can refer to a saturated straight-chain or branched-chain hydrocarbon having, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more carbon atoms, where one carbon-carbon bond can be unsaturated and one CH2 moiety can 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 otherwise specifically stated in the specification, the hydrocarbyl group can be optionally substituted.

[0067] The term "alkynyl" can refer to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monovalent group having one or more carbon-carbon triple bonds. In some embodiments, the alkynyl group can have from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples can include but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" can mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the definitions of the present invention can also cover the occurrence of the term "alkynyl" where no numerical range can be specified. In some embodiments, the alkynyl can be C1-C 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 substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, halohydrocarbyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl can be optionally substituted by oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2 or NO2. In some embodiments, the alkynyl can be optionally substituted by oxo, halogen, -CN, -CF3, -OH or -OMe. In some embodiments, the alkynyl can be optionally substituted by halogen.

[0068] The term "aryl" can refer to a cyclic aromatic C5-C 10Hydrocarbons. Examples of aryl groups can include, but are not limited to, phenyl, naphthyl, and heteroaryl. The term "heteroaryl" can 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 can include, but are not limited to, pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrimidine, thiazine, quinoline, benzofuran, and indole. The aryl or heteroaryl can be optionally substituted. The aromatic hydrocarbon can be neutral or charged. As used herein, the aryl or heteroaryl group can optionally include one or more additional substituent groups.

[0069] "Cycloalkyl" can refer to a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can include a fused ring system (when fused to an aryl ring or a heteroaryl ring, the cycloalkyl can be bonded through a non-aromatic ring atom), a bridged ring system, or a spiro ring system. Representative cycloalkyls can include, but are not limited to, cycloalkyls having: from 3 to 15 carbon atoms (C3-C 15 cycloalkyl), from 3 to 10 carbon atoms (C3-C 10 cycloalkyl), from 3 to 8 carbon atoms (C3-C8 cycloalkyl), from 3 to 6 carbon atoms (C3-C6 cycloalkyl), from 3 to 5 carbon atoms (C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl). In some embodiments, the cycloalkyl can be a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl can be a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls can include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or polycyclic carbocyclics can include, for example, adamantyl, norbornyl, decahydronaphthyl, 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 cycloalkyls can include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, the cycloalkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl can be optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or NO2. In some embodiments, the cycloalkyl can be optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0070] "Halo" or "halogen" can refer to bromine (Br), chlorine (Cl), fluorine (F) or iodine (I). In some embodiments, the halogen can be Br, F or Cl. In some embodiments, the halogen can be F.

[0071] The term "about" can mean within an acceptable error range of a particular value as determined by a person 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 measuring system. For example, "about" can mean within 1 or more standard deviations 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 of the value, within 5-fold or within 2-fold. When describing a particular value in this application and the claims, unless otherwise stated, the term "about" means within the acceptable error range of the particular value that should be assumed.

[0072] condition

[0073] Compounds for treating epileptic conditions are disclosed herein. The compounds described herein (e.g., GABA A receptor modulators) can be used to at least partially alleviate epileptic conditions. For example, administering a GABA A receptor modulator can effectively treat the onset of seizures associated with an epileptic condition. As used herein, the term epileptic condition can refer to a condition associated with seizures. In some embodiments, treatment includes reducing or preventing the onset of seizures associated with an epileptic condition. In some embodiments, seizures are accompanied by convulsions. In some embodiments, an epileptic condition with seizures is also accompanied by convulsions. In some embodiments, an epileptic condition with seizures may not be accompanied by convulsions.

[0074] Seizures are often associated with many diseases or conditions. For example, seizures can be associated with Angelman syndrome, arteriovenous malformation, brain abscess, brain tumor, cavernous malformation, 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, penicillin, fluoroquinolones, and carbapenems.

[0075] In some cases, the epileptic condition is epilepsy. Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures. These seizures are transient signs and / or symptoms due to abnormal, excessive, or synchronous neuronal activity in the brain. There are many different epileptic conditions, each presenting a unique combination of 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 genetic epilepsy.

[0076] Other exemplary epileptic conditions include those that may occur in association with seizures, such as benign childhood epilepsy with centrotemporal spikes, 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, progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS). Genetic, congenital, and developmental conditions are often associated with epilepsy in younger patients. Tumors can 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 can be administered AReceptor modulators for the treatment of breakthrough seizures. As described herein, a "breakthrough seizure" can refer to a seizure that occurs after an extended period of seizure freedom. In some cases, breakthrough seizures may occur because the subject is not taking their medication. In some cases, breakthrough seizures may occur due to resistance or intractability of the seizures to existing therapeutic agents such as clobazam. Thus, as described herein, GABA A receptor modulators can be used as an alternative first-line treatment for breakthrough seizures.

[0077] In some embodiments, the epileptic condition is a focal seizure. A focal seizure can be a simple focal seizure (aura). A simple focal seizure with motor symptoms can affect muscle activity, causing jerking movements of the foot, face, arm, or other parts of the body. A simple focal seizure may cause sensory symptoms that affect sensation, such as hearing problems, hallucinations, and olfactory or other distortions. A simple focal seizure with autonomic symptoms can affect the part of the brain responsible for involuntary functions. These seizures can cause changes in blood pressure, heart rate, or bowel or bladder function. Some simple focal seizures may attack the part of the brain that triggers emotions or memories of previous experiences, causing feelings of fear, anxiety, or the illusory feeling of having experienced something before. A focal seizure can be a complex focal seizure. In some cases, a complex focal seizure is preceded by a simple focal seizure. In some cases, a subject experiencing a complex focal seizure may stare blankly into space or experience automatisms (purposeless, repetitive movements such as lip smacking, blinking, grunting, swallowing, or shouting).

[0078] In some cases, the disease or condition treatable by a GABA A receptor modulator as described herein is epilepsy associated with a sodium channel mutation in the subject. By a GABA ASuch diseases or conditions treatable by a receptor modulator are Dravet syndrome. Dravet syndrome is a rare, genetic epileptic encephalopathy. In some cases, Dravet syndrome is associated with sodium channel mutations. For example, Dravet syndrome may be associated with mutations in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene. Such mutations in SCN1A can include missense mutations, nonsense mutations, frameshift mutations, splicing mutations, or in-frame deletions. For example, SCN1A mutations can include D79H, R101Q, R222X, I227S, R377X, R393C, R613X, R712X, R859C, R1596C, R1213X, R1648H, M1780T, A1783V, R1892X, or R1912X mutations.

[0079] Dravet syndrome can begin in infancy and persist throughout the subject's life. Dravet syndrome can manifest as different seizure types, including myoclonic seizures, tonic-clonic seizures, absence seizures, atypical absence seizures, atonic seizures, focal aware seizures, or status epilepticus. As described herein, GABA A receptor modulators can be administered to a subject suffering from Dravet syndrome to at least partially alleviate seizures associated with Dravet syndrome.

[0080] As described in the examples in this application, GABA A receptor modulators are effective in treating heat-induced seizures in the Scn1a+ / - knockout mouse model. The Scn1a + / - knockout mouse model is recognized in the art as a model for multiple epileptic conditions, including Dravet syndrome. Thus, GABA A receptor modulators are expected to be efficacious as a class in treating or preventing seizures of multiple epileptic conditions as described herein.

[0081] Compound

[0082] Compounds for treating epileptic conditions are disclosed herein. In some cases, the compounds for treating epileptic conditions can be GABA A receptor modulators. In certain embodiments, the compounds are positive allosteric α2 and / or α3 GABA A receptor modulators. GABA receptor modulators that are specific for the α2 subunit or the α3 subunit and that avoid modulation of the α1 subunit can be useful for treating epileptic conditions as described herein without causing drowsiness associated with α1 subunit modulation. Thus, GABA as described herein A A ​Receptor modulators can be formulated into non-sedating or non-drowsy formulations. In some cases, non-drowsy formulations can include other components that can further counteract any sedating effects associated with administration, including stimulants (such as caffeine).

[0083] GABA A Receptor modulators and their metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives can be included in the exemplary embodiments and are expected to be effective in treating epileptic conditions as described herein.

[0084] GABA that can be used to treat epileptic conditions A The receptor modulator can be a compound of general formula (1a), general formula (1b) or general formula (1c):

[0085]

[0086] wherein

[0087] -X 1 、X 2 、X 3 、X 4 and X 5 are each independently -C, -N, -S or -O, where at least two of X 1 、X 2 、X 3 、X 4 and X 5 are -N,

[0088] -Y 1 and Y 2 are each independently -C or -N,

[0089] -R 1 m m of -R

[0090] -R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 where R 3 is a substituted or unsubstituted C6 heteroaryl,

[0091] -R 2 n n of -R

[0092] - Each R 2 with any other R 2Independently is a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C6 hydrocarbon group, a substituted or unsubstituted C1-C6 alcohol, a substituted or unsubstituted C6 heteroaryl group, a halogen, and in some cases is -F or -O-CH2-R 4 , wherein R 4 is a substituted or unsubstituted C4 heteroaryl group,

[0093] -Z 1 、Z 2 、Z 3 、Z 4 and Z 5 are independently of each other -C, -N, -S or -O,

[0094] -A 1 and A 2 and A 3 are independently of each other -C, -N or -C(C=O)-O-R 7 , or

[0095]

[0096] -wherein R 7 is a hydrocarbon group,

[0097] -B 1 、B 2 、B 3 and B 4 are independently of each other -C, -N or -O,

[0098] -R 21 S s is 1, 2, 3 or 4, and

[0099] -each R 21 is independently hydrogen or a C1-C6 hydrocarbon group,

[0100] -R 5 l l is 1 or 2,

[0101] -each R 5 is independently a C1-C4 alkynyl group or a halogen, and in some cases is -Cl,

[0102] -R 6 k k is 1, 2, 3 or 4, and in some cases is 1 or 2,

[0103] -each R 6 is independently a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted C1-C3 hydrocarbon group, oxygen or hydrogen.

[0104] In certain embodiments, compounds of formula (1a) are provided, wherein X 1 , X 2 , X 3 , X 4 and X 5 are each independently -C, -N, -S or -O, wherein at least two of X 1 , X 2 , X 3 , X 4 and X 5 are -N, Y 1 and Y 2 are each independently -C or -N, R 1 m has m equal to 1, R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 , wherein R 3 is a substituted or unsubstituted C6 heteroaryl, R 2 n has n equal to 1 or 2, each R 2 is independently of any other R 2 a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C1-C6 hydrocarbon group, a substituted or unsubstituted C1-C6 alcohol, a substituted or unsubstituted C6 heteroaryl, a halogen, in some cases -F or -O-CH2-R 4 , wherein R 4 is a substituted or unsubstituted C4 heteroaryl.

[0105] In certain embodiments, compounds of formula (1b) are provided, wherein Z 3 , Z 4 and Z 5 are each independently -C, -N, -S or -O, A 1 , A 2 and A 3 are each independently -C, -N or -C(C=O)-O-R 7 , wherein R 7 is a hydrocarbon group, R 5 l has l equal to 1 or 2, each R 5 is independently a C1-C4 alkynyl or a halogen, in some cases -Cl, R 6 k has k equal to 1, 2, 3 or 4, in some cases 1 or 2, each R 6Each independently is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbyl, oxygen, or hydrogen.

[0106] In certain embodiments, there is provided a compound comprising a compound of formula (1c), wherein Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently -C, -N, -S, or -O, l of R 5 l is 1 or 2, each R 5 is independently a C1-C4 alkynyl or a halogen, in some cases -Cl, k of R 6 k is 1, 2, 3, or 4, in some cases 1 or 2, each R 6 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbyl, oxygen, or hydrogen.

[0107] In certain embodiments, the compound comprises a compound of formula (1a), formula (1b), or formula (1c), wherein X 1 , X 2 , X 3 , X 4 and X 5 are each independently -C, -N, wherein at least two of X 1 , X 2 , X 3 , X 4 and X 5 are -N, Y 1 and Y 2 are each independently -C or -N, m of R 1 m is 1, R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 , wherein R 3 is a substituted or unsubstituted C6 heteroaryl, n of R 2 n is 1 or 2, each R 2 is independently of any other R 2 a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted C1-C6 hydrocarbyl, a substituted or unsubstituted C1-C6 alcohol, a substituted or unsubstituted C6 heteroaryl, a halogen, in some cases -F or -O-CH2-R 4 , wherein R 4is a substituted or unsubstituted C4 heteroaryl, Z 1 、Z 2 、Z 3 、Z 4 and Z 5 are each independently -C, -N or -O, A 1 、A 2 and A 3 are each independently -C, -N or -C(C=O)-O-R 7 wherein R 7 is a hydrocarbon group, R 5 l 's l is 1 or 2, each R 5 is independently a C1-C4 alkynyl or a halogen, in some cases -Cl, R 6 k 's k is 1, 2, 3 or 4, each R 6 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbon group, oxygen or hydrogen.

[0108] In certain embodiments, there is provided a compound comprising a compound of formula (1a), wherein X 1 、X 2 、X 3 、X 4 and X 5 are each independently -C or -N, wherein at least two of X 1 、X 2 、X 3 、X 4 and X 5 are -N, Y 1 and Y 2 are each independently -C or -N, R 1 m 's m is 1, R 1 is a substituted or unsubstituted C6 aryl or -(C=O)-R 3 wherein R 3 is a substituted or unsubstituted C6 heteroaryl, R 2 n 's n is 1 or 2, each R 2 is independently from any other R 2 a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C6 hydrocarbon group, a substituted or unsubstituted C1-C6 alcohol, a substituted or unsubstituted C6 heteroaryl, a halogen, in some cases -F or -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted C4 heteroaryl.

[0109] In certain embodiments, compounds of formula (1b) are provided, wherein Z 3 , Z 4 and Z 5 are each independently -C or -N, A 1 , A 2 and A 3 are each independently -C, -N or -C(C=O)-O-R 7 , wherein R 7 is a hydrocarbon group, l of R 5 l is 1 or 2, each R 5 is independently a C1-C4 alkynyl or a halogen, in some cases -Cl, k of R 6 k is 1, 2, 3 or 4, in some cases 1 or 2, each R 6 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbon group, oxygen or hydrogen.

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

[0111] A GABA A receptor modulator that can be used to treat epileptic conditions can be a compound of formula (2), formula (3), formula (4), formula (5), formula (6) or formula (7)

[0112]

[0113] wherein Y 1 , Y 2 , Z 1 , Z 4 , Z 5 , R 1m of m, R 1 , R 3 , R 2 n of n, R 2 , R 4 , R 5 1 of 1, R 5 , R 6 k of k, R 6 , A 1 , A 2 and A 3 have the same meanings as defined above.

[0114] In certain embodiments, the compound comprises general formula (2), general formula (3), general formula (4), or general formula (5), wherein Y 1 , Y 2 , R 1 m of m, R 1 , R 3 , R 2 n of n, R 2 and R 4 have the same meanings as defined above.

[0115] In certain embodiments, the compound comprises general formula (6), wherein Z 1 , Z 4 , Z 5 , R 5 l of l, R 5 , R 6 k of k and R 6 have the same meanings as defined above.

[0116] In certain embodiments, the compound comprises general formula (7), wherein Z 4 , Z 5 , R 5 l of l, R 5 , R 6 k of k, R 6 , A l , A 2 and A 3 have the same meanings as defined above.

[0117] GABA that can be used to treat epileptic conditions AThe receptor modulator can be a compound of general formula (2a), general formula (3a), general formula (4a), general formula (5a), general formula (5b), general formula (6a), general formula (6b) or general formula (7a).

[0118]

[0119] wherein R 1 m of m, R 1 、R 3 、R 2 n of n, R 2 、R 4 、R 5 l of l, R 5 、R 6 k of k and R 6 has the same meaning as defined above.

[0120] In certain embodiments, the compound comprises general formula (2a), general formula (3a), general formula (4a), general formula (5a) or general formula (5b), wherein R 1 m of m, R 1 、R 3 、R 2 n of n, R 2 and R 4 has the same meaning as defined above.

[0121] In certain embodiments, the compound comprises general formula (6a) or general formula (6b), wherein R 5 l of l, R 5 、R 6 k of k and R 6 has the same meaning as defined above.

[0122] In certain embodiments, the compound comprises general formula (7a), wherein R 5 l of l, R 5 、R 6 k of k and R 6 has the same meaning as defined above.

[0123] In certain embodiments, the compound comprises general formula 1a, general formula 1b, general formula 1c, general formula 2, general formula 3, general formula 4, general formula 5, general formula 6, general formula 7, general formula 2a, general formula 3a, general formula 4a, general formula 5a, general formula 5b, general formula 6a, general formula 6b or general formula 7a, wherein R1 m where m is 1 and R 1 is: unsubstituted phenyl, substituted phenyl containing at least one -F as a substituent, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as a substituent, in some cases on the phenyl moiety not attached to the parent moiety; or substituted biphenyl containing at least one -CN as a substituent, in some cases at least one -CN on the phenyl moiety is not directly attached to the parent moiety, where in some cases one phenyl moiety additionally contains at least one -F as a substituent, in some cases each phenyl moiety additionally contains at least one -F as a substituent, or -(C=O)-R 3 where R 3 is pyridine, and R 5 l where l is 1 and R 5 is Cl, Br, F or C2 alkynyl.

[0124] In certain embodiments, the compound comprises general formula 1a, general formula 2, general formula 3, general formula 4, general formula 5, general formula 2a, general formula 3a, general formula 4a, general formula 5a or general formula 5b, where R 1 m where m is 1 and R 1 is: unsubstituted phenyl, substituted phenyl containing at least one -F as a substituent, unsubstituted biphenyl, substituted biphenyl containing at least one -CN as a substituent, in some cases on the phenyl moiety not attached to the parent moiety; or substituted biphenyl containing at least one -CN as a substituent, in some cases at least one -CN on the phenyl moiety is not directly attached to the parent moiety, where in some cases one phenyl moiety additionally contains at least one -F as a substituent, in some cases each phenyl moiety additionally contains at least one -F as a substituent, or -(C=O)-R 3 where R 3 is pyridine.

[0125] In certain embodiments, the compound comprises general formula 1b, general formula 7 or general formula 7a, where R 5 l where l is 1 and R 5 is Cl, Br, F or C2 alkynyl.

[0126] In certain embodiments, the compound comprises general formula 1c, general formula 6, general formula 6a or general formula 6b, where R 5 l where l is 1 and R 5 is Cl, Br, F or C2 alkynyl.

[0127] In certain embodiments, the compound comprises General Formula 1a, General Formula 1b, General Formula 1c, General Formula 2, General Formula 3, General Formula 4, General Formula 5, General Formula 6, General Formula 7, General Formula 2a, General Formula 3a, General Formula 4a, General Formula 5a, General Formula 5b, General Formula 6a, General Formula 6b or General Formula 7a, wherein R 2 n n is 1 or 2, and when n is 2, each R 2 is independently an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group, an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group or -O-CH2-R 4 wherein 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; when n is 1, R 2 is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, an unsubstituted C6 heteroaryl group, in some cases pyridine, and R 6 k k is 1 or 4, and when 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 is independently a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group, oxygen or hydrogen.

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

[0129] In certain embodiments, the compound comprises general formula la, general formula 2, general formula 3, general formula 4, general formula 5, general formula 2a, general formula 3a, general formula 4a, general formula 5a or general formula 5b, wherein R 2 n n is 1 or 2, and in the case where n is 2, each R 2 is independently of one another an unsubstituted C3-C8 cycloalkyl, in some cases a C4 cycloalkyl, an unsubstituted C1-C6 hydrocarbyl, in some cases a tert-butyl group or -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted C4 heteroaryl, 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.

[0130] In certain embodiments, the compound comprises general formula 1b, general formula 7 or general 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, a substituted or unsubstituted heteroaryl; in the case where k is 4, each R 6 is independently of one another a substituted or unsubstituted aryl, a substituted or unsubstituted C1-C3 hydrocarbyl, oxygen or hydrogen.

[0131] In certain embodiments, the compound comprises general formula 1c, general formula 6, general formula 6a or general 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, a substituted or unsubstituted heteroaryl; in the case where k is 4, each R 6 is independently of one another a substituted or unsubstituted aryl, a substituted or unsubstituted C1-C3 hydrocarbyl, oxygen or hydrogen.

[0132] In certain embodiments, the compound comprises general formula 1a, general formula 1b, general formula 1c, general formula 2, general formula 3, general formula 4, general formula 5, general formula 6, general formula 7, general formula 2a, general formula 3a, general formula 4a, general formula 5a, general formula 5b, general formula 6a, general formula 6b, or general formula 7a, wherein R 2 n n is 2 and one R 2 is an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group or an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group, and the other R 2 is -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted C4 heteroaryl group, in some cases a substituted or unsubstituted triazole, or one 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 two R 6 are oxygen, and the other R 6 are independently of each other a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group, or hydrogen.

[0133] In certain embodiments, the compound comprises general formula 1a, general formula 2, general formula 3, general formula 4, general formula 5, general formula 2a, general formula 3a, general formula 4a, general formula 5a, or general formula 5b, wherein R 2 n n is 2 and one R 2 is an unsubstituted C3-C8 cycloalkyl group, in some cases a C4 cycloalkyl group, or an unsubstituted C1-C6 hydrocarbon group, in some cases a tert-butyl group, and the other R 2 is O-CH2-R 4 wherein R 4 is a substituted or unsubstituted C4 heteroaryl group, in some cases a substituted or unsubstituted triazole, or one 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.

[0134] In certain embodiments, the compound comprises general formula 1b, general formula 7, or general formula 7a, wherein R 6 k k is 4, and two R 6 are oxygen, and the other R 6 are independently of each other a substituted or unsubstituted aryl group, a substituted or unsubstituted C1-C3 hydrocarbon group, or hydrogen.

[0135] In certain embodiments, the compound comprises general formula 1c, general formula 6, general formula 6a or general formula 6b, wherein R 6 k for k is 4, and two R 6 are oxygen, and the additional R 6 are, independently of one another, substituted or unsubstituted aryl, substituted or unsubstituted C1-C3 hydrocarbyl or hydrogen.

[0136] A GABA A receptor modulator that can be used to treat epileptic conditions can be a compound of general formula (2a’), general formula (3a’), general formula (4a’), general formula (5a’), general formula (5b’), general formula (6a’), general formula (6b’) or general formula (7a’)

[0137]

[0138] wherein R 1 , R 3 , R 2 n for n, R 2 , R 4 , R 5 , R 6 k for k and R 6 have the same meanings as defined above.

[0139] In certain embodiments, the compound comprises general formula (2a’), general formula (3a’), general formula (4a’), general formula (5a’) or general formula (5b’), wherein R 1 , R 3 , R 2 n for n, R 2 and R 4 have the same meanings as defined above.

[0140] In certain embodiments, the compound comprises general formula (6a’) or general formula (6b’), wherein R 6 k for k and R 6 have the same meanings as defined above.

[0141] In certain embodiments, the compound comprises general formula (7a’), wherein R 6 k for k and R 6 have the same meanings as defined above.

[0142] In certain embodiments, the compound comprises general formula (2a’), general formula (3a’), general formula (4a’), general formula (5a’), general formula (5b’), general formula (6a’), general formula (6b’), or general formula (7a’), wherein R 1 in the case of formula (2a’) is a substituted or unsubstituted C6 aryl, in some cases an unsubstituted phenyl, a substituted phenyl comprising at least one -F as a substituent, in the case of formula (3a’), formula (5a’), or formula (5b’) is a substituted or unsubstituted biphenyl, in some cases an unsubstituted biphenyl, a substituted biphenyl comprising at least one -CN as a substituent, in some cases on the phenyl moiety not connected to the parent moiety, wherein in some cases one phenyl moiety further comprises at least one -F as a substituent, in some cases each phenyl moiety further comprises at least one -F as a substituent, or in the case of formula (4a’), is -(C=O)-R 3 , wherein 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’) is Cl, Br, or F, in the case of formula (7a’) is C2 alkynyl, wherein R 2 n and R 6 k have the same meanings as defined above.

[0143] In certain embodiments, the compound comprises general formula (2a’), general formula (3a’), general formula (4a’), general formula (5a’), or general formula (5b’), wherein R 1 in the case of formula (2a’) is a substituted or unsubstituted C6 aryl, in some cases an unsubstituted phenyl, a substituted phenyl comprising at least one -F as a substituent, in the case of formula (3a’), formula (5a’), or formula (5b’) is a substituted or unsubstituted biphenyl, in some cases an unsubstituted biphenyl, a substituted biphenyl comprising at least one -CN as a substituent, in some cases on the phenyl moiety not connected to the parent moiety, wherein in some cases one phenyl moiety further comprises at least one -F as a substituent, in some cases each phenyl moiety further comprises at least one -F as a substituent, or in the case of formula (4a’), is -(C=O)-R 3 , wherein R 3 is a substituted or unsubstituted C6 heteroaryl, in some cases wherein R 3 is pyridine, wherein R 2 n have the same meanings as defined above.

[0144] In certain embodiments, the compound comprises Formula (6a') or Formula (6b'), wherein R 5 is Cl, Br or F, wherein R 6 k has the same meaning as defined above.

[0145] In certain embodiments, the compound comprises Formula (7a'), wherein R 5 is C2 alkynyl, wherein R 6 k has the same meaning as defined above.

[0146] A GABA A receptor modulator that can be used to treat epileptic conditions can be a compound of Formula (2a"), Formula (3a"), Formula (4a"), Formula (5a"), Formula (5b"), Formula (6a") or Formula (7a")

[0147]

[0148] 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, in some cases R 7 in the case of Formula (2a") 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") is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 8 is -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted C4 heteroaryl group, 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") is -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted C4 heteroaryl group, in some cases a substituted or unsubstituted triazole, or R 8 in the case of Formula (3a") is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, R 9 is an unsubstituted C6 heteroaryl group, in some cases pyridine or a halogen, in some cases -F, R 9is an unsubstituted C6 heteroaryl, in some cases pyridine, or R 9 is halogen in the case of formula (5b”), in some cases -F, R 10 is a C1-C3 hydrocarbyl or hydrogen, R 11 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, in some cases R 11 is a substituted or unsubstituted aryl in the case of formula (6a”), in some cases phenyl, R 11 is a substituted or unsubstituted heteroaryl in the case of formula (7a”), in some cases pyridine, a substituted or unsubstituted aryl, in some cases phenyl, R 5 is Cl, Br or F in the case of formula (6a”), and is C2 alkynyl in the case of formula (7a”).

[0149] In certain embodiments, the compound comprises general formula (2a”), general formula (3a”), general formula (4a”), general formula (5a”) or general formula (5b”), wherein R 7 is an unsubstituted C1-C6 hydrocarbyl, in some cases tert-butyl, an unsubstituted C3-C8 cycloalkyl, in some cases C4 cycloalkyl, an unsubstituted C1-C6 alcohol, in some cases C4 alcohol, in some cases R 7 is an unsubstituted C1-C6 hydrocarbyl, in some cases tert-butyl, or an unsubstituted C3-C8 cycloalkyl, in some cases C4 cycloalkyl, in the case of formula (2a”), or R 7 is an unsubstituted C1-C6 alcohol, in some cases C4 alcohol, in the case of formula (5a”) or formula (5b”), R 8 is -O-CH2-R 4 , wherein 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 C4 alcohol, in some cases R 8 is -O-CH2-R in the case of formula (2a”), 4 , wherein R 4 is a substituted or unsubstituted C4 heteroaryl, in some cases a substituted or unsubstituted triazole, or R 8 is an unsubstituted C1-C6 alcohol, in some cases C4 alcohol, in the case of formula (3a”), R 9 is an 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, in some cases pyridine, or R 9 In the case of formula (5b”), it is a halogen, in some cases -F.

[0150] In certain embodiments, a compound for treating an epileptic condition comprises general formula (6a”), wherein R 10 is a C1-C3 hydrocarbyl 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”), it is a substituted or unsubstituted aryl, in some cases phenyl, R 11 In the case of formula (7a”), it is a substituted or unsubstituted heteroaryl, in some cases pyridine, R 5 is Cl, Br or F.

[0151] In certain embodiments, a compound comprises 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”), it is a substituted or unsubstituted aryl, in some cases phenyl, R 11 In the case of formula (7a”), it is a substituted or unsubstituted heteroaryl, in some cases pyridine, R 5 is a C2 alkynyl.

[0152] In certain embodiments, a compound comprises general formula (2a”), general formula (3a”), general formula (4a”), general formula (5a”) or general formula (5b”), wherein in the case of formula (2a”), R 1 is an unsubstituted phenyl, a substituted phenyl containing at least one -F as a substituent, R 7 is an unsubstituted C1-C6 hydrocarbyl, in some cases tert-butyl, or an unsubstituted C3-C8 cycloalkyl, in some cases a C4 cycloalkyl, and R 8 is -O-CH2-R 4 wherein 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, a substituted biphenyl containing at least one -CN as a substituent, in some cases on the phenyl moiety not attached 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, R 8is an unsubstituted C1-C6 alcohol, in some cases a C4 alcohol, and in the case of formula (4a”), R 1 is -(C=O)-R 3 wherein R 3 is an unsubstituted C6 heteroaryl, and in some cases R 3 is pyridine, and R 9 is an unsubstituted C6 heteroaryl, and in some cases is pyridine; in the case of formula (5a”), R 1 is an unsubstituted biphenyl, a substituted biphenyl 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 additionally contains at least one -F as a substituent, and in some cases each phenyl moiety additionally contains 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, a substituted biphenyl 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 additionally contains at least one -F as a substituent, and in some cases each phenyl moiety additionally contains 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, and in some cases is F.

[0153] A GABA A receptor modulator that can be used to treat epileptic conditions can be a compound of formula (8):

[0154]

[0155] wherein

[0156] -Z 4 and Z 5 are independently of each other -C, -N, -S or -O,

[0157] -A 1 and A 2 are independently of each other -C, -N or -C(C=O)-O-R 7 wherein R 7 is a hydrocarbyl group,

[0158] -B 1 、B 2 、B 3 and B 4 are independently of each other -C, -N or -O,

[0159] -R5 l l is 1 or 2,

[0160] - Each R 5 independently of one another is C1-C4 alkynyl or halogen, and in some cases is -Cl,

[0161] - R 6 k k is 1, 2, 3 or 4, and in some cases is 1 or 2,

[0162] - Each R 6 independently of one another is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbyl, oxygen or hydrogen,

[0163] - R 21 S s is 1, 2, 3 or 4, or

[0164] - Each R 21 independently is hydrogen or C1-C6 hydrocarbyl.

[0165] In certain embodiments, the compound is selected from Figure 14 the 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.

[0166] In some cases, the compound is selected from the group consisting of

[0167]

[0168] or a salt, prodrug, polymorph, solvate, ester, stereoisomer or derivative thereof.

[0169] In some cases, the compound can be or a salt, prodrug, polymorph, solvate, ester, stereoisomer or derivative thereof.

[0170] As shown in the examples below, the exemplary GABA A receptor modulator compounds 1 and 2 are effective in preventing heat-induced seizures. The structures of compounds 1 and 2 are described below:

[0171]

[0172] As described herein, it is contemplated that GABA A receptor modulators such as Compound 1 and Compound 2 are effective in treating epileptic conditions due to their modulation of the GABA A receptor.

[0173] Also disclosed herein are pharmaceutically acceptable salt forms of the GABA A receptor modulators. The salts can include counterions selected from the group consisting of acetate, benzoate, hydrogen tartrate, aspartate, formate, bromide, chloride, iodide, fumarate, citrate, maleate, nitrate, salicylate, succinate, sulfate, phosphate, benzenesulfonate, hippurate, naphthoate, naphthalenesulfonate, sulfosalicylate, toluenesulfonate, caprylate, oleate, pamoate, stearate, propionate, caproate, caprate, aspartate, hydrogen tartrate, salicylate, naphthalenesulfonate, or sulfite and any combination thereof.

[0174] Also disclosed herein are polymorphs of the GABA A receptor modulators. The polymorphs can include the free base polymorphs of the GABA A receptor modulators described herein, or salt polymorphs of the GABA A receptor modulators, or co-crystals of the GABA A receptor modulators described herein. In some cases, the polymorphs can have improved solubility, improved oral bioavailability, more consistent oral bioavailability, improved stability, improved manufacturability, and corresponding improved formulations. Such polymorphs can be prepared by crystallizing or co-crystallizing the GABA A receptor modulator free base or salt form in a crystallization solvent 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.

[0175] The preparation of the polymorphs can be confirmed by collecting the diffraction patterns of the crystals or co-crystals. In some cases, X-ray powder diffraction (XRPD) can be used to collect the diffraction patterns. Exemplary XRPD parameters are provided below:

[0176]

[0177] In some exemplary cases, a polymorph of Compound 1 can be administered, such as a polymorph of Compound 1 having the following XRPD pattern, which has characteristic peak positions of at least three values 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, 29.6 degrees ± 0.2 degrees, 30.2 degrees ± 0.2 degrees and 32.3 degrees ± 0.2 degrees 2θ, 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 when measured using the XRPD parameters described above.

[0178] Pharmaceutical composition

[0179] Also disclosed herein is a composition comprising GABA as described herein AA pharmaceutical composition of a receptor modulator. In some embodiments, the pharmaceutical composition can comprise 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.

[0180] In some cases, the pharmaceutical composition can comprise a GABA receptor modulator described herein. A Receptor modulator and at least one of the following: an excipient, a diluent or a carrier. In some cases, the GABA receptor modulator described herein can be dissolved or suspended in a diluent or a carrier. A Receptor modulators can be dissolved or suspended in a diluent or a carrier.

[0181] In some embodiments, the pharmaceutical composition can comprise an excipient. The excipient can be an excipient described in the American Pharmaceutical Association's Handbook of Pharmaceutical Excipients (1986).

[0182] Non-limiting examples of suitable excipients can include buffering agents, preservatives, stabilizers, binders, compaction agents, lubricants, chelating agents, dispersion enhancers, disintegrants, flavoring agents, sweetening agents, coloring agents.

[0183] In some embodiments, the excipient can be a buffering agent. Non-limiting examples of suitable buffering agents can include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. As buffering agents, 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 combinations thereof can be used in the pharmaceutical composition.

[0184] In some embodiments, the excipient can include a preservative. Non-limiting examples of suitable preservatives can include antioxidants such as α-tocopherol and ascorbate, and antibacterial agents such as parabens, chlorobutanol, and phenol. Antioxidants can 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-acetylcysteine. In some cases, the preservative can include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, N-α-p-toluenesulfonyl-Phe-chloromethyl ketone, N-α-p-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.

[0185] In some embodiments, the pharmaceutical composition can contain a binder as an excipient. Non-limiting examples of suitable binders can include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidinone, polyvinyl alcohol, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, sugars, oligosaccharides, and combinations thereof.

[0186] 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 methylcellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol, and water, or combinations thereof.

[0187] In some embodiments, the pharmaceutical composition can comprise a lubricant as an excipient. Non-limiting examples of suitable lubricants can include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, polyethylene glycol monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. Lubricants that can be used in the pharmaceutical composition can be selected from metal stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffin wax, hydrogenated vegetable oil, leucine, polyethylene glycol (PEG), metal lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate, and talc or combinations thereof.

[0188] In some embodiments, the pharmaceutical composition can comprise a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants can include starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as a high HLB emulsifier surfactant.

[0189] In some embodiments, the pharmaceutical composition can comprise a disintegrant as an excipient. In some embodiments, the disintegrant can be a non-effervescent disintegrant. Non-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, alginates, sodium starch glycolate, gums such as agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth. In some embodiments, the disintegrant can be an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants can include a combination of sodium bicarbonate and citric acid, and a combination of sodium bicarbonate and tartaric acid.

[0190] In some embodiments, the excipient can include a flavoring agent. Flavoring agents incorporated into the outer layer can 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 can 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.

[0191] In some embodiments, the excipient may include a sweetening agent. Non-limiting examples of suitable sweetening agents 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 the 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.

[0192] In some cases, the pharmaceutical composition may contain a coloring agent. Non-limiting examples of suitable coloring agents may include colors for food, drug, and cosmetic (FD&C), colors for drug and cosmetic (D&C), and colors for external drug and cosmetic (Ext.D&C). The coloring agent may be used as a dye or its corresponding lake.

[0193] In some cases, the pharmaceutical composition may contain 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 consisting of 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, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol, and / or its anhydrous, hydrate, and / or pharmaceutically acceptable derivatives or combinations thereof.

[0194] In other embodiments, the pharmaceutical composition may contain a surfactant. The surfactant may be selected from, but not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulfate, sodium stearoyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycol (PEG), polyoxyethylene castor oil derivatives, sodium docusate, quaternary ammonium compounds, amino acids such as L-leucine, sugar esters of fatty acids, glycerol esters of fatty acids, or combinations thereof.

[0195] The pharmaceutical compositions disclosed herein can be formulated in a variety of forms and administered in many different ways. The pharmaceutical compositions can be administered orally, rectally, or parenterally in formulations that include the required conventional acceptable carriers, adjuvants, and vehicles. As used herein, the term "parenteral" can include subcutaneous, intravenous, intramuscular, or intrasternal injection and infusion techniques. Administration can include injection or infusion, including intraarterial, intracardiac, intraventricular, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous, inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration. In some exemplary embodiments, the route of administration can be via injection, such as intramuscular injection, intravenous injection, subcutaneous injection, or intraperitoneal injection.

[0196] Solid dosage forms for oral administration can include capsules, tablets, troches, pills, lozenges, pastilles, powders, and granules. Capsules can include a core material containing a nutritional protein or composition and a shell wall encapsulating 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 soft gelatin, hard gelatin, and polymers. Suitable polymers can include, but are not limited to: cellulose polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC), methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, and sodium carboxymethylcellulose; 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 polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (purified lac). In some embodiments, at least one polymer can function as a taste masking agent.

[0197] Tablets, pills, and the like can be compressed, compressed multiple times, layered multiple times, and / or coated. The coating can be single or multiple. In some embodiments, the coating material can include at least one of sugars, polysaccharides, and glycoproteins 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, the coating material can include proteins. In some embodiments, the coating material can include at least one of fats and / or oils. In some embodiments, at least one of the fats and / or oils can be melted at high temperatures. In some embodiments, at least one of the fats and / or oils can be hydrogenated or partially hydrogenated. In some embodiments, at least one of the fats and / or oils can be derived from plants. In some embodiments, at least one of the fats and / or oils can include at least one of glycerides, free fatty acids, and fatty acid esters. In some embodiments, the coating material can include at least one edible wax. The edible wax can be derived from animals, insects, or plants. Non-limiting examples can include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills can additionally be prepared with enteric coatings.

[0198] Liquid formulations can include syrups (e.g., for oral administration), intravenous formulations, intranasal formulations, ophthalmic formulations (e.g., for treating eye infections), otic formulations (e.g., for treating ear infections), ointments, creams, aerosols, etc. In some cases, combinations of multiple formulations can be administered. 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 environmental conditions.

[0199] Administration and Application

[0200] In one aspect, a method of treating a subject's epileptic condition is described herein, the method comprising administering to the subject a GABA A receptor modulator compound described herein or a pharmaceutical composition comprising the compound. In some cases, the GABA A receptor modulator, its salt, or a pharmaceutical composition comprising the GABA AA pharmaceutical composition of a receptor modulator or a salt thereof can be administered at the following doses: 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 4 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 50 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, 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 a salt thereof is administered at a dose of 1 mg to 5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 1 mg to 3 mg. In some embodiments, GABA AThe receptor modulator or a salt thereof is administered at a dose of 1.5 mg to 2.5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 1.9 mg to 2.1 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 1.8 mg to 2.2 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.5 mg to 5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.5 mg to 4 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.1 mg to 10 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.01 mg to 10 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.01 mg to 5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.1 mg to 20 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.1 mg to 15 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 1 mg to 8 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.5 mg to 10 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 0.25 mg to 5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 2 mg to 5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 2 mg to 10 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 3 mg to 5 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 2 mg to 4 mg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose of 6 mg to 7 mg. In some embodiments, GABA A The receptor modulator or a 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.

[0201] In some cases, GABA A receptor modulators, their salts or GABA containing those described herein AA pharmaceutical composition of a receptor modulator or a salt thereof can be administered in the following doses: 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, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg,161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg. In some cases, GABA, A receptor modulators, salts thereof or GABA as described herein AA pharmaceutical composition of a receptor modulator or a salt thereof can be administered in the following doses: 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, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg,161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg. In some cases, GABA, A a receptor modulator or a salt thereof is administered at a dose of about 0.5 mg. In some cases, GABA A a receptor modulator or a salt thereof is administered at a dose of about 1 mg. In some cases, GABA A a receptor modulator or a salt thereof is administered at a dose of about 1.5 mg. In some cases, GABA A a receptor modulator or a salt thereof is administered at a dose of about 2 mg. In some cases, GABA A a receptor modulator or a salt thereof is administered at a dose of about 2.5 mg. In some cases, GABA A a receptor modulator or a salt thereof is administered at a dose of about 3 mg. In some cases, GABAA The GABA receptor modulator or a salt thereof is administered at a dose of about 3.5 mg. In some cases, A The GABA receptor modulator or a salt thereof is administered at a dose of about 4 mg. In some cases, A The GABA receptor modulator or a salt thereof is administered at a dose of about 4.5 mg. In some cases, A The GABA receptor modulator or a salt thereof is administered at a dose of about 5 mg. In some cases, A The GABA receptor modulator or a salt thereof is administered at a dose of about 10 mg. In some cases, A The GABA receptor modulator or a salt thereof is administered at a dose of about 15 mg.

[0202] In some embodiments, the described GABA A receptor modulator or a salt thereof is administered daily. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered once a day. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered twice a day. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered three times a day. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered 1 to 4 times a day. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered once a week.

[0203] In some cases, A the GABA receptor modulator, a salt thereof, or a pharmaceutical composition comprising the GABA A receptor modulator or a salt thereof described herein can be administered at a dose relative to the body weight of the subject. In some cases, A the GABA receptor modulator, a salt thereof, or a pharmaceutical composition comprising the GABA A receptor modulator or a salt thereof described herein can be administered at a dose of at least 0.0003 mg / kg. In some cases, A the GABA receptor modulator, a salt thereof, or a pharmaceutical composition comprising the GABA AA pharmaceutical composition of a receptor modulator or a salt thereof can be administered at the following doses: 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 a salt thereof is administered at from 0.003 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at from 0.0003 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at from 0.0005 mg / kg to 0.5 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at from 0.001 mg / kg to 0.5 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at from 0.001 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at from 0.001 mg / kg to 1 mg / kg. In some embodiments, GABAA The receptor modulator or a 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 a 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 a 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 a 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 a salt thereof is administered at a dose of from 0.003 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or a 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 a salt thereof is administered at a dose of from 0.003 mg / kg to 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or a 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 a 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 a 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 a 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 a salt thereof is administered at a dose of from 0.01 mg / kg to 0.05 mg / kg. In some embodiments, GABA A The receptor modulator or a 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 a salt thereof is administered at a dose of from 0.01 mg / kg to 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or a 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 a 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 a 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 a salt thereof is administered at a dose from 0.03 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.03 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.05 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.05 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.05 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.05 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.05 mg / kg to 0.1 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.1 mg / kg to 10 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.1 mg / kg to 2 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.1 mg / kg to 1 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.1 mg / kg to 0.3 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.1 mg / kg to 0.5 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at a dose from 0.1 mg / kg to 0.05 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.01 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.02 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.03 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.04 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.05 mg / kg. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.06 mg / kg. In some embodiments, GABAA The GABA receptor modulator or a salt thereof is administered at about 0.07 mg / kg. In some embodiments, A the GABA receptor modulator or a salt thereof is administered at about 0.08 mg / kg. In some embodiments, A the GABA receptor modulator or a salt thereof is administered at about 0.09 mg / kg. In some embodiments, A the GABA receptor modulator or a salt thereof is administered at about 0.1 mg / kg.

[0204] In some cases, GABA A receptor modulator, a salt thereof or a composition comprising GABA described herein AA pharmaceutical composition of a receptor modulator or a salt thereof may be administered at the following doses: 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, less than 0.09 mg / kg, less than 0.1 mg / kg, less than 0.11 mg / kg, less than 0.12 mg / kg, less than 0.13 mg / kg, less than 0.14 mg / kg, less than 0.15 mg / kg, less than 0.16 mg / kg, less than 0.17 mg / kg, less than 0.18 mg / kg, less than 0.19 mg / kg, less than 0.2 mg / kg, less than 0.21 mg / kg, less than 0.22 mg / kg, less than 0.23 mg / kg, less than 0.24 mg / kg, less than 0.25 mg / kg, less than 0.26 mg / kg, less than 0.27 mg / kg, less than 0.28 mg / kg, less than 0.29 mg / kg, less than 0.3 mg / kg, less than 0.31 mg / kg, less than 0.32 mg / kg, less than 0.33 mg / kg, less than 0.34 mg / kg, less than 0.35 mg / kg, less than 0.36 mg / kg, less than 0.37 mg / kg, less than 0.38 mg / kg, less than 0.39 mg / kg, less than 0.4 mg / kg, less than 0.41 mg / kg, less than 0.42 mg / kg, less than 0.43 mg / kg, less than 0.44 mg / kg, less than 0.45 mg / kg, less than 0.46 mg / kg, less than 0.47 mg / kg, less than 0.48 mg / kg, less than 0.49 mg / kg, less than 0.5 mg / kg, less than 0.51 mg / kg, less than 0.52 mg / kg, less than 0.53 mg / kg, less than 0.54 mg / kg, less than 0.55 mg / kg, less than 0.56 mg / kg, less than 0.57 mg / kg, less than 0.58 mg / kg, less than 0.59 mg / kg, less than 0.6 mg / kg, less than 0.61 mg / kg, less than 0.62 mg / kg, less than 0.63 mg / kg, less than 0.64 mg / kg, less than 0.65 mg / kg, less than 0.66 mg / kg, less than 0.67 mg / kg, less than 0.68 mg / kg, less than 0.69 mg / kg, less than 0.7 mg / kg, less than 0.71 mg / kg, less than 0.72 mg / kg, less than 0.73 mg / kg, less than 0.74 mg / kg, less than 0.75 mg / kg, less than 0.76 mg / kg, less than 0.77 mg / kg, less than 0.78 mg / kg, less than 0.79 mg / kg, less than 0.8 mg / kg, less than 0.81 mg / kg, less than 0.82 mg / kg, less than 0.83 mg / kg, less than 0.84 mg / kg, less than 0.85 mg / kg, less than 0.86 mg / kg, less than 0.87 mg / kg, less than 0.88 mg / kg, less than 0.89 mg / kg, less than 0.9 mg / kg, less than 0.91 mg / kg, less than 0.92 mg / kg, less than 0.93 mg / kg, less than 0.94 mg / kg, less than 0.95 mg / kg, less than 0.96 mg / kg, less than 0.97 mg / kg, less than 0.98 mg / kg, less than 0.99 mg / kg, less than 1 mg / kg, less than 2 mg / kg, less than 2.1 mg / kg, less than 2.2 mg / kg, less than 2.3 mg / kg, less than 2.4 mg / kg, less than 2.5 mg / kg, less than 2.6 mg / kg, less than 2.7 mg / kg, less than 2.8 mg / kg, less than 2.9 mg / kg, less than 3 mg / kg, less than 3.1 mg / kg, less than 3.2 mg / kg, less than 3.3 mg / kg, less than 3.4 mg / kg, less than 3.5 mg / kg, less than 3.6 mg / kg, less than 3.7 mg / kg, less than 3.8 mg / kg, less than 3.9 mg / kg, less than 4 mg / kg, less than 4.1 mg / kg, less than 4.2 mg / kg, less than 4.3 mg / kg, less than 4.4 mg / kg, less than 4.5 mg / kg, less than 4.6 mg / kg, less than 4.7 mg / kg, less than 4.8 mg / kg, less than 4.9 mg / kg, less than 5 mg / kg, less than 5.1 mg / kg, less than 5.2 mg / kg, less than 5.3 mg / kg, less than 5.4 mg / kg, less than 5.5 mg / kg, less than 5.6 mg / kg, less than 5.7 mg / kg, less than 5.8 mg / kg, less than 5.9 mg / kg, less than 6 mg / kg, less than 6.1 mg / kg, less than 6.2 mg / kg, less than 6.3 mg / kg, less than 6.4 mg / kg, less than 6.5 mg / kg, less than 6.6 mg / kg, less than 6.7 mg / kg, less than 6.8 mg / kg, less than 6.9 mg / kg, less than 7 mg / kg, less than 7.1 mg / kg, less than 7.2 mg / kg, less than 7.3 mg / kg, less than 7.4 mg / kg, less than 7.5 mg / kg, less than 7.6 mg / kg, less than 7.7 mg / kg, less than 7.8 mg / kg, less than 7.9 mg / kg, less than 8 mg / kg, less than 8.1 mg / kg, less than 8.2 mg / kg, less than 8.3 mg / kg, less than 8.4 mg / kg, less than 8.5 mg / kg, less than 8.6 mg / kg, less than 8.7 mg / kg, less than 8.8 mg / kg, less than 8.9 mg / kg, less than 9 mg / kg, less than 9.1 mg / kg, less than 9.2 mg / kg, less than 9.3 mg / kg, less than 9.4 mg / kg, less than 9.5 mg / kg, less than 9.6 mg / kg, less than 9.7 mg / kg, less than 9.8 mg / kg, less than 9.9 mg / kg, less than 10 mg / kg, less than 11 mg / kg, less than 12 mg / kg, less than 13 mg / kg, less than 14 mg / kg, less than 15 mg / kg, less than 16 mg / kg, less than 17 mg / kg, less than 18 mg / kg, less than 19 mg / kg, less than 20 mg / kg, less than 21 mg / kg, less than 22 mg / kg, less than 23 mg / kg, less than 24 mg / kg, less than 25 mg / kg, less than 26 mg / kg, less than 27 mg / kg, less than 28 mg / kg, less than 29 mg / kg, less than 30 mg / kg, less than 31 mg / kg, less than 32 mg / kg, less than 33 mg / kg, less than 34 mg / kg, less than 35 mg / kg, less than 36 mg / kg, less than 37 mg / kg, less than 38 mg / kg, less than 39 mg / kg, less than 40 mg / kg, less than 41 mg / kg, less than 42 mg / kg, less than 43 mg / kg, less than 44 mg / kg, less than 45 mg / kg, less than 46 mg / kg, less than 47 mg / kg, less than 48 mg / kg, less than 49 mg / kg or less than 50 mg / kg. In some embodiments, GABA. A The GABA A receptor modulator or a salt thereof is administered at a dose of less than 1 mg / kg. In some embodiments, GABA A receptor modulator or a salt thereof is administered at a dose of less than 0.3 mg / kg. In some embodiments, GABA A receptor modulator or a salt thereof is administered at a dose of less than 0.1 mg / kg. In some embodiments, GABA A receptor modulator or a salt thereof is administered at a dose of less than 0.03 mg / kg. In some embodiments, GABA

[0205] In some embodiments, GABA A receptor modulator, a salt thereof or a composition comprising GABA described herein AA pharmaceutical composition of a receptor modulator or a salt thereof can be administered as a liquid preparation. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.01 mg / ml to 100 mg / ml. In some embodiments, the described GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.001 mg / ml to 10 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.1 mg / ml to 10 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.001 mg / ml to 10 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.001 mg / ml to 1 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.001 mg / ml to 0.5 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.5 mg / ml to 5 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 1 mg / ml to 2 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.5 mg / ml to 2 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.2 mg / ml to 1 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.2 mg / ml to 0.5 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.2 mg / ml to 0.4 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.1 mg / ml to 0.5 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.1 mg / ml to 0.3 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at a concentration ranging from 0.05 mg / ml to 0.5 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at approximately 0.1 mg / ml. In some embodiments, the GABA A receptor modulator or a salt thereof is administered at approximately 0.25 mg / ml. In some embodiments, the GABA AThe receptor modulator or a salt thereof is administered at about 0.3 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.5 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 0.75 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 1 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 1.25 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 1.5 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 2 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 2.5 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 5 mg / ml. In some embodiments, GABA A The receptor modulator or a salt thereof is administered at about 10 mg / ml. In some embodiments, a liquid preparation of 0.01 ml to 500 ml is administered daily. In some embodiments, a liquid preparation of 0.05 ml to 250 ml is administered daily. In some embodiments, a liquid preparation of 0.05 ml to 50 ml is administered daily. In some embodiments, a liquid preparation of 0.1 ml to 25 ml is administered daily. In some embodiments, a liquid preparation of 1 ml to 250 ml is administered daily. In some embodiments, a liquid preparation of 1 ml to 200 ml is administered daily. In some embodiments, a liquid preparation of 50 ml to 200 ml is administered daily. In some embodiments, a liquid preparation of 25 ml to 100 ml is administered daily. In some embodiments, a liquid preparation of 5 ml to 50 ml is administered daily. In some embodiments, a liquid preparation of 1 ml to 20 ml is administered daily. In some embodiments, a liquid preparation of 1 ml to 5 ml is administered daily.

[0206] In some embodiments, described herein is a method of treating a subject's epileptic condition, the method comprising administering to the subject a pharmaceutical composition comprising a compound having the following structure

[0207] or a salt or polymorph thereof, wherein the administration is in an amount effective to treat a seizure condition in a subject. In some embodiments, an amount effective to treat a seizure condition includes 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 amount includes a dose 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 includes a dose 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 includes a dose of less than 0.03 mg of the compound or a salt or polymorph thereof per kg of subject body weight per day.

[0208] One of ordinary skill in the art can extrapolate an effective dose 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.

[0209] GABA A Administration of a GABA 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 GABA 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 the 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, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 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 times per month. In some embodiments, GABA A The receptor modulator or its salt is administered to a 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.

[0210] The present invention is further illustrated by the following examples, from which additional embodiments and advantages can be derived. These examples are intended to illustrate the invention and not to limit its scope.

[0211] Example 1 - Formulations

[0212] Exemplary GABA A receptor modulators are formulated prior to administration. Each modulator is combined with Tylose MH 300 (0.5% w / v), Tween 80 (1% final volume) and 0.9% bacteriostatic saline (to final volume). The resulting suspension is then sonicated at 37 °C for at least 10 minutes.

[0213] A control solution of 0.5% Tylose MH 300 (w / v) and 1% Tween 80 (v / v) in 0.9% bacteriostatic saline is also prepared.

[0214] Example 2 - Study Design

[0215] Animals

[0216] Reasons for species selection: Scn1a + / - knockout mice ([129xB]F1.Scn1a + / -) is a model object of DS and has a high translational value.

[0217] Number: 112 (56 males and 56 females) first-generation Scn1a + / - Heterozygous knockout mice ([129xB]F1.Scn1a + / - ).

[0218] Spare animals: 112 wild-type littermates. A portion of the spare animals was used to determine the PK profile of an exemplary GABA A receptor modulator.

[0219] Strain / health status: Scn1a + / - Heterozygous knockout mice ([129xB]F1.Scn1a + / - )

[0220] Breeders: Obtained Scn1a + / - Breeding male mice (129S-Scn1a + / - , n = 12), and were set up with C57BL / 6J females (n = 24) as breeding trios.

[0221] Age / weight: Scn1a between P14 and P16 + / - heterozygous knockout mice were randomly assigned to treatment groups.

[0222] Receiving: Upon arrival, breeding female C57BL / 6J mice were given a physical examination to ensure they were healthy. Scn1a + / - breeding male mice (129S-Scn1a + / - , n = 12) were isolated for 2 weeks until cleared by PCR testing.

[0223] Acclimation: Acclimation was not required. After Scn1a + / - heterozygous knockout, weaned mice were included in the study and received treatment.

[0224] Allocation to groups: After weaning, the required number of animals was randomly assigned to treatment groups (by sex).

[0225] Identification: Scn1a obtained from breeding trios + / - heterozygous knockout mice were numbered by toe clipping at P7-10 days of age in each cage. The cage card indicates the number of animals in each cage. Wild-type littermates not designated for PK testing were euthanized. Only Scn1a + / - heterozygous knockout mice ([129xB]F1.Scn1a + / -)Were included in the study of heat-induced seizures.

[0226] Environmental conditions

[0227] From arrival, animals were housed in a SPF barrier rodent unit. Animal room conditions were set as follows:

[0228] Temperature: 20°C - 26°C (68°F - 79°F)

[0229] Relative humidity: 50 ± 20%,

[0230] Light / dark cycle: 12h / 12h; light starts at 07:00,

[0231] Ventilation: Filtered, non-recirculated air at approximately 10 to 15 cycles per hour.

[0232] The corresponding instruments and equipment were inspected and calibrated at regular intervals. Temperature and relative humidity were continuously recorded (recording device equipped with an alarm system).

[0233] The animal room was disinfected before the arrival of the animals and then cleaned regularly thereafter.

[0234] Housing

[0235] The Scn1a + / - Breeding male mice (129S - Scn1a + / - ) and C57BL / 6J females were each housed at 4 per cage in autoclaved polycarbonate cages equipped with a stainless steel lid with a microfilter top and containing 1 / 4 - corncob bedding in a perforated holder.

[0236] One breeding male and two females were set up to breed three litters. Offspring (Scn1a + / - heterozygous knockout mice ([129xB]F1.Scn1a + / - and wild-type) were kept with their mother (C57BL / 6J female) until they were included in the study. Unless designated for PK studies, the wild-type littermates were euthanized after the [129xB]F1.Scn1a + / - littermates were included in the study.

[0237] Example 3 - Treatment of cold-induced seizures

[0238] Treatment group

[0239] Rationale for dose level selection - Dose levels were selected based on the results of previous studies.

[0240] Between P14 and P16 of Scn1a+ / - Heterozygous knockout mice were randomly assigned to treatment groups (n = 7 males, 7 females per treatment group). The Scn1a + / - knockout mouse model was selected because it is an animal model of epilepsy conditions (including Dravet syndrome) recognized in the art. The treatment was a GABA A receptor modulator 1 (“Compound 1”, as the phosphate at 0.1 mg / kg, 0.3 mg / kg, 1.0 mg / kg), a 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).

[0241] Duration

[0242] For this study, the dose formulations were administered individually.

[0243] Administration

[0244] GABA A receptor modulators were administered intraperitoneally (i.p.) using a 0.5 ml or 1 ml plastic syringe equipped with a 27- or 30-gauge 0.5” long bevel needle.

[0245] Animals received 10 mL of the formulation per kg body weight (as measured on the day of the experiment).

[0246] Throughout the procedure, the formulation was adjusted to the delivery condition (37 °C temperature) and maintained at the delivery condition.

[0247] The formulation was mixed by inverting its container 2 - 3 times immediately before administration.

[0248] To verify the dose concentration, mice were dosed with the test article or control and placed in individual housing cages. A temperature probe was gently inserted into the rectum of the mouse and secured by tying the wire of the probe to the mouse's tail, with the label end on the dorsal side of the mouse. For each group, the probe was inserted as follows:

[0249] a. For mice administered CBZ, after five (5) minutes, the probe was inserted to allow a pre-treatment time of 20 - 30 min when the high temperature state was reached.

[0250] b. For mice administered Compound 1, after thirty-five (35) minutes, the probe was inserted to allow a pre-treatment time of 50 - 60 min when the high temperature state was reached.

[0251] c. For the mice administered with Compound 2, after five (5) minutes, a probe was inserted to allow a pre-treatment time of 20 - 30 min when the high temperature state was reached.

[0252] Each mouse was allowed to acclimatize to the temperature probe for five (5) minutes, and then the baseline temperature was recorded. Figures 1 - 3 Depicts the starting temperatures of female mice, male mice, and the average starting temperature of all mice before heat-induced seizures.

[0253] The core body temperature of the mice was increased by approximately 0.5 °C every 2 min by keeping the mice on a heating pad until the first tonic-clonic seizure accompanied by loss of posture was observed, or until a body temperature of 42.5 °C was reached. Figures 4 - 6 Depicts the final core body temperatures of female mice, male mice, and the average final core body temperature of all mice after heating. Figures 7 - 9 The figure shows the total temperature changes of female mice, male mice, and the average value of all mice; while Figures 10 - 12 Depicts the average temperature change per minute of female mice, male mice, and the average value of all mice. The body temperature of the mice was maintained at 42.5 °C for 3 min. If no seizure occurred, the mouse was considered seizure-free.

[0254] Tables 1 - 9 below depict the administration results of the control, CBZ, Compound 1, and Compound 2, and the variation of their ability to protect against seizures with the dose.

[0255] Table 1 - Control vehicle (30 - minute pre-treatment)

[0256]

[0257]

[0258] Table 2: 10 mg / kg Clobazam (30 - minute pre-treatment)

[0259]

[0260]

[0261] Table 3 - 0.1 mg / kg Compound 1 (60 - minute pre-treatment)

[0262]

[0263] Table 4: 0.3 mg / kg Compound 1 (60 - minute pre-treatment)

[0264]

[0265] Table 5 - 1.0 mg / kg Compound 1 (60 - minute pretreatment)

[0266]

[0267]

[0268] Table 6: 3 mg / kg Compound 2 (30 - minute pretreatment)

[0269]

[0270]

[0271] Table 7: 10 mg / kg Compound 2 (30 - minute pretreatment)

[0272]

[0273] Table 8: 30 mg / kg Compound 2 (30 - minute pretreatment)

[0274]

[0275]

[0276] Table 9: 100 mg / kg Compound 2 (30 - minute pretreatment)

[0277]

[0278] The summary of the data is presented in Table 10 and Figure 13 .

[0279] Table 10: Summary of seizure data

[0280]

[0281] As shown in Table 10, the GABA A receptor modulators Compound 1 and Compound 2 reduced the amount of seizures in the animal model relative to the vehicle administered. 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 seizures, the GABA A receptor modulators are promising therapeutic agents for the treatment of seizures. In fact, the data show that Compound 2 treats seizures in a dose - dependent manner, where the 100 mg / kg dose completely prevents seizures in each animal (n = 8).

[0282] In fact, administration of Compound 1 or Compound 2 from about 0.1 mg / kg to about 100 mg / kg has been shown to be effective in preventing seizures in a mouse model. A person of ordinary skill in the art will be able to extrapolate this effective amount to other animals. For example, using a human analog factor of 12, the human equivalent dose would be about 0.008 mg / kg to about 10 mg / kg.

[0283] A person skilled in the art will understand that the efficacy of Compound 1 and Compound 2 in treating seizures in a heat-induced animal model is not limited to a particular compound. Rather, a person of ordinary skill in the art would reasonably expect that GABA A receptor modulators as a class will be effective in treating seizures in a manner comparable to the efficacy observed with Compound 1 and Compound 2. In addition, a skilled person will understand that the efficacy will not be limited to preventing seizures in Scn1a + / - knockout mice. Rather, the animal model is a well-established animal model for multiple seizure conditions including Dravet syndrome. Thus, a skilled person would reasonably expect that the entire class of GABA A receptor modulators will be effective in treating seizure conditions by preventing seizures.

[0284] Thus, the results demonstrate the potential of GABA A receptor modulators as a class in treating seizure conditions, as demonstrated in a mouse model of heat-induced seizures.

[0285] Example 4 - Pharmacokinetic Determination

[0286] To determine the pharmacokinetic parameters of Compound 1 and Compound 2, P14 - P16 mice (n = 7 groups -1 · sex -1 · time points -1 ) were dosed with Compound 1 and Compound 2, and terminal blood samples were collected at the following time points:

[0287] a. Compound 1: 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h,

[0288] b. Compound 2: 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h.

[0289] Blood collection: Immediately before blood collection, the mice were euthanized by CO2 inhalation. Blood was collected via cardiac puncture using a 27-gauge needle and transferred to 500 μL K3EDTA tubes and immediately placed on wet ice. Samples were centrifuged at 2900 g for 10 minutes under refrigerated conditions (set to maintain +4°C) within 2 hours of collection. Plasma was transferred to separate tubes within 2 hours and stored at -20°C.

[0290] Verification of Dosage Formulation Concentration

[0291] Collect 0.3 mL aliquots of each formulation from the mid-dose concentration position and store them in sealed vials wrapped with paraffin film at a temperature of 2 °C - 4 °C or lower until the end of the study.

[0292] A calibration curve consisting of at least 6 calibration standards will be constructed using the LC / UV method.

[0293] The concentration of the test compound in the dosage form samples will be determined by the LC / UV method.

[0294] Determination of Plasma Levels of Test Items

[0295] The LC-MS / MS method for the quantitative determination of the test compound in biological matrices will be developed under non-GLP compliance.

[0296] For the LC-MS / MS method, a calibration curve with at least 6 non-zero calibration standards (STD) will be constructed.

[0297] Determination of Study Samples

[0298] Study samples will be assayed in batches using LC-MS / MS after appropriate preparation. Generally, if the number of samples is no more than 48, one set of calibration curves and two sets of QC samples consisting of low, medium, and high concentrations will be applied. If the number of samples is more than 48, two sets of calibration curves and two sets of QC samples will be applied.

[0299] Generally, one reagent blank, one plasma blank, and, if applicable, two plasma blanks containing only the internal standard will be run.

[0300] Samples in the same matrix for different PK projects will be quantified in the same analytical run.

[0301] Acceptance Criteria for Analytical Batches

[0302] Linearity: ≥75% of the STDs are back-calculated within ±20% of the nominal value in their biological fluids (±25% for the LLOQ) and within 25% of the nominal value in their tissue homogenates and fecal samples (30% for the LLOQ).

[0303] Accuracy: ≥67% of all QC samples are back-calculated within ±20% of their biological fluid nominal values and within 25% of their tissue and fecal sample nominal values.

[0304] Specificity: The average calculated concentration of the analyte in the single blank matrix should be less than 0.5 times the LLOQ.

[0305] Pharmacokinetic analysis

[0306] The analysis of pharmacokinetic data will be performed for each dose level, sex, and sampling occasion.

[0307] Generally, if possible, the following toxicokinetic parameters will be calculated / measured: 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.

[0308] Values below the lower limit of quantification will be reported as BLQ in a separate table, and considered zero for descriptive statistics and incorporated into statistical calculations. BLQ will be reported when the mean of the individual concentrations is below the quantification limit.

[0309] Although the 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. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

[0310] Example 5 - Evaluation of the Acute Anticonvulsant Efficacy of Compound 1 in Mouse and Rat Models of Acute Seizures

[0311] Methods:

[0312] The anticonvulsant efficacy of Compound 1 was tested in a CF-1 mouse acute 6Hz seizure model at 32 mA and 44 mA intensities. After acute administration at a single time point, the dose-related efficacy of Compound 1 was evaluated in a 6Hz seizure test 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 the negative control.

[0313] After oral administration of the compound, mice were challenged at appropriate time points with a 32 mA or 44 mA current delivered via corneal electrodes for 3 seconds to elicit typical seizures. 6 Hz seizures are characterized by an initial momentary dizziness, followed immediately by forelimb clonus, whisker twitching, and Straub tail 1. Animals that did not exhibit all of these behaviors during the immediate (5 - 10 seconds) post - stimulation period were considered "protected" (N = number protected / F = number tested).

[0314] Compound 1 was administered 3 hours later and the antiseizure 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) at a volume of 0.01 mL / g. Testing was conducted over a 1 - 2 day period, where animals in each test group were randomly assigned to receive a single dose of the study compound or vehicle. For each day of testing, animals were tested in groups of 20 - 30 mice / phase, and treatment was randomized across 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, P.O.) mice were also tested in parallel at the previously determined DZP peak - effect time (0.5 hours); all testing was performed by investigators blinded to the treatment status. A statistically significant increase (P ≤ 0.05) in the number of protected mice compared to the number of protected mice in the negative control was considered to be effective. An overview of the results is provided in Table 11.

[0315] Table 11: Dose and potency relative to vehicle of Compound 1 in the 6 Hz seizure study in 32 mA mice

[0316]

[0317] The present disclosure also provides the following items:

[0318] 1. A method of treating a seizure disorder 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 seizure disorder in the subject,

[0319]

[0320] wherein

[0321] X 1 , X 2 , X 3 , X 4 and X5 is independently -C, -N, -S or -O, where X 1 , X 2 , X 3 , X 4 and X 5 and at least two of X

[0322] Y 1 and Y 2 are independently -C or -N,

[0323] R 1 m has m of 1, where R 1 is unsubstituted phenyl, phenyl substituted with a C1-C4 hydrocarbyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 , where R 3 is substituted or unsubstituted aryl or 5- to 6-membered heteroaryl,

[0324] R 2 n has n of 1 or 2, where each R 2 is independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 hydrocarbyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen or -O-CH2-R 4 , where R 4 is substituted or unsubstituted 5- or 6-membered heteroaryl,

[0325] Z 1 , Z 3 , Z 4 and Z 5 are independently -C, -N, -S or -O,

[0326] A 1 and A 2 and A 3 are independently -C, -N or -(C=O)-O-R 7 , or

[0327]

[0328] where

[0329] R 7 is a hydrocarbyl group,

[0330] B 1 , B 2 , B 3 and B 4 are independently -C, -N or -O,

[0331] R 21 S s is 1, 2, 3 or 4, and

[0332] R 5 l l is 1 or 2, wherein each R 5 is independently C1-C4 alkynyl or halogen,

[0333] R 6 k k is 1, 2, 3 or 4, wherein each R 6 is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbyl or hydrogen,

[0334] R 12 p p is 1 or 2, wherein each R 12 is independently substituted or unsubstituted C1-C4 hydrocarbyl, I, Br, Cl or F, and

[0335] R 13 q q is 1, 2, 3 or 4, wherein each R 13 is independently substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C1-C3 hydrocarbyl, oxygen or hydrogen.

[0336] 2. A method of treating epilepsy associated with sodium channel mutations in a subject, the method comprising administering to the subject a compound of formula (1a), formula (1b) or formula (1c) to treat the epilepsy associated with sodium channel mutations,

[0337]

[0338] wherein

[0339] X 1 、X 2 、X 3 、X 4 and X 5 are independently -C, -N, -S or -O, wherein at least two of X 1 、X 2 、X 3 、X 4 and X 5 are -N,

[0340] Y 1 and Y 2 are independently -C or -N,

[0341] R 1 m has m equal to 1, where R 1 is unsubstituted phenyl, phenyl substituted with a C1-C4 hydrocarbyl, F, Cl, Br, I, -CN, substituted or unsubstituted biphenyl or -(C=O)-R 3 , where R 3 is substituted or unsubstituted aryl or 5- to 6-membered heteroaryl,

[0342] R 2 n has n equal to 1 or 2, where each R 2 is independently substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 hydrocarbyl, substituted or unsubstituted C1-C6 alcohol, substituted or unsubstituted 6-membered heteroaryl, halogen or -O-CH2-R 4 , where R 4 is substituted or unsubstituted 5- or 6-membered heteroaryl,

[0343] Z 1 、Z 3 、Z 4 and Z 5 are independently -C, -N, -S or -O,

[0344] -A 1 and A 2 and A 3 are independently -C, -N or -(C=O)-O-R 7 , or

[0345]

[0346] where

[0347] R 7 is hydrocarbyl,

[0348] B 1 、B 2 、B 3 and B 4 are independently -C, -N or -O,

[0349] R 21 s has s equal to 1, 2, 3 or 4, and

[0350] R 5 l has l equal to 1 or 2, where each R 5 is independently C1-C4 alkynyl or halogen,

[0351] R 6k k is 1, 2, 3 or 4, wherein each R 6 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbyl or hydrogen,

[0352] R 12 p p is 1 or 2, wherein each R 12 is independently a substituted or unsubstituted C1-C4 hydrocarbyl, I, Br, Cl or F, and

[0353] R 13 q q is 1, 2, 3 or 4, wherein each R 13 is independently a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted C1-C3 hydrocarbyl, oxygen or hydrogen.

[0354] 3. The method according to item 1 or 2, wherein the compound has the general formula (2), general formula (3), general formula (4), general formula (5), general formula (1c) or general formula (7),

[0355]

[0356] 4. The method according to any one of items 1-3, wherein the compound has the general formula (2a), general formula (3a), general formula (4a), general formula (5a), general formula (5b), general formula (1c) or general formula (7a),

[0357]

[0358]

[0359] 5. The method according to any one of items 1-4, wherein:

[0360] R 1 m m is 1, and wherein R 1 is:

[0361] unsubstituted phenyl,

[0362] substituted phenyl containing C1-C4 hydrocarbyl, F, Cl, Br, I, -CN as substituents,

[0363] unsubstituted biphenyl,

[0364] substituted biphenyl containing at least one -CN as a substituent,

[0365] A substituted biphenyl containing at least one -F as a substituent, or

[0366] -(C=O)-R 3 , wherein R 3 is pyridine.

[0367] 6. The method according to any one of items 1 - 5, wherein the compound has the general formula (2a'), general formula (3a'), general formula (4a'), general formula (5a'), general formula (5b'), general formula (VI) or general formula (7a'),

[0368]

[0369] wherein

[0370] R 10 is a substituted or unsubstituted aryl, a substituted or unsubstituted C1 - C3 hydrocarbyl or hydrogen,

[0371] R 11 is a substituted or unsubstituted aryl, a substituted or unsubstituted C1 - C3 hydrocarbyl or hydrogen, and

[0372] R 12 p the p of is 1, and R 12 is I, Br, Cl or F.

[0373] 7. The method according to any one of items 1 - 6, wherein the compound has the general formula (2a''), general formula (3a''), general formula (4a''), general formula (5a''), general formula (5b''), general formula (VIa'') or general formula (7a''),

[0374]

[0375] wherein R 7 is:

[0376] an unsubstituted C1 - C6 hydrocarbyl,

[0377] an unsubstituted C3 - C8 cyclo - hydrocarbyl,

[0378] an unsubstituted C1 - C6 alcohol,

[0379] R 8 is:

[0380] -O-CH2-R 4 wherein R 4 is a substituted or unsubstituted 5 - membered heteroaryl, or an unsubstituted C1 - C6 alcohol,

[0381] R 9 is:

[0382] an unsubstituted C6 heteroaryl, or a halogen, or

[0383] R 9 is an unsubstituted 6-membered heteroaryl in formula (4a”) or a halogen in formula (5b”),

[0384] R 10 is a C1-C3 hydrocarbyl or hydrogen,

[0385] R 11 is a substituted or unsubstituted aryl or heteroaryl,

[0386] R 14 is a substituted or unsubstituted aryl or heteroaryl,

[0387] R 12 is I, Cl, Br or F, or

[0388] R 5 is a C2 alkynyl or I.

[0389] 8. The method according to any one of items 1-7, wherein the compound is an α1, α2, α3 or α5 GABA A receptor modulator.

[0390] 9. The method according to item 8, wherein the compound is a positive allosteric α2 or α3 GABA A receptor modulator.

[0391] 10. The method according to any one of items 1-9, wherein the subject is human.

[0392] 11. The method according to any one of items 1-9, wherein the subject is a dog.

[0393] 12. The method according to any one of items 1-9, wherein the age of the subject is from 0 to 17 years old.

[0394] 13. The method according to any one of items 1-9, wherein the age of the subject is from 18 to 130 years old.

[0395] 14. The method according to any one of items 1-13, wherein the therapeutically effective amount of the compound is present in a pharmaceutical composition, the pharmaceutical composition comprising a pharmaceutically acceptable excipient, diluent or carrier.

[0396] 15. The method according to item 1, wherein the epileptic condition is selected from the group consisting of: childhood benign centrotemporal epilepsy, childhood benign occipital epilepsy (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, West syndrome, Dravet syndrome, progressive myoclonic epilepsy, and Lennox-Gastaut syndrome (LGS).

[0397] 16. The method according to item 2, wherein the sodium channel mutation comprises a mutation in the voltage-gated sodium channel alpha subunit 1 (SCN1A) gene.

[0398] 17. A method of treating Dravet syndrome in a subject, the method comprising administering to the subject an amount of a pharmaceutical composition to treat the Dravet syndrome in the subject, the pharmaceutical composition comprising a compound selected from the group consisting of:

[0399]

[0400] its salts and its polymorphs.

[0401] 18. The method according to item 17, wherein the compound is:

[0402]

[0403] its salt, or its polymorph.

[0404] 19. The method according to item 17, wherein the amount is effective for treating the Dravet syndrome when administered at a dose 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 the subject.

[0405] 20. The method according to item 17, wherein the subject is human.

[0406] 21. The method according to item 17, wherein the subject is a dog.

[0407] 22. The method according to item 17, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, diluent, or carrier.

[0408] 23. The method according to item 22, comprising the carrier, wherein the carrier is methylcellulose.

[0409] 24. The method according to item 17, wherein the compound is a polymorph thereof or a salt thereof.

[0410] 25. The method according to item 24, comprising the salt, wherein the salt is a phosphate.

[0411] 26. The method according to item 24, comprising the salt, wherein the salt is a sulfate.

[0412] 27. The method according to any one of items 24 - 26, comprising the polymorph, wherein the polymorph has characteristic peak positions in X-ray powder diffraction (XRPD) having values containing at least three 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 when measured using: (a) X-ray wavelength parameter of Cu:K-α (b) X-ray tube voltage setting of 40 kV and current of 40 mA; (c) scanning range from about 3 degrees to about 40 degrees; (d) sample rotation speed of about 15 rpm; and (e) scanning rate of 10 degrees per minute.

[0413] 28. The method according to item 17, wherein the administration comprises oral administration.

[0414] 29. The method according to item 17, wherein the administration is performed at least once a day.

[0415] 30. The method according to any one of items 17 - 29, wherein administration of an amount effective to treat Dravet syndrome does not produce drowsiness or sedation in the subject.

[0416] 31. A method of treating an epileptic condition in a subject, the method comprising administering to the subject an amount of a compound of the following formula:

[0417]

[0418] its pharmaceutically acceptable salt or polymorph to treat the epileptic condition of the subject, wherein the amount comprises a dose from about 0.003 mg / kg of the body weight of the subject to about 10 mg / kg of the body weight of the subject.

[0419] 32. The method according to item 31, wherein the administration reduces the amount of seizures to an amount that is at least 20% less than the amount of seizures that occur based on administration of an equal dose of clobazam.

[0420] 33. The method according to item 31, wherein the amount comprises a dose from about 0.08 mg / kg of the body weight of the subject to about 2.5 mg / kg of the body weight of the subject.

[0421] 34. The method according to item 31, wherein the compound is present in a storage-stable formulation.

[0422] 35. The method according to item 31, wherein the compound is formulated as a non-sedating formulation.

[0423] 36. The method according to item 35, wherein the non-sedating formulation comprises caffeine.

[0424] 37. The method according to item 31, wherein the compound, its pharmaceutically acceptable salt or polymorph is a phosphate or its polymorph.

[0425] 38. The method according to item 31, wherein the compound, its pharmaceutically acceptable salt or polymorph is a sulfate or its polymorph.

[0426] 39. A method of treating an epileptic condition of a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula (5a') or a salt or polymorph thereof,

[0427]

[0428] wherein

[0429] R 1 is an unsubstituted phenyl, a phenyl substituted with a C1-C4 hydrocarbyl, F, Cl, Br, I, -CN, a substituted or unsubstituted biphenyl or -(C=O)-R 3 wherein R 3 is a substituted or unsubstituted aryl or a 5- to 6-membered heteroaryl, and

[0430] R 2 n the n of is 1 or 2, wherein each R 2independently is a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted C1-C6 hydrocarbon group, a substituted or unsubstituted C1-C6 alcohol, a substituted or unsubstituted 6-membered heteroaryl group, a halogen or -O-CH2-R 4 , wherein R 4 is a substituted or unsubstituted 5-membered or 6-membered heteroaryl group,

[0431] wherein the administration is in an amount effective to treat the epileptic condition of the subject, and wherein the amount comprises a dose of from about 0.003 mg to about 1 mg of the compound or its salt or polymorph per kg of body weight of the subject per day.

[0432] 40. A method of treating an epileptic condition of a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound having the following structure or a salt or polymorph thereof, wherein the administration is in an amount effective to treat the epileptic condition of the subject, and wherein the amount comprises a dose of from about 0.0003 mg to about 1 mg of the compound or its salt or polymorph per kg of body weight of the subject per day.

[0433] 41. The method according to item 39 or 40, wherein the compound or its salt or polymorph is a phosphate or a polymorph thereof.

[0434] 42. The method according to item 39 or 40, wherein the compound or its salt or polymorph is a sulfate or a polymorph thereof.

[0435] 43. The method according to item 40, wherein the compound or its salt or polymorph is a phosphate polymorph, and wherein the phosphate polymorph exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values 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 when measured using: (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 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.

[0436] 44. The method according to item 39 or 40, wherein the pharmaceutical composition is formulated for oral or transdermal administration.

[0437] 45. The method according to item 39 or 40, wherein the amount comprises a dose of less than 0.3 mg of the compound or its salt or polymorph per kg of body weight of the subject per day.

[0438] 46. The method according to item 39 or 40, wherein the amount comprises a dose of less than 0.1 mg of the compound or its salt or polymorph per kg of body weight of the subject per day.

[0439] 47. The method according to item 39 or 40, wherein the amount comprises a dose of less than 0.03 mg of the compound or its salt or polymorph per kg of body weight of the subject per day.

[0440] 48. The method according to item 39 or 40, wherein the epileptic condition is Dravet syndrome.

[0441] 49. The method according to item 39 or 40, wherein the epileptic condition is focal seizures.

[0442] 50. The method according to item 39 or 40, wherein the epileptic condition is generalized epilepsy or genetic epilepsy.

[0443] 51. The method according to item 39 or 40, wherein the compound or its salt or polymorph is not a phosphate or its polymorph, and is not a sulfate or its polymorph.

[0444] 52. The method according to item 39 or 40, wherein the compound is formulated as a non-sedating preparation.

[0445] 53. The method according to item 52, wherein the non-sedating preparation comprises caffeine.

[0446] 54. The method according to item 39 or 40, wherein the epileptic condition is selected from the group consisting of: childhood absence epilepsy, childhood benign occipital epilepsy (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 or Lennox-Gastaut syndrome (LGS).

[0447] 55. The method according to item 39 or 40, wherein the subject is a human.

Claims

1. Use of a compound for the manufacture of a medicament for treating a subject's (1) general epilepsy; (2) epilepsy with focal seizures; or (3) Lennox-Gastaut syndrome epilepsy condition, wherein the compound is or a salt thereof.

2. Use according to claim 1, wherein the compound is an α1, α2, α3 or α5 GABA A receptor modulator.

3. Use according to claim 2, wherein the compound is a positive allosteric α2 or α3 GABA A receptor modulator.

4. The use according to any one of claims 1 - 3, wherein the subject is a human.

5. The use according to any one of claims 1 - 4, wherein a 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 a subject's (1) general epilepsy; (2) epilepsy with focal seizures; or (3) Lennox-Gastaut syndrome epilepsy condition, the medicament comprising a pharmaceutical composition comprising the compound, wherein the compound is or a salt thereof, wherein the pharmaceutical composition is in an amount effective for treating the subject's epilepsy condition.

7. Use of a compound for the manufacture of a medicament for treating in a subject an epileptic condition of (1) general epilepsy; (2) epilepsy with focal seizures; or (3) Lennox-Gastaut syndrome, said medicament comprising a pharmaceutical composition comprising said compound, said compound being or a salt thereof, wherein said pharmaceutical composition is in an amount effective for treating said epileptic condition in said subject, and wherein said amount comprises a dose of from 0.0003 mg to 1 mg per kg of body weight of said subject of said compound or a salt thereof per day.

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

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

10. The use according to claim 7, wherein the compound or its salt is a phosphate, and wherein the phosphate exhibits an X-ray powder diffraction (XRPD) pattern having characteristic peak positions of at least three values selected from the group consisting of 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: (a) X-ray wavelength parameter of Cu:K-α (b) X-ray tube voltage setting of 40 kV and current of 40 mA; (c) scanning range from 3 degrees to 40 degrees; (d) sample rotation speed of about 15 rpm; and (e) scanning rate of 10 degrees per minute.

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

12. The use according to claim 6 or 7, wherein the amount comprises a dose of less than 0.3 mg of the compound or its salt per kg of the subject's body weight per day.

13. The use according to claim 6 or 7, wherein the amount comprises a dose of less than 0.1 mg of the compound or its salt per kg of the subject's body weight per day.

14. The use according to claim 6 or 7, wherein the amount comprises a dose of less than 0.03 mg of the compound or its salt per kg of the subject's body weight per day.

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

16. The use according to claim 11, wherein the pharmaceutical composition comprises caffeine.

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

Images