T-type calcium channel modulators containing a diazaspiroheptane core and methods of use thereof

Abstract

Disclosed herein are compounds and pharmaceutical compositions comprising the compounds for treating conditions regulated by calcium channel ion activity, the compounds comprising a diazaspiroheptane core and left- and right-side substitutions of the diazaspiroheptane core. Also disclosed herein are methods for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels using the compounds. The disclosure provides compounds for treating conditions associated with calcium channel activity, particularly T-type calcium channel activity. Specifically disclosed herein are compounds of formula (I) or compounds of formula (IA) comprising a diazaspiroheptane core, including right- and left-side substitutions.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 326,699, filed April 1, 2022, the entire contents of which are incorporated herein by reference.

[0002] Disclosed herein are compounds for treating conditions associated with calcium channel activity, particularly T-type calcium channel activity.Specifically disclosed herein are compounds that include a diazaspiroheptane core, including left-handed and right-handed substitutions.Disclosed herein are methods for treating conditions associated with T-type calcium channel activity by administering the compounds disclosed herein. [Background technology]

[0003] Calcium entry into cells through voltage-gated calcium channels mediates a wide variety of cellular and physiological responses, including excitation-contraction coupling, hormone secretion, and gene expression. In neurons, calcium channels directly affect membrane potential, contribute to electrical properties, and also regulate the activity of calcium-dependent enzymes such as protein kinase C and calmodulin-dependent protein kinase II. T-type calcium channels are low-voltage-activated ion channels that mediate calcium influx into cells.

[0004] T-type calcium channel modulators having a piperidinyl core are disclosed, for example, in PCT Publication No. 2009 / 146540, published December 10, 2009, as well as U.S. Pat. Nos. 8,377,968 (published February 19, 2013), 8,569,344 (published October 29, 2013), and 9,096,522 (published August 4, 2015), the entire contents of which are incorporated herein by reference. Abnormal function of these T-type calcium ion channels is associated with several diseases or conditions, including psychiatric disorders (e.g., mood disorders such as major depressive disorder), pain, tremors (e.g., essential tremor), epilepsy, or epilepsy syndromes (e.g., absence seizures and juvenile myoclonus epilepsy).Accordingly, additional compounds that selectively modulate T-type calcium channels in mammals may be useful in treating such diseases. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2009 / 146540 [Patent Document 2] U.S. Pat. No. 8,377,968 [Patent Document 3] U.S. Pat. No. 8,569,344 [Patent Document 4] U.S. Pat. No. 9,096,522 Summary of the Invention [Means for solving the problem]

[0006] The present disclosure provides compounds for treating conditions associated with calcium channel activity, particularly T-type calcium channel activity. Specifically, disclosed herein are compounds of formula (I) or compounds of formula (IA) that include a diazaspiroheptane core, including right- and left-sided substitutions.

[0007] In one aspect, the compounds disclosed herein are compounds of formula (IA) having a diazaspiroheptane core: [ka] In the formula, X 1 but, [ka] is a left-handed substitution on the diazaspiroheptane core selected from In the formula, R 1 But, -H, -CH 3 , -CH 2 OCH 3 , -CF 3 , -CH 2 CH 3 , or -(CH 2 ) 2 OCH 3 is selected from R 2 is -H, R 3 is -H, R 4 is -H or -CH 3 or R 1 and R 4 together form a cyclopropane, cyclobutane, cyclopentane, or oxetane ring, R 5 But, -H, -CH 3 , -CF 3 , -CH 2 OH, -COOCH 3 , -COOH, or -CH 2 OCH 3 is selected from R 6 is -H or -CH 3 or R 5 and R 6 together form an azetidine, pyrrolidine, morpholine, or piperidine ring, each of which is -CH 3 , -OH, -CF 3 or -F, R 7 is 1, 2, or 3, and -Cl, -F, -CF 3 , -CH 3 , -OCHF 2 , or -OCH 3 are independently selected from R 8 Benzene, -CH 3 or tert-butyl; R9 optionally at least one -F or -CH 3 cyclohexane, optionally substituted with -O-, or benzimidazole; R 10 But -C(CH 3 ) 3 , cyclopentyl, -(CH 2 )C(CH 3 ) 3 or cyclohexane optionally substituted with -N- and optionally containing at least one substituent selected from -F or =O, -OCH 3 or cyclopentane, optionally containing an -OH substituent, tert-butyl, -CF 3 or cyclopropyl, optionally containing a methyl substituent; A 1 is selected from -CH or -N; A 2 is independently selected from -CH, -N, or -O; and A 3 But, -O, CH 2 , or CF 2 is selected from X 2 But -CH 2 CONH-, -CH 2 -, -CH 2 NHCO-, -CH 2 NHCOCH 2 -, -CH 2 NHCO(CH 2 ) 2 -, -NHCO-, -NHCH 2 CONH-, -N(CH 3 )CH 2 CONH-, -CH 2 N(CH 3 )CO-, -CONH-, -CONHCH 2 -, CONHCH 2 C(CH 2 CH 3 ) 2 - or -CH 2 NH-, and X 3 but, Adamantane ring, benzofuran, Halogen, -CH 3 , -CF 3 , -CHF 2 , -OCHF 2 , -CN, -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CHF 2 , -OCH 3 or cyclopentane; 1,4-CH 2 CH 2 Cyclohexane, optionally containing a bridge; Optionally, fluorine, chlorine, cyclohexane, -CH 3 , -OCHF 2 , benzene optionally containing halogen substituents, isobutyl, cyclopropyl, tert-butyl, methylpyrazole, -CH(CH 3 ) 2 or methylpiperidine; Methylpyrazole, cyclopropyl, or -CH 3 Pyridine, optionally containing at least one substituent independently selected from Naphthalene, or a compound which is a right-side substitution of a diazaspiroheptane core selected from isoquinolines which optionally contain at least one halogen substituent; or a pharma- ceutically acceptable salt thereof.

[0008] In one aspect, disclosed herein is a compound of formula (I) having a diazaspiroheptane core, [ka] In the formula, X 1 but, [ka] is a left-handed substitution on the diazaspiroheptane core selected from In the formula, R 1 But, -H, -CH 3 , -CH 2 OCH 3 , -CF 3 , -CH 2 CH 3 , or -(CH 2 ) 2 OCH 3 is selected from R 2 is -H, R 3 is -H, R 4 is -H or -CH 3 or R 1 and R 4 together form a cyclobutane, cyclopentane, or oxetane ring, R 5 But, -H, -CH 3 , -CH 2 OH, -COOCH 3 , -COOH, or -CH 2 OCH 3 is selected from R 6 is -H or -CH 3 or R 5 and R 6 together form an azetidine, pyrrolidine, morpholine, or piperidine ring, each of which is -CH 3 , -OH, -CF 3 or -F, R 7 is 1, 2, or 3, and -Cl, -F, -CF 3 , -CH 3 , -OCHF 2 , or -OCH 3 are independently selected from R 8 Benzene, -CH 3 or tert-butyl; R 9optionally at least one -F or -CH 3 cyclohexane, optionally substituted with -OH, or benzimidazole; R 10 cyclohexane or piperidine, optionally containing at least one substituent selected from -F or =O, -OCH 3 or cyclopentane, optionally containing an -OH substituent, tert-butyl, -CF 3 or cyclopropyl, optionally containing a methyl substituent; A 1 is selected from -CH or -N; A 2 is independently selected from -CH, -N, or -O; and A 3 But, -O, CH 2 , or CF 2 is selected from X 2 But -CH 2 CONH-, -CH 2 -, -CH 2 NHCO-, -CH 2 NHCOCH 2 -, -CH 2 NHCO(CH 2 ) 2 -, -NHCO-, -NHCH 2 CONH-, -N(CH 3 )CH 2 CONH-, -CH 2 N(CH 3 )CO-, -CONH-, -CONHCH 2 -, CONHCH 2 C(CH 2 CH 3 ) 2 - or -CH 2 NH-, and X 3 but, Adamantane ring, benzofuran, Halogen, -CH 3 , -CF 3 , -CHF 2 , -OCHF 2, -CN, -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CHF 2 , -OCH 3 or cyclopentane; 1,4-CH 2 CH 2 Cyclohexane, optionally containing a bridge; Optionally, chlorine, cyclohexane, -CH 3 , benzene optionally containing halogen substituents, isobutyl, cyclopropyl, tert-butyl, methylpyrazole, -CH(CH 3 ) 2 or methylpiperidine; Methylpyrazole, cyclopropyl, or -CH 3 Pyridine, optionally containing at least one substituent independently selected from Naphthalene, or a compound which is a right-side substitution of a diazaspiroheptane core selected from isoquinolines which optionally contain at least one halogen substituent; or a pharma- ceutically acceptable salt thereof.

[0009] In certain embodiments, the compound of formula (I) is: [ka] [ka] [ka] and pharma- ceutically acceptable salts thereof.

[0010] In certain embodiments, the compound of formula (IA) is: [ka] and pharma- ceutically acceptable salts thereof.

[0011] In certain embodiments of the compounds disclosed herein, X 1 is formula (a), and in certain embodiments, R 1 , R 4 , and R 5 Each of 3 In a further embodiment, R of formula (a) is 2 , R 3 , and R 6 Each of X is -H. In certain embodiments, 2 is -CH 2 CONH- or -CH 2 -, and in certain embodiments, X 2 is -CONH-. In certain embodiments, R 9 is a cyclohexane having two halogen substituents, such as two fluorine substituents.

[0012] In certain embodiments of all aspects, X 3 is an adamantane ring, and in certain embodiments, X 3 is phenyl. X 3 In certain embodiments, X is phenyl, and the phenyl group comprises at least one halogen substituent, such as at least two halogen substituents, and in certain embodiments, the at least one halogen is selected from fluorine or chlorine. 3 is phenyl containing fluorine and chlorine substituents.

[0013] In certain embodiments of the compounds disclosed herein, the compounds include at least one deuterium, and in certain embodiments, the at least one deuterium is selected from the group consisting of X 1 is located.

[0014] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of formula (I) or formula (IA) disclosed herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In certain aspects, the pharmaceutical composition further comprises a release modifying polymer, such as hydroxypropylmethylcellulose, ethylcellulose, or a polyacrylate polymer.

[0015] In yet another aspect, disclosed herein is a method for treating a disease or condition associated with abnormal function or activity of T-type calcium channels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (IA) disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In certain aspects, the disease or condition associated with abnormal function or activity of T-type calcium channels is psychiatric disorder, pain, tremor, seizures, epilepsy, or epilepsy syndrome. In certain embodiments, the disease or condition associated with abnormal function or activity of T-type calcium channels is tremor, such as essential tremor.

[0016] In yet another aspect, disclosed herein is a compound of formula (I) or formula (IA) disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or condition associated with abnormal function or activity of T-type calcium channels. In certain aspects, the disease or condition associated with abnormal function or activity of T-type calcium channels is psychiatric disorder, pain, tremor, seizures, epilepsy, or epilepsy syndrome. In certain embodiments, the disease or condition associated with abnormal function or activity of T-type calcium channels is tremor, such as essential tremor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Disclosed herein are compounds and compositions useful for the prevention and / or treatment of pain, tremor (e.g., essential tremor), epilepsy, or epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy). The compounds and compositions disclosed herein may also be useful for the prevention and / or treatment of psychiatric disorders. Psychiatric disorders may include, for example, mood disorders such as depression, major depressive disorder, and mood disorders (e.g., minor depression); bipolar disorder (e.g., type I and / or type II); anxiety disorders (e.g., generalized anxiety disorder (GAD) and social anxiety disorder); stress; post-traumatic stress disorder (PTSD); and compulsive disorder (e.g., obsessive compulsive disorder, OCD). Methods useful for modulating the function and enhancing the efficacy of T-type calcium channels are also presented.

[0018] definition In order to make this disclosure more readily understandable, certain terms are first defined below. Additional definitions of the following terms, as well as other terms, may be set forth throughout the specification. In the event that a definition of a term set forth below conflicts with a definition in an application or patent incorporated by reference, the definition set forth in this application shall be used to understand the meaning of the term.

[0019] As used herein, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compounds disclosed herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health, and condition of the subject.The effective amount includes therapeutic and prophylactic treatment.

[0020] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0021] As used herein, the term "refractory" refers to a disease, disorder, or condition that does not readily succumb or respond to a therapy or treatment, or is not controlled by a therapy or treatment. In some embodiments, the disease, disorder, or condition described herein is refractory (e.g., refractory epilepsy or refractory absence seizures) and does not respond to standard therapies or treatments.

[0022] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents), or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human" and "patient" are used interchangeably herein.

[0023] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0024] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions performed while a subject is afflicted with a specified disease, disorder, or condition that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as actions performed before a subject begins to suffer from the specified disease, disorder, or condition.

[0025] As used herein, the terms "in some embodiments," "in other embodiments," and the like refer to embodiments of all aspects of the disclosure unless the context clearly indicates otherwise.

[0026] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 7th Edition, John Wiley & Sons, Inc., New York, 2013; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004.

[0027] The compounds described herein may contain one or more asymmetric centers and therefore may exist in the form of various isomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Race mates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). In certain embodiments, the compounds described herein may be individual isomers substantially free of other isomers, or may be mixtures of various isomers.

[0028] As used herein, an enantiomerically pure compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of an enantiomer. In certain embodiments, these weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0029] In the compositions provided herein, the enantiomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound may comprise, for example, about 90% of excipients and about 10% of an enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may comprise, for example, at least about 95% by weight of the R compound and at most about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may comprise, for example, at least about 95% by weight of the S compound and at most about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0030] The compounds described herein may also contain one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and 3H may be any isotope, including T or tritium. C may be 12 C. 13 C, and 14 C may be any isotope, including O. 16 O and 18 It may be any isotope, including O, etc.

[0031] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present disclosure. In describing certain aspects of the present disclosure, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. It should also be understood that, as described herein, any of the moieties defined below may be substituted with a variety of substituents, and each definition is intended to include such substituted moieties within their scope as described below. Unless otherwise indicated, the term "substituted" is as defined below. It should further be understood that the terms "group" and "radical" may be considered interchangeable as used herein. The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0032] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0033] "Alkyl" refers to, for example, the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom (C 1 Alkyl). C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0034] "Alkenyl" refers to the radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and, optionally, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 In certain embodiments, an alkenyl does not contain a triple bond. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C 2 The carbon-carbon double bond or bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups, as well as pentenyl (C5 ), pentadienyl (C 5 ), hexenyl (C 6 Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ) etc.

[0035] "Alkynyl" refers to the radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 In certain embodiments, alkynyl does not contain a double bond. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C 2 The carbon-carbon triple bond(s) may be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Additional examples of alkynyl include heptynyl (C 7 ), Octynyl (C 8 ) etc.

[0036] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared within the cyclic array) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C 6 aryl" (e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl", e.g., anthracyl). "Aryl" also includes ring systems in which the aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such instances the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0037] "Hetero", when used to describe a compound or a group present in a compound, means that one or more carbon atoms in the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the above alkyl groups, such as alkyl, e.g., heteroalkyl; alkenyl, e.g., heteroalkenyl; alkynyl, e.g., heteroalkynyl; carbocyclyl, e.g., heterocyclyl; aryl, e.g., heteroaryl, having 1 to 5, especially 1 to 3, heteroatoms.

[0038] "Heteroaryl" refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared within the cyclic array) having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in such instances the number of ring members continues to specify the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, and in such instances the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring bearing a heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0039] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having ring carbon atoms provided in the aromatic ring system and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0040] As used herein, "carbocyclyl" or "carbocyclic" refers to a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Exemplary C 3-6 The carbocyclyl group is cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like. Exemplary C 3-5 The carbocyclyl group is the aforementioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and the like. Exemplary C 3-10 The carbocyclyl group is the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 As the foregoing examples illustrate, in certain embodiments, a carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl"), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclyl ring, in such instances the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[0041] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system ("3- to 10-membered heterocyclyl") having ring carbon atoms and one to four ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, where valence permits. Heterocyclyl groups may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), which may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or heterocyclyl ring or ring system, and a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, in such instances the number of ring members continues to specify the number of ring members in the heterocyclyl ring system.

[0042] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0043] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. (Also referred to herein as 5,6-bicyclic heterocyclic rings) C 6 Exemplary 5-membered heterocyclyl groups fused to an aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0044] The term "optionally substituted with --O--" refers to an alkyl or cycloalkyl group in which a carbon atom in the carbon chain is replaced with an oxygen atom.

[0045] The term "optionally substituted with -N-" refers to an alkyl or cycloalkyl group in which a carbon atom in the carbon chain is replaced with a nitrogen atom.

[0046] "Cyano" refers to -CN.

[0047] "Halo" or "halogen" refers to fluorine atoms (i.e., fluoro or -F), chlorine atoms (i.e., chloro or -Cl), bromine atoms (i.e., bromo or -Br), and iodine atoms (i.e., iodo or -I). In certain embodiments, the halo group is fluoro or chloro.

[0048] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0049] "Nitro" is -NO 2 Refers to...

[0050] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions in the group, and when more than one position in any given structure is substituted, the substituents are either the same or different at each position.

[0051] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electron neutrality. Exemplary counterions include halide ions (e.g., F- , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HSO 4 - , S.O. 4 - , sulfonate ions (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.), and carboxylate ions (e.g., acetic acid, ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, etc.).

[0052] The term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. The general concept of pharmaceutically acceptable salts has been discussed in the art, including, for example, Berge et al., J Pharmaceutical Sciences (1977) 66:1-19, which describes pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Pharmaceutically acceptable salts include, but are not limited to, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Alkyl) 4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0053] The term "release modifying polymer" refers to a polymer used in formulations (e.g., tablets and capsules) to modify the release rate of a drug upon administration to a subject. For example, release modifying polymers are used to dissolve a drug over time so that it is released more slowly and steadily into the bloodstream. For example, the release modifying polymer is a sustained release polymer. For example, the release modifying polymer or sustained release polymer is an HPMC polymer. In some embodiments, the release modifying polymer may include a hydrophilic matrix polymer (e.g., hypromellose, hydroxyl-propylmethylcellulose (HPMC)), a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit® RL100, Eudragit® RS100).

[0054] As used herein, the term "diluent" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starches (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dibasic calcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0055] As used herein, the term "lubricant" refers to an excipient used to promote powder flow by reducing interparticle friction and cohesion. For example, lubricants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0056] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from clumping together and sticking to tablet punches or capsule filling machines. Lubricants are also used to ensure that tablet formation and ejection can occur with low friction between the solids and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silica, and fats (e.g., vegetable stearin).

[0057] As used herein, the term "coating" refers to an excipient that protects the tablet ingredients from deterioration due to moisture in the air and makes large or unpleasant tasting tablets easier to swallow.

[0058] The embodiments disclosed herein are not intended to be limited in any way by the recitation of exemplary chemical groups and substituents above.

[0059] compound In one aspect, disclosed herein are compounds and compositions thereof for the modulation of T-type calcium channels and diseases, disorders, or conditions associated with their abnormal functioning (e.g., psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)); pain; tremors, such as essential tremor; epilepsy or epileptic seizures, such as absence seizures, juvenile myoclonic epilepsy, status epilepticus, or genetic epilepsy).

[0060] In some embodiments, the compounds disclosed herein are compounds of formula (IA) having a diazaspiroheptane core: [ka] In the formula, X 1 but, [ka] is a left-handed substitution on the diazaspiroheptane core selected from In the formula, R 1But, -H, -CH 3 , -CH 2 OCH 3 , -CF 3 , -CH 2 CH 3 , or -(CH 2 ) 2 OCH 3 is selected from R 2 is -H, R 3 is -H, R 4 is -H or -CH 3 or R 1 and R 4 together form a cyclopropane, cyclobutane, cyclopentane, or oxetane ring, R 5 But, -H, -CH 3 , -CF3, -CH 2 OH, -COOCH 3 , -COOH, or -CH 2 OCH 3 is selected from R 6 is -H or -CH 3 or R 5 and R 6 together form an azetidine, pyrrolidine, morpholine, or piperidine ring, each of which is -CH 3 , -OH, -CF 3 or -F, R 7 is 1, 2, or 3, and -Cl, -F, -CF 3 , -CH 3 , -OCHF 2 , or -OCH 3 are independently selected from R 8 Benzene, -CH 3 or tert-butyl; R 9 optionally at least one -F or -CH 3cyclohexane, optionally substituted with -O-, or benzimidazole; R 10 But -C(CH 3 ) 3 , cyclopentyl, -(CH 2 )C(CH 3 ) 3 or cyclohexane optionally substituted with -N- and optionally containing at least one substituent selected from -F or =O, -OCH 3 or cyclopentane, optionally containing an -OH substituent, tert-butyl, -CF 3 or cyclopropyl, optionally containing a methyl substituent; A 1 is selected from -CH or -N; A 2 is independently selected from -CH, -N, or -O; and A 3 But, -O, CH 2 , or CF 2 is selected from X 2 But -CH 2 CONH-, -CH 2 -, -CH 2 NHCO-, -CH 2 NHCOCH 2 -, -CH 2 NHCO(CH 2 ) 2 -, -NHCO-, -NHCH 2 CONH-, -N(CH 3 )CH 2 CONH-, -CH 2 N(CH 3 )CO-, -CONH-, -CONHCH 2 -, CONHCH 2 C(CH 2 CH 3 ) 2 - or -CH 2 NH-, and X 3 but, Adamantane ring, benzofuran, Halogen, -CH 3, -CF 3 , -CHF 2 , -OCHF 2 , -CN, -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CHF 2 , -OCH 3 or cyclopentane; 1,4-CH 2 CH 2 Cyclohexane, optionally containing a bridge; Optionally, fluorine, chlorine, cyclohexane, -CH 3 , -OCHF 2 , benzene optionally containing halogen substituents, isobutyl, cyclopropyl, tert-butyl, methylpyrazole, -CH(CH 3 ) 2 or methylpiperidine; Methylpyrazole, cyclopropyl, or -CH 3 Pyridine, optionally containing at least one substituent independently selected from Naphthalene, or a compound which is a right-side substitution of a diazaspiroheptane core selected from isoquinolines which optionally contain at least one halogen substituent;

[0061] or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the compounds disclosed herein are compounds of formula (I) having a diazaspiroheptane core, [ka] In the formula, X 1 but, [ka] is a left-handed substitution on the diazaspiroheptane core selected from In the formula, R 1 But, -H, -CH 3 , -CH 2 OCH 3 , -CF 3 , -CH 2 CH 3 , or -(CH 2 ) 2 OCH 3 is selected from R 2 is -H, R 3 is -H, R 4 is -H or -CH 3 or R 1 and R 4 together form a cyclobutane, cyclopentane, or oxetane ring, R 5 But, -H, -CH 3 , -CH 2 OH, -COOCH 3 , -COOH, or -CH 2 OCH 3 is selected from R 6 is -H or -CH 3 or R 5 and R 6 together form an azetidine, pyrrolidine, morpholine, or piperidine ring, each of which is -CH 3 , -OH, -CF 3 or -F, R 7 is 1, 2, or 3, and -Cl, -F, -CF 3 , -CH 3 , -OCHF 2 , or -OCH 3 are independently selected from R 8 Benzene, -CH 3 or tert-butyl; R 9optionally at least one -F or -CH 3 cyclohexane, optionally substituted with -O-, or benzimidazole; R 10 cyclohexane, optionally substituted with -N- and optionally containing at least one substituent selected from -F or =O, -OCH 3 or cyclopentane, optionally containing an -OH substituent, tert-butyl, -CF 3 or cyclopropyl, optionally containing a methyl substituent; A 1 is selected from -CH or -N; A 2 is independently selected from -CH, -N, or -O; and A 3 But, -O, CH 2 , or CF 2 is selected from X 2 But -CH 2 CONH-, -CH 2 -, -CH 2 NHCO-, -CH 2 NHCOCH 2 -, -CH 2 NHCO(CH 2 ) 2 -, -NHCO-, -NHCH 2 CONH-, -N(CH 3 )CH 2 CONH-, -CH 2 N(CH 3 )CO-, -CONH-, -CONHCH 2 -, CONHCH 2 C(CH 2 CH 3 ) 2 - or -CH 2 NH-, and X 3 but, Adamantane ring, benzofuran, Halogen, -CH 3 , -CF 3 , -CHF 2 , -OCHF2 , -CN, -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CHF 2 , -OCH 3 or cyclopentane; 1,4-CH 2 CH 2 Cyclohexane, optionally containing a bridge; Optionally, chlorine, cyclohexane, -CH 3 , benzene optionally containing halogen substituents, isobutyl, cyclopropyl, tert-butyl, methylpyrazole, -CH(CH 3 ) 2 or methylpiperidine; Methylpyrazole, cyclopropyl, or -CH 3 Pyridine, optionally containing at least one substituent independently selected from Naphthalene, or a compound which is a right-side substitution of a diazaspiroheptane core selected from isoquinolines which optionally contain at least one halogen substituent; or a pharma- ceutically acceptable salt thereof.

[0063] In certain embodiments, X 1 is formula (a), and R 2 , R 3 , and R 6 is -H, and in certain embodiments, R 1 , R 5 , and R 6 Ha-CH 3 In certain embodiments, X 2 is -CH 2 CONH- or -CH 2 -, and in certain embodiments, X 2 X 2 is -CH 2 In certain embodiments, X3 is an adamantane ring, and in certain embodiments, X 3 is a phenyl group, e.g., a phenyl group that includes at least two halogen substituents. In certain embodiments, the halogen substituents can be selected from chlorine, fluorine, or any combination thereof. In certain embodiments, R 9 is a cyclohexane having two halogen substituents, such as two fluorine substituents.

[0064] In certain embodiments, the compounds disclosed herein are compounds of formula (I) having the structure depicted below: [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0065] In another embodiment, the compounds disclosed herein are compounds of formula (IA) having the structure depicted below: [ka] or a pharma- ceutically acceptable salt thereof.

[0066] composition In one aspect, the compound of Formula (I) or Formula (IA), or a pharma- ceutically acceptable salt thereof, can be a pharmaceutical composition, such as a dosage form. As used herein, the terms pharmaceutical composition and dosage form can be used interchangeably.

[0067] In some embodiments, the compositions that can be used in the methods described herein can be pharmaceutical compositions that include a compound of formula (I) or formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof, and an excipient that functions to modify the release rate of the compound of formula (I) or formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition can be a swellable core technology formulation.

[0068] In certain embodiments, the dosage form that can be used in the methods described herein can be a dosage form, such as an oral dosage form, that includes a compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof, and a release modifying polymer (e.g., a release controlling polymer, a hydrophilic matrix polymer, e.g., an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit® RL100, Eudragit® RS100)) in an amount sufficient to modify the release rate of the compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof.

[0069] In some embodiments, the dosage form comprises from about 0.9% to about 40% by weight (e.g., from about 0.9% to about 30% by weight, from about 1% to about 25% by weight, from about 2% to about 25% by weight, from about 3% to about 20% by weight, from about 4% to about 20% by weight, from about 5% to about 20% by weight, from about 5% to about 15% by weight, from about 5% to about 10% by weight, or from about 0.9% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or from about 10% by weight. %, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 40% by weight of a compound of formula (I) or formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 30% to about 40% by weight of a compound of formula (I) or formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof.

[0070] In some embodiments, the dosage form may contain from about 4% to about 25% by weight, such as, for example, about 19% to about 20% by weight, about 21% to about 22% by weight, about 4% to about 15% by weight, about 4% to about 10% by weight, about 4% to about 5% by weight, about 5% to about 6% by weight, or about 9% to about 10% by weight of a compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof.

[0071] In some embodiments, a dosage form that can be used in the methods described herein can be a dosage form or composition that contains about 0 mg to about 60 mg (e.g., about 1 mg to about 20 mg, about 5 mg to about 25 mg, about 10 mg to about 30 mg, about 15 mg to about 35 mg, about 20 mg to about 40 mg, about 25 mg to about 55 mg, or about 30 mg to about 60 mg of a compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof. In other embodiments, a dosage form that can be used in the methods described herein can be a dosage form or composition that contains about 1 mg to about 60 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg) of a compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof, and a release modifying polymer (e.g., a sustained release polymer and a release modifying polymer (e.g., a controlled release polymer, a hydrophilic matrix polymer, e.g., an HPMC polymer, a hydrophobic matrix polymer (e.g., ethylcellulose, Ethocel), or a polyacrylate polymer (e.g., Eudragit® RL100, Eudragit® RS100)) in an amount sufficient to modify the release rate of the compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof, e.g., upon administration to a subject.

[0072] In other embodiments, the dosage form contains about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof. In certain embodiments, the dosage form contains about 15 mg to about 45 mg (e.g., about 20 mg) of a compound of formula (I) or formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof, such as about 5 mg to about 15 mg (e.g., about 10 mg), about 15 mg to about 25 mg, about 25 mg to about 35 mg (e.g., about 30 mg), or about 35 mg to about 45 mg (e.g., about 40 mg).

[0073] In some embodiments, the dosage form comprises about 55 mg to 65 mg of a release modifying polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 10% to about 70% by weight of a release modifying polymer (e.g., an HPMC polymer). In some embodiments, the dosage form comprises about 50% to about 60% by weight of a release modifying polymer (e.g., an HPMC polymer).

[0074] In some embodiments, the dosage form further comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the dosage form comprises about 15 mg to about 40 mg of microcrystalline cellulose (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 40 mg). In some embodiments, the dosage form comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 15% by weight to about 35% by weight (e.g., about 15% by weight to about 20% by weight, about 20% by weight to about 25% by weight, 25% by weight to about 30% by weight, or 30% by weight to about 35% by weight).

[0075] In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises colloidal silicon dioxide. In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the dosage form further comprises a coating agent.

[0076] In some embodiments, upon administration to a subject, about 80% of the compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof is released within 7 hours. In certain embodiments, about 80% of the compound of Formula (I) or Formula (IA) disclosed herein or a pharma- ceutically acceptable salt thereof is released in 7 hours using a USP Apparatus Type I, medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

[0077] In some embodiments, the dosage form, upon administration to a subject, has a lower C than a reference oral dosage form (e.g., a dosage form that does not have any intended release rate profile (e.g., a dosage form that does not have a modified release rate profile or a dosage form that does not have a modified release polymer, e.g., an HPMC polymer)). max In some embodiments, the dosage form, upon administration to a subject, has a higher t value than a reference oral dosage form (e.g., a dosage form that does not have any intended release rate profile (e.g., a dosage form that does not have a modified release rate profile or a dosage form that does not have a modified release polymer, e.g., an HPMC polymer)). max It has a value.

[0078] In other embodiments, the dosage form is administered to a patient once daily. In certain embodiments, the dosage form is administered to a patient twice daily. In some embodiments, the dosage form is a tablet. In other embodiments, the dosage form is a capsule. In certain embodiments, the dosage form is a suspension.

[0079] In some embodiments, a dosage form that can be used in the methods described herein may be an oral dosage form (e.g., microparticles) comprising about 15 mg to 25 mg of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof, and about 55 mg to 65 mg of an HPMC polymer.

[0080] In other embodiments, the dosage form that can be used in the methods described herein may be an oral dosage form (e.g., microparticles) comprising about 14% to about 25% by weight of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof, and about 53% to about 64% by weight of an HPMC polymer.

[0081] In certain embodiments, a dosage form that can be used in the methods described herein may be an oral dosage form (e.g., microparticles) comprising about 3 mg to 8 mg of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof, and about 55 mg to 65 mg of an HPMC polymer.

[0082] In some embodiments, a dosage form that can be used in the methods described herein may be an oral dosage form (e.g., microparticles) comprising about 3% to about 8% by weight of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof, and about 53% to about 64% by weight of an HPMC polymer.

[0083] In other embodiments, the dosage form that can be used in the methods described herein can be an oral (e.g., microparticle) composition comprising a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof and a release modifying polymer (e.g., a sustained release polymer, e.g., an HPMC polymer as a hydrophilic matrix polymer).

[0084] In some embodiments, the composition comprises about 0.9% to about 40% by weight of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 14% to about 25%, about 19% to about 20%, about 21% to about 22%, about 4% to about 15%, about 4% to about 10%, about 4% to about 5%, about 5% to about 6%, or about 9% to about 10% by weight of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, the composition comprises about 1 mg to about 60 mg (e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg) of a compound of formula (I) or formula (IA) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the composition comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of formula (I) or formula (IA) or a pharma- ceutically acceptable salt thereof. In other embodiments, the composition comprises about 15 mg to about 25 mg (e.g., about 20 mg) of a compound of formula (I) or formula (IA) or a pharma- ceutically acceptable salt thereof.

[0086] In some embodiments, the composition includes a diluent. In some embodiments, the diluent includes microcrystalline cellulose. In other embodiments, the composition includes about 15 mg to about 40 mg (e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 40 mg) of microcrystalline cellulose. In some embodiments, the composition includes about 15% by weight to about 35% by weight (e.g., about 15% by weight to about 20% by weight, about 20% by weight to about 25% by weight, 25% by weight to about 30% by weight, or 30% by weight to about 35% by weight) of microcrystalline cellulose.

[0087] In some embodiments, the composition comprises about 15 mg to about 25 mg of microcrystalline cellulose. In some embodiments, the composition comprises about 30 mg to about 40 mg of microcrystalline cellulose. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises colloidal silicon dioxide. In some embodiments, the composition further comprises a lubricant. In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the composition further comprises a coating agent. In some embodiments, the compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof is stable in the composition at about 25°C and 60% relative humidity for at least 24 months. In some embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 36 months. In some embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at about 25°C and 60% relative humidity for at least 60 months. In some embodiments, the compounds are stable at about 40° C. and 75% relative humidity for at least 6 months.

[0088] Immediate-release formulations In some embodiments, a dosage form or composition that can be used in the methods described herein can be a dosage form or composition that comprises a compound of Formula (I) or Formula (IA), or a pharma- ceutically acceptable salt thereof, and that releases the compound of Formula (I) or Formula (IA), or a pharma- ceutically acceptable salt thereof, immediately after administration to a subject.

[0089] In other embodiments, a dosage form that can be used in the methods described herein can be an oral capsule for immediate release comprising about 15 mg to about 20 mg of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof, and about 75 mg to 85 mg of a diluent; about 2 mg to 10 mg of a binder; about 1% to about 5% disintegrant; and about 0.1 mg to 5 mg of a lubricant.

[0090] Administration In one aspect, the compounds, compositions, dosage forms, etc. described herein can be administered to a subject. In some embodiments, the dosage forms are administered to a subject more than once a day (e.g., twice a day, three times a day, or four times a day).

[0091] In some embodiments, the dosage form is administered to the subject once a day (e.g., one 20 mg tablet once a day, two 20 mg tablets once a day, or three 20 mg tablets once a day). In some embodiments, the dosage form is administered to the subject twice a day (e.g., one 10 mg tablet twice a day, one 20 mg tablet twice a day, two 20 mg tablets twice a day, or three 20 mg tablets twice a day). In some embodiments, the dosage form is administered to the subject every other day. In certain embodiments, about 1 mg to 60 mg, such as 20 mg to 40 mg, of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof is administered to the subject daily. In other embodiments, about 15 mg to about 25 mg of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof is administered to the subject daily. In certain embodiments, about 30 mg to about 40 mg of a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof is administered to a subject daily.

[0092] The compounds provided according to the present invention are usually administered in the form of a pharmaceutical composition. Thus, the present invention provides pharmaceutical compositions containing, as an active ingredient, one or more of the compounds described, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutical acceptable excipients, carriers including inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. General techniques for preparing pharmaceutical compositions are disclosed in the pharmaceutical art (e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17). th Ed.(1985), and Modern Pharmaceutics, Marcel Dekker, Inc.3 rd Ed. (See G.S. Banker & C.T. Rhodes, Eds.).

[0093] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration for drugs, for example, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, including rectal, buccal, intranasal, and transdermal routes, as an inhalant, or via impregnated or coated devices such as, for example, stents or arterially inserted cylindrical polymers, having similar utilities as those described in those patents and patent applications incorporated by reference.

[0094] In some embodiments, the compounds and compositions described herein are administered orally. The compounds or compositions thereof may be formulated in liquid or oral dosage forms. Administration may be via capsules or tablets (e.g., enteric coated tablets), and the like. In making pharmaceutical compositions containing at least one compound described herein, the active ingredient is usually diluted by an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of a tablet, pill, powder, lozenge, sachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), or ointment (e.g., containing up to 10% by weight of the active compound), or capsule (e.g., soft or hard gelatin capsule).

[0095] In some embodiments, the compounds and compositions described herein are administered parenterally, for example, by injection or intravenously. The compounds or compositions thereof may be formulated in a liquid dosage form and may include one or more excipients.

[0096] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulations can further include lubricants such as talc, magnesium stearate, and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxy-benzoates, sweeteners, and flavoring agents.

[0097] The compositions disclosed herein can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are described in U.S. Pat. Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds disclosed herein in controlled amounts. The general construction and use of transdermal patches for delivery of pharmaceutical agents has been described in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0098] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compound is generally administered in a pharma- ceutical effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably, 0.1 to 700 mg of a compound described herein. However, it will be understood that the amount of compound actually administered will usually be determined by the physician in view of the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0099] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogenous mixture of the compounds disclosed herein. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0100] The tablets or pills disclosed herein may be coated or otherwise compounded to provide a dosage form that provides sustained release benefits or to protect against the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be released in a delayed manner. A variety of materials may be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0101] Methods for Treating Diseases or Conditions Associated with Abnormal Function or Activity of T-Type Calcium Channels In one aspect, the disclosure provides a method of treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (IA) disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, daily (e.g., once, twice, three times). The disclosure also provides a therapeutically effective amount of a compound of formula (I) or formula (IA) disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for use in treating a disease or condition associated with abnormal function or activity of a T-type calcium channel in a subject in need thereof.

[0102] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein, as well as pharma- ceutically acceptable salts, tautomers, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes pharma- ceutically acceptable addition salts, hydrates of addition salts, tautomers, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or stereoisomeric compounds (pure or as racemic or non-racemic mixtures) of the compounds described herein. In all embodiments of the methods disclosed herein, the compounds may be in the form of compositions, including pharmaceutical compositions or dosage forms.

[0103] Epilepsy and epilepsy syndromes The compositions described herein are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a central nervous system disorder in which neuronal activity in the brain becomes disrupted, causing repeated seizures that may manifest as abnormal movements, periods of unusual behavior, agitation, and sometimes loss of consciousness. Seizure symptoms vary widely, from a simple blank stare for a few seconds to repeated twitching of the arms or legs during a seizure.

[0104] Epilepsy may include generalized seizures, which involve multiple areas of the brain, or partial or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may scream or make some noise, stiffen for a few seconds to a minute, and then have rhythmic movements of the limbs. The eyes may be open and / or the person may appear not to be breathing and turn blue. Return of consciousness may be gradual and the person may be confused for minutes to hours. The main types of generalized seizures are: tonic-clonic, tonic-clonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, and absence (typical, atypical, myoclonic, lid myoclonic) seizures, and epileptic spasms. Partial or focal seizures involve only a part of the brain and therefore only one part of the body is affected. Symptoms can vary, depending on the part of the brain that has abnormal electrical activity.

[0105] Epilepsy as described herein includes generalized, partial, complex partial (e.g., seizures involving only part of the brain, but in which consciousness is impaired), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0106] The compositions described herein can also be useful in treating epilepsy syndromes.Severe syndromes with diffuse brain dysfunction caused at least in part by some aspects of epilepsy are also called epileptic encephalopathies.They are associated with frequent seizures that are resistant to treatment, and severe cognitive impairment, such as West syndrome.

[0107] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with a mutation in a gene encoding a T-type calcium channel (e.g., CACNA1G, EEF1A2, and GABRG2 for genetic generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)), as discussed, for example, in Feng, YCA, et al., “Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals,” Am. J. Human Gen. 2019; 105(2): 267-282. In some embodiments, the epilepsy syndrome is Dawes syndrome or myoclonus-astatic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spike-and-wave sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0108] Absence seizures Absence seizures are one of the most common seizure types in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsia 2000). Absence seizures are relatively short, nonconvulsive seizures characterized by the sudden onset of loss of consciousness and responsiveness, usually lasting 10-30 seconds, with a rapid return to normal consciousness without postictal confusion. Seizures are characterized by the sudden onset and disappearance of generalized 1-6 Hz (e.g., 3 Hz) spike-wave discharges in the accompanying EEG recording. Absence seizures often occur multiple times per day, disrupting learning and psychosocial functioning, and presenting a risk of injury due to the frequent episodes of loss of consciousness. Typically, absence seizures begin in early childhood and remit by the late teenage years. However, in a minority of patients, they persist into adulthood, where they are often drug-resistant, and may be associated with other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures, in particular, are usually highly disabling and are associated with significant psychosocial impairments, as the accompanying periods during which the affected individual is unconscious pose a safety risk and disqualify them from obtaining a driver's license or pursuing occupations and hobbies (Wirrell et al., 1997).

[0109] Although there is a general perception that absence seizures are relatively "easy" to treat, randomized controlled trials in patients with childhood absence epilepsy showed that even the most effective antiepileptic drugs, ethosuximide and valproate, completely controlled seizures in only 53% and 58% of patients, respectively, at 16 weeks and in 45% and 44% of patients, respectively, at 12 months, as assessed by video-EEG recordings (Glauser et al., 2010). Lamotrigine, another antiepileptic drug commonly used to treat absence seizures, controlled seizures in only 29% of patients at 16 weeks and 21% of patients at 12 months. Furthermore, both ethosuximide and valproate are commonly associated with intolerable side effects (occurring in 24% of patients treated with either of these drugs) (Glauser et al., 2010), and the latter is now generally considered to be contraindicated in girls and women of childbearing age. Other treatment options for absence seizures are limited, with only benzodiazepines having established efficacy, which are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, and patients are often treated with multiple medications resulting in significant side effects without achieving seizure control.

[0110] There is ample evidence that low-threshold (T-type) calcium channels play a role in the generation and maintenance of absence seizures and are an important component of the oscillatory burst firing that occurs in thalamocortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the present disclosure is directed to a method for treating absence seizures with a composition comprising a compound of formula (I) or formula (IA) or a pharma- ceutically acceptable salt thereof as described herein. In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0111] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizures are atypical absence seizures. In some embodiments, the absence seizures include adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0112] In some embodiments, the methods described herein further include identifying a subject having absence seizures.

[0113] Hereditary epilepsy In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0114] In some embodiments, the methods described herein further comprise identifying the subject with epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy) prior to administration of a composition described herein.

[0115] In one aspect, disclosed herein is a method of treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile onset epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy), comprising administering a composition described herein to a subject in need thereof.

[0116] The compositions of the invention may also be used to treat epileptic encephalopathy, in which the subject is , KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0117] In some embodiments, the methods described herein include administering to the patient an amount of ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, ME, The method further includes identifying a subject having a mutation in one or more of F2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0118] The compositions of the invention may also be used to treat epileptic encephalopathy, in which the subject is: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM 1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GO SR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1 , KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SE RPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3 GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15,The patient has one or more mutations in ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0119] In some embodiments, the methods described herein include, but are not limited to, ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2(TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN 1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, L GI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PN KD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, S GCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STR ADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2,The method further includes identifying a subject having one or more mutations in CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0120] The compositions disclosed herein also include methods for treating ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRR S1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, K CNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3, NR2F1, NRXN1, PACS1, PCDH19, PIGA The present invention may be used to treat epileptic encephalopathies having mutations in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0121] In some embodiments, the methods described herein include, but are not limited to, ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FOXG2, FOXG3, FOXG4, FOXG5, FOXG6, FOXG7, FOXG8, FOXG9, FOXG10, FOXG11, FOXG12, FOXG23, FOXG14, FOXG15, FOXG16, FOXG17, FOXG28, FOXG18, FOXG19, FOXG29, FOXG10, FOXG11, FOXG12, FOXG15, FOXG16, FOXG17, FOXG18, FOXG19, FOXG20, FOXG19, FOXG10, FOXG11, FOXG12, FOXG13, FOXG14, FOXG15, FOXG16, FOXG17, FOXG18, FOXG19, FOXG19, FOXG19, FOXG19, FOXG19, FOXG19, FOXG10, FOXG10, FOXG11, FOXG11, RRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3, NR2F1, NRXN1, PACS1, PCDH19, PIGA The method further includes identifying a subject having a mutation in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0122] The compositions disclosed herein also include methods for treating cancer, including the treatment of cancer, for which the subject is at least one of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KC TD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT 1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC3 The present invention may be used to treat epileptic encephalopathies having mutations in one or more of the following genes: 5A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0123] In some embodiments, the methods described herein include any of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KC NT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, PO LG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC2 The method further includes identifying a subject having a mutation in one or more of: SLC1A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0124] Mood disorders Also provided herein are methods of using the compounds disclosed herein to treat psychiatric disorders such as mood disorders, for example, clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0125] Clinical depression, also known as major depression, major depressive disorder (MDD), major depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression may also have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects the way an individual feels, thinks, and behaves, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may struggle to carry out everyday activities and feel like life is not worth living.

[0126] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, emotional withdrawal from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0127] Postpartum depression (PND), also called postpartum depression (PPD), refers to a type of clinical depression that affects women after birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, episodes of crying, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0128] In some embodiments, the subject with PND also experienced depression or symptoms of depression during pregnancy. This depression is referred to herein as perinatal depression. In embodiments, the subject experiencing perinatal depression is at increased risk of experiencing PND.

[0129] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positive, significant weight gain or increased appetite. Patients suffering from AD may also have significant social impairment as a result of excessive sleep or drowsiness (hypersomnia), a feeling of heaviness in the legs, and hypersensitivity to perceived interpersonal rejection.

[0130] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, depressed mood that is more prominent than sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0131] Psychotic major depression (PMD) or psychotic depression specifically refers to a major depressive episode of a melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0132] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, unable to move, or exhibit purposeless or bizarre movements.

[0133] Seasonal Affective Disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that fall in the fall or winter.

[0134] Dysthymia refers to conditions related to unipolar depression in which the same physical and cognitive problems are manifested. These tend to be less severe but last longer (e.g., at least two years).

[0135] Dual depression refers to a significant depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0136] Depressive personality disorder (DPD) refers to a personality disorder that has depressive traits.

[0137] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting less than two weeks, typically less than two to three days.

[0138] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0139] Bipolar or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may feel or behave unusually happy, energetic, or irritable. They often make decisions with little consideration for the consequences. The need for sleep is usually reduced. During periods of depression, there may be crying, poor eye contact with others, and a negative outlook on life. The risk of suicide in those with the disorder is high at over 6% over a 20-year period, but self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0140] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition such as cancer, or chronic pain, chemotherapy, or chronic stress.

[0141] Treatment-resistant depression refers to a state where an individual is treated for depression, but symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve symptoms, but also relapse.Treatment-resistant depression occurs in patients who suffer from depression that is resistant to at least one standard pharmacological treatment (including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics) and non-pharmacological treatment (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0142] Postoperative depression refers to feelings of depression following a surgical procedure (e.g., as a result of having to face death). For example, an individual may experience persistent sadness or a feeling of emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0143] A mood disorder associated with a female health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a female health condition or disorder (e.g., as described herein).

[0144] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal obsession with suicide. The spectrum of suicidal ideation can vary widely, for example, from flashes of thought to reflective thoughts, detailed plans, role-playing, and / or unfinished attempts. Symptoms can include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, being preoccupied with death, feeling trapped or hopeless about the situation, increasing alcohol or drug use, doing dangerous or self-destructive things, saying goodbye to people as if they will never see each other again.

[0145] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, challenging exercise, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thinking or planning, excessive sleeping, overeating, loss of appetite, insomnia, self-harm, thoughts of suicide, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms and their relief may be confirmed by a doctor or psychologist (e.g., by a mental status examination).

[0146] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysthymic disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0147] In some embodiments, the method includes monitoring the subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression-Improvement scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total scale exhibited by the subject. The therapeutic effect can be evaluated over a particular treatment period. For example, the therapeutic effect can be determined by a reduction from baseline in the HAM-D total scale after administration of the compositions described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more after administration; or 1 day, 2 days, 14 days, 21 days, or 28 days after administration; or 1 week, 2 weeks, 3 weeks, or 4 weeks after administration; or 1 month, 2 months, 6 months, or 10 months after administration; or 1 year, 2 years, or lifetime).

[0148] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is 14 or greater and 18 or less. In some embodiments, the subject's baseline HAM-D total score is 19 or greater and 22 or less. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a compound or composition disclosed herein is about 0-10 (e.g., less than 10, 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the HAM-D total score after treatment with a compound or composition disclosed herein is less than 10, 7, 5, or 3. In some embodiments, the reduction in HAM-D total score is a reduction from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D total score of about 0-10 (e.g., less than 10, 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8) after treatment with a compound or composition disclosed herein. In some embodiments, the reduction in baseline HAM-D total score after treatment with a compound or composition disclosed herein is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50).In some embodiments, the percentage reduction in the baseline HAM-D total score after treatment with a compound or composition disclosed herein is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment with a compound or composition disclosed herein compared to the baseline HAM-D total score.

[0149] In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as measured by a reduction in HAM-D score within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours). In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within the first or second day of treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 14 days from the start of treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 21 days from the start of treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in HAM-D total score) within 28 days of initiating treatment with a compound or composition disclosed herein. In some embodiments, the therapeutic benefit is a reduction from baseline in HAM-D total score after treatment with a compound or composition disclosed herein. In some embodiments, the subject's HAM-D total score before treatment with a compound or composition disclosed herein is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound or composition disclosed herein is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a compound or composition disclosed herein is 14-18 (including borderline values). In some embodiments, the reduction in HAM-D total score after treatment of a subject with a compound or composition disclosed herein compared to the baseline HAM-D total score is at least 10.In some embodiments, the reduction in HAM-D total score after treating a subject with a compound or composition disclosed herein compared to a baseline HAM-D total score is at least 15. In some embodiments, the HAM-D total score associated with treating a subject with a compound or composition disclosed herein is equal to or less than a number in the range of 6 to 8. In some embodiments, the HAM-D total score associated with treating a subject with a compound or composition disclosed herein is equal to or less than 7.

[0150] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression-Improvement scale (CGI)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in CGI score at the end of the treatment period (e.g., 14 days after administration).

[0151] The therapeutic effect for major depressive disorder can be determined by the reduction of the Montgomery-Asberg Depression Rating Scale (MADRS) score presented by the subject. For example, the MADRS score can be reduced within 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The MADRS is a ten-item diagnostic questionnaire (related to externalized sadness, verbalized sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, inability to feel, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. In some embodiments, the therapeutic effect is the reduction of the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0152] pain The compounds and compositions described herein may be useful in the treatment of pain. In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0153] In some embodiments, the methods described herein further include identifying a subject having pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine) prior to administration of a dosage form or composition described herein (e.g., a dosage form or composition comprising a compound of Formula (I) or Formula (IA) or a pharma- ceutically acceptable salt thereof).

[0154] Tremor The methods described herein can be used to treat tremor, for example, the compounds or compositions disclosed herein can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, or rubral tremor. Tremor includes genetic, degenerative, and idiopathic disorders such as Wilson's disease (genetic), Parkinson's disease (degenerative), and essential tremor (idiopathic); metabolic diseases; peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced (tricyclic neuroleptics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be neuropathic tremor, and can be classified into physiological tremor, strong physiological tremor, essential tremor syndrome (including classic essential tremor), primary orthostatic tremor, task-specific and position-specific tremor, dystonic tremor, Parkinsonism tremor, cerebellar tremor, Holmes tremor (i.e., Rubral tremor), palatal tremor, tremor induced by toxins or drugs, and psychogenic tremor. Tremor can be familial tremor.

[0155] In some embodiments, a subject is selected for treatment with a compound of Formula (IA), a compound of Formula (I), or a pharmaceutical composition of a compound of Formula (IA) or Formula (I) because of a clinical diagnosis of essential tremor. In some embodiments, a subject selected for treatment with a compound of Formula (IA), a compound of Formula (I), or a pharmaceutical composition of a compound of Formula (IA) or Formula (I) has essential tremor but does not have intention tremor.

[0156] Tremor is an involuntary, rhythmic vibration of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0157] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after purposeful movement.Cerebellar tremor is caused by lesions or damage to the cerebellum or pathways, for example, from tumors, strokes, or other focal lesion diseases (e.g., multiple sclerosis), or neurodegenerative diseases.

[0158] Dystonic tremor occurs in individuals suffering from dystonia and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions.Dystonic tremor can affect any muscle in the body.Dystonic tremor occurs irregularly and can often be relieved by complete rest or certain sensory manipulations.

[0159] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, starting on one side of the body and progressing slowly, typically affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremor can decrease with age, but the severity can increase. Increased emotion, stress, fever, physical exhaustion, or hypoglycemia can induce tremors and / or increase their severity. Symptoms generally progress over time and can be visible and persistent after onset.

[0160] Orthostatic tremor is characterized by rapid (>12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. Spasms can be felt in the thighs and legs, and patients may shake uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0161] Parkinsonism tremor is caused by damage to structures in the brain that control movement. Parkinson's tremor is typically seen as a "pill-making" movement of the hand that may also affect the jaw, lips, legs, and trunk. Onset of Parkinson's tremor usually begins after age 60. Movements may begin in one leg or one side of the body and progress to include the other side.

[0162] Rubral tremor is characterized by a rough, slow tremor that can be present at rest, in position, and with will. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0163] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor.

[0164] The efficacy of the compounds or compositions disclosed herein for treating essential tremor can be measured by methods known to those skilled in the art, such as those described in the following references: Ferreira, JJ et al., "MDS Evidence-Based Review of Treatments for Essential Tremor," Mov. Disord. 2019 July; 34(7): 950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor," Mov. Disord. 2013 November; 28(13): 1793-800; Deuschl G. et al., "Treatment of patients with essential tremor," Lancet Neurol. 2011; 10: 148-61; and Reich SGet al., "Essential Tremor," Med. Clin. N. Am. 2019; 103: 351-356. The disclosures of the references are incorporated herein in their entirety.

[0165] In some embodiments, the methods described herein result in at least a 25% reduction in upper extremity tremor score, which may be converted to amplitude, compared to baseline. For example, in certain embodiments, the methods described herein result in an average reduction of about 40% in tremor amplitude as measured by the Essential Tremor Rating Scale (TETRAS) upper extremity score, e.g., as described in Elble, RJ, "The Essential Tremor Rating Assessment Scale," J. Neurol. Neuromed. 2016; 1(4): 34-38. In some embodiments, the methods described herein result in at least a 25% reduction in TETRAS performance score, compared to baseline. In some embodiments, the methods described herein result in an average reduction of at least a 35% reduction in symptom severity, as measured by TETRAS performance score, compared to baseline.

[0166] ataxia Ataxia, including both cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally accompanied by a loss or failure of coordination. Patients with ataxia may have difficulty controlling the force, range, direction, speed, and rhythm involved in posture, balance, and limb movements. Trunk ataxia may, for example, result in increased postural sway and an inability to maintain the center of gravity over the base of support. Ataxia and primary or secondary symptoms of ataxic gait and leg tremor may be accompanied by speech disorders, dysphagia, abnormal ventilation and speech, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, which may substantially interfere with activities of daily living.

[0167] As mentioned above, ataxia can result from a wide variety of underlying diseases and conditions in a patient, including cerebellar and neurodegenerative disorders and diseases resulting from chronic or long-term exposure to toxins. Ataxic symptoms can result from a wide variety of diseases, disorders, and environmental factors, including infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol), among others, and in one embodiment, for example, ataxia is the result of a metabolic disease, a neurodegenerative disease, a vascular disease, a neuromuscular disease, or a disease resulting from long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may result in ataxic symptoms that may be treated according to the methods described herein include, among others, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endosteal sclerosis), cerebellar stenosis, ... cerebellar hypoplasia (pigment epithelium retinal degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar agenesis (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, dorsal column conditions, autonomic dysfunction, imbalance syndromes, paresthesia, endocrine disorders, disorders caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptics), fragile X / movement tremors Ataxia syndrome, Friedreich's ataxia, frontal lobe dysfunction, genetic disorders, granulomatous vasculitis of the central nervous system, Hallervorden-Spatz disease, hereditary motor and sensory neuropathy, hydrocephalus (e.g. low or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller-Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonic ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, Parkinsonism (atypical), peroneal muscular atrophy, phenyloin toxicity, spinal ataxia with retinitis pigmentosa, post-polio syndrome, severe damage to the brain (e.g. head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infection,or caused by brain tumor), spastic incomplete hemiplegia, spastic paraplegia 23, spastic paraplegia glaucoma precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy-hearing loss), spinocerebellar ataxia (dysmorphism), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal recessive 1), spinocerebellar ataxia (autosomal recessive 3), spinocerebellar ataxia (autosomal recessive chromosomal recessive 4), spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive, with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph type II), spinocerebellar ataxia (X-linked, 2), spinocerebellar ataxia (X-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellar degeneration (Book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and diseases caused by vitamin deficiency. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia, and fragile X-associated / tremor ataxia syndrome. In another particular embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X-associated / tremor ataxia syndrome.

[0168] Tinnitus Methods of treating tinnitus in a subject in need thereof are provided herein, comprising administering a compound or composition disclosed herein. Tinnitus is a condition in which the affected perceives sound in one or both ears or in the head in the absence of external sound. Tinnitus, often referred to as "ringing" in the ears, occurs intermittently or consistently, with a perceived loudness ranging from a low volume to a painfully loud volume. However, the perceived loudness of tinnitus may vary from patient to patient, and one patient may perceive an objective measure of tinnitus loudness as painful, while another may perceive the same volume as insignificant.

[0169] Sleep disorders Provided herein is a method for treating or preventing a sleep disorder (e.g., narcolepsy), comprising administering a compound or composition disclosed herein. For example, the sleep disorder can be hypersomnia, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, progressive sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or a core disorder of circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0170] Combination therapy In another aspect, the compounds or compositions described herein (e.g., for use in modulating T-type calcium ion channels) can be administered in combination with at least one other drug or therapy. The subject to whom the compounds or compositions disclosed herein are administered can have a disease, disorder, or condition, or at least one symptom thereof, that would benefit from treatment with another drug or therapy. In certain embodiments, these diseases or conditions can be associated with epilepsy or epilepsy syndromes (e.g., absence seizures, juvenile myoclonus epilepsy, or genetic epilepsy), or tremor (e.g., essential tremor).

[0171] Anticonvulsants Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbezepine, midazolam, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0172] Painkillers Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphine-like agents, such as fentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors.Given the ability of the compounds disclosed herein to treat pain through the inhibition of T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combination with analgesics is particularly envisioned.

[0173] Tremor Drug Treatment Drugs for treating tremors include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, midazolam, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0174] The present disclosure will be more fully understood with reference to the following examples. EXAMPLES

[0175] In order that the embodiments described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0176] In the following examples, purification by chromatography refers to purification using a Biotage® Isolera™ One purification system. When products were purified using Santai® SepaFlash™ Irregular Silica, "Santai SepaFlash™ Irregular Silica" refers to a pre-packed polypropylene column containing unbonded activated silica with irregular particles having an average size of 40-63 μm and a nominal porosity of 60 Å. Fractions containing the required product (identified by TLC and / or LCMS analysis) were pooled and the organic fraction was recovered by evaporation to obtain the final product. When thin layer chromatography (TLC) was used, this refers to a silica gel TLC plate, typically a 3×6 cm silica gel glass plate with a fluorescent indicator (254 nm) (e.g., UV-III). Microwave experiments were performed using a Biotage Initiator+ using a single mode resonator and dynamic electric field tuning. Temperatures of 40-300° C. can be achieved and pressures up to 30 bar can be achieved.

[0177] NMR spectra were obtained on a Bruker Ascend™ 400 MHz, 5 mm BBFO probe H, C, F, P, single Z gradient, dual channel instrument running TopSpin 4.1.

[0178] Compound names were generated in the standard manner using the structure naming functionality of ChemDraw Professional 20.

[0179] Abbreviation: CD 3 OD Deuterated Methanol DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6 Deuterated dimethyl sulfoxide-d6 DPPA Diphenylphosphoryl azide FA Formic Acid HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate K 2 CO 3 Potassium carbonate MeCN Acetonitrile MeOH Methanol PE Petroleum Ether TFA Trifluoroacetic acid THF Tetrahydrofuran

[0180] Analytical LC-MS conditions Method 1 included the following conditions: Column: HALO C18 2.7 μm, 3.0 mm x 30 mm. Mobile phase: MeCN (0.05% HCOOH)-water (0.05% HCOOH). Gradient: 5% to 95% MeCN over 1.4 min, hold 0.6 min, total run time 2.5 min. Flow rate: 1.8 mL / min. Column temperature: 50° C. Wavelength: 214 nm and 254 nm PDA. A Shimadzu LCMS 2020 mass spectrometer was used.

[0181] Method 2 included the following conditions: Column: XBridge C18 3.5 μm, 2.1 mm × 50 mm. Mobile phase: MeCN-water (0.1% NH 4 OH). Gradient: 5% to 95% MeCN over 1.8 min, hold 0.7 min, total run time 3.0 min. Flow rate: 1.0 mL / min. Column temperature: 50° C. Wavelengths: 214 nm and 254 nm PDA. A Shimadzu LCMS 2020 mass spectrometer was used.

[0182] Analytical HPLC conditions Method A included the following conditions: Column: ZORBAX ECLIPES PLUS C18, 1.8 μm, 4.6 mm x 50 mm. Mobile phase: water (0.05% TFA)-MeCN (0.05% TFA). Gradient: 5% to 95% MeCN over 4.5 min, 1 min hold, total run time 7.0 min. Column temperature: 55°C. Flow rate: 2.0 mL / min. Wavelength range: 190 nm to 800 nm. Instrument: SHIMADZU LC-2030C 3D Plus.

[0183] Method B included the following conditions: Column: XBridge BEH C18, 2.5 μm, 3.0 mm x 30 mm. Mobile phase: Water (0.1% NH 3 / H 2 O)-MeCN (100%). Gradient: 5% to 95% MeCN over 5.5 min, 1 min hold, total run time 8 min. Column temperature: 45 °C. Flow rate: 1.5 mL / min. Wavelength range: 190 nm to 800 nm. Instrument: SHIMADZU LC-2030C 3D Plus.

[0184] HNMR conditions for analysis: HNMR: BRUKER 400, temperature: 25℃. Example 1 - Preparation of N-(tert-butyl)-2-(6-(2-((3,5-dichlorophenyl)amino)-2-oxoethyl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide [ka] Scheme 1:

[0185] General method 1: Step 1: Preparation of tert-butyl 6-(2-(tert-butylamino)-2-oxoethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 3) [ka]

[0186] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (2.0 g, 10 mmol) (Intermediate 3) in MeCN (20 mL) was added N-tert-butyl-2-chloro-acetamide (1.51 g, 10 mmol) (Intermediate 2), KI (1.67, 10 mmol), and K 2 CO 3 (4.18 g, 30 mmol) was added. The reaction solution was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was taken up in EtOAc (3×20 mL). The organics were washed with water (2×5 mL) followed by saturated brine solution (1×5 mL). The combined organic layers were separated and dried (Na 2 SO 4 ) and then concentrated in vacuo. The resulting residue was then purified by flash column chromatography eluting with 5% MeOH in DCM to give tert-butyl 6-[2-(tert-butylamino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.15 g, 65% yield, 95% purity) as a yellow oil. MS observed (ESI+): [(M+H) + ]:312.1 R t :1.28 minutes (method 2).

[0187] Step 2: Preparation of N-(tert-butyl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Intermediate 4) [ka]

[0188] tert-Butyl 6-[2-(tert-butylamino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.15 g, 7.0 mmol) (Intermediate 3) was added to FA (30 mL) and stirred at 30° C. for 18 h. The reaction was concentrated in vacuo to give N-tert-butyl-2-(2,6-diazaspiro[3.3]heptane-2-yl)acetamide (3.1 g, 100% yield, 47% purity) as a yellow oil. MS observed (ESI+): [(M+H) + ]:212.0Rt :0.70 minutes (method 1).

[0189] Step 3: Preparation of 2-chloro-N-(3,5-dichlorophenyl)acetamide (Intermediate 6) [ka]

[0190] To a solution of 3,5-dichloroaniline (200 mg, 1.23 mmol) (Intermediate 5) in DCM (5 mL) was added chloroacetyl chloride (0.10 mL, 1.23 mmol) and TEA (0.51 mL, 3.7 mmol). The reaction solution was stirred at room temperature overnight. The reaction was concentrated in vacuo and the residue was taken up in EtOAc (3×5 mL). The organics were washed with water (2×3 mL) followed by saturated brine solution (3 mL). The combined organics were separated and dried (Na 2 SO 4 ) and then concentrated in vacuo. The resulting residue was purified by flash column chromatography eluting with 15% EtOAc in PE to give 2-chloro-N-(3,5-dichlorophenyl)acetamide (208 mg, 67% yield, 95% purity) as an off-white solid.

[0191] 1 H NMR (400MHz, DMSO) δ 10.63(s, 1H), 7.65(d, J=2.0Hz, 2H), 7.34(t, J=1.8Hz, 1H), 4.29(s, 2H).

[0192] Step 4: Preparation of N-(tert-butyl)-2-(6-(2-((3,5-dichlorophenyl)amino)-2-oxoethyl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Example 1) [ka]

[0193] A solution of N-tert-butyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)acetamide (70 mg, 0.33 mmol) (Intermediate 4) in MeCN (3 mL) was mixed with 2-chloro-N-(3,5-dichlorophenyl)acetamide (79 mg, 0.33 mmol) (Intermediate 6) and K 2 CO 3 (137 mg, 0.99 mmol) was added. The reaction was stirred at room temperature overnight and then concentrated in vacuo. The residue was taken up in EtOAc (3×5 mL) and the organics were washed with water (2×3 mL) and then with saturated brine solution (3 mL). The combined organics were separated and dried (Na 2 SO 4 ) and then concentrated in vacuo. The resulting residue was purified by flash column chromatography eluting with 5% MeOH in DCM to give 2-[2-[2-(tert-butylamino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptan-6-yl]-N-(3,5-dichlorophenyl)acetamide (26 mg, 18% yield) as a yellow solid.

[0194] MS Observation (ESI+): [(M+H) + ]:413.3R t :1.51 minutes (method 2). 1 H NMR (400MHz, DMSO-d6)δ:9.99(s, 1H), 7.75(d, J=1.6Hz, 2H), 7.27(s, 1H), 7.03 (s, 1H), 3.36(s, 4H), 3.32-3.30(s, 4H), 3.20(s, 2H), 2.89(s, 2H), 1.24(s, 9H).

[0195] The following compounds listed in Table 1 below were similarly prepared, and certain compounds (where indicated) were tested for human Cav3.1 calcium channel activity by the patch clamp assay disclosed herein.

[0196] Inhibition of T-type voltage-gated calcium channels (Cav3.1) was assessed using the HEK-293 natClytin / TASK1+Cav3.1 cell line. Currents were recorded using a SyncroPatch384PE automated patch clamp system. Pulse generation and data collection were performed with PatchController384 V1.3.0 and DataController384 V1.2.1 (Nanion Technologies). Offline analysis was performed using Excel and Graphpad Prism (version 8.4.2) and complete data files were uploaded to Dotmatics. Access resistance and apparent membrane capacitance were estimated using built-in protocols. Currents were recorded in whole-cell configuration from cell populations. Cells were lifted, triturated and resuspended at 800,000 cells / mL. Cells were allowed to recover in a cell hotel prior to the experiment. Currents were recorded at room temperature. The external solution contained 80 mM NaCl, 60 mM NMDG, 4 mM KCl, and MgCl 2 1 mM CaCl 2The extracellular solution contained 6 mM, glucose 5 mM, and HEPES 10 mM (pH=7.4, osmolality approximately 300 mOsm). The extracellular solution was used as the wash solution, reference solution, and compound delivery solution. The internal solution contained CsF 110 mM, CsCl 10 mM, NaCl 10 mM, EGTA 10 mM, HEPES 10 mM (pH=7.2, osmolality approximately 295 mOsm). Compound plates were made at 2x concentrations in the extracellular solution. Compounds were diluted 1:2 when added to the recording wells. The amount of DMSO in the extracellular solution was kept constant at the level used for the highest test concentration. For voltage clamp experiments on Cav3.1, data were sampled at 10 KHz. After establishing a seal and passing in the whole-cell configuration, cells were held at -120 mV. Cav3.1 currents were elicited using a 100 ms step to -20 mV (to measure resting state block), followed by a 1600 ms step to -65 mV and a second 100 ms step to -20 mV (to measure voltage-dependent block). Voltage protocols were applied every 15 seconds in the absence and presence of the compound under investigation. Nickel 2.5 mM was used to completely inhibit Cav3.1 currents, allowing offline subtraction of non-Cav3.1 currents. Current amplitudes (pA) were measured at peak 1 and peak 2. The average of the last three sweeps of each liquid period (vehicle, compound under investigation, complete block) was calculated. Nickel-sensitive currents were used to calculate % inhibition in the presence of the compound under investigation. In Tables 1 and 2 below, human Cav3.1 IC 50 is indicated as either A (less than 1 μM), B (1 μM to less than 10 μM), or C (more than 10 μM). [Table 1-1] [Table 1-2]

[0197] Examples 2 to 8 1 H NMR (400 MHz, DMSO-d6) δ data was as follows:

[0198] Example 2: 9.79 (s, 1H), 7.17 (dd, J = 11.2, 1.8 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J = 12.8 Hz, 1H), 6.51 (m, 1H), 3.73 (s, 3H), 3.35 (s, 4H), 3.30 (s, 4H), 3.16 (s, 2H), 2.87 (s, 2H), 1.24 (s, 9H).

[0199] Example 3: 10.06 (s, 1H), 7.72 (s, 1H), 7.70 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.02 (obs.s, 1H), 7.02 (t, J = 56 Hz, 1H), 3.37 (s, 4H), 3.31 (s, 4H), 3.20 (s, 2H), 2.88 (s, 2H), 1.24 (s, 9H).

[0200] Example 4: 9.74 (s, 1H), 7.39 (d, J = 11.6 Hz, 1H), 7.21 (s, 1H), 7.02 (s, 1H), 6.71 (d, J = 9.6 Hz, 1H), 3.36 (s, 4H), 3.31 (s, 4H), 3.16 (s, 2H), 2.89 (s, 2H), 2.27 (s, 3H), 1.24 (s, 9H).

[0201] Example 5: 9.86 (s, 1H), 7.94 (dd, J=6.8, 2.4 Hz, 1H), 7.61-7.53 (m, 1H), 7.35 (s, 1H), 7.02 (s, 1H), 3.36 (s, 4H), 3.31 (s, 4H), 3.17 (s, 2H), 2.88 (s, 2H), 1.24 (s, 9H).

[0202] Example 6: 9.83 (s, 1H), 7.83 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 3.36 (s, 4H), 3.30 (s, 4H), 3.17 (s, 2H), 2.87 (s, 2H), 1.24 (s, 9H).

[0203] Example 7: 10.05(s,1H),7.50(d,J=3.8Hz,4H),7.42-7.35(m,1H),7.00(s,1H),6.56(s, 1H),3.34(s,4H),3.29(s,4H),3.15(s,2H),2.86(s,2H),2.32(s,3H),1.24(s,9H).

[0204] Example 8: 9.60(s,1H),7.80(t,J=7.6Hz,1H),7.34(t,J=7.6Hz,1H),7.19(t,J=8.2Hz, 1H),7.01(s,1H),3.39(s,4H),3.30(s,4H),3.23(s,2H),2.87(s,2H),1.24(s,9H).

[0205] Example 9 - Preparation of N-(tert-butyl)-2-(6-((7-chloro-5-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide [ka] Step 1: Preparation of 4-chloro-2-(chloromethyl)-6-fluoro-1H-benzo[d]imidazole (Intermediate 7) [ka]

[0206] To a solution of 3-chloro-5-fluoro-benzene-1,2-diamine (2.0 g, 12.45 mmol) in DCM (21 mL) was added 2-chloro-1,1,1-trimethoxy-ethane (2.50 g, 16.19 mmol) and p-toluenesulfonic acid (2.38 g, 1.25 mmol). The reaction solution was stirred at room temperature for 12 hours. The reaction was concentrated to dryness and the residue was taken up in DCM (80 mL). The organics were washed with water (2×13 mL) followed by saturated brine solution (13 mL). The organics were then separated and dried (Na 2 SO 4) and then concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 1-2% MeOH in DCM to give 4-chloro-2-(chloromethyl)-6-fluoro-1H-benzimidazole (2.5 g, 84% yield, 92% purity) as an off-white solid. MS observed (ESI+): [(M+H) + ]:218.9. R t :0.83 minutes (method 1).

[0207] Step 2: Preparation of N-(tert-butyl)-2-(6-((7-chloro-5-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Example 9) [ka]

[0208] A solution of N-(tert-butyl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)acetamide (150 mg, 0.71 mmol) (Intermediate 4) in MeCN (10 mL) was 3 N (0.30 mL, 2.13 mmol) and 4-chloro-2-(chloromethyl)-6-fluoro-1H-benzo[d]imidazole (156 mg, 0.71 mmol) (Intermediate 7) were added. The reaction was concentrated to dryness and the residue was partitioned between water (3 mL) and EtOAc (3×10 mL). The organics were washed with water (3 mL) followed by saturated brine solution (3 mL). The organics were then separated, dried (Na 2 SO 4 ) and then concentrated in vacuo. The crude was purified by silica gel chromatography eluting with 10% MeOH in DCM to give N-(tert-butyl)-2-(6-((7-chloro-5-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)acetamide (38 mg, 13% yield, 96.9% purity) as an off-white solid.

[0209] MS Observation (ESI+): [(M+H)+ ]:394.3. R t :1.41 minutes (method 2). 1 H NMR (400MHz, DMSO-d6) δ 12.69(s, 1H), 7.20(d, J=9.6Hz, 2H), 7.10(s, 1H), 3.75(s, 2H), 3.37(s, 4H), 3.32(s, 4H), 2.96(s, 2H), 1.24(s, 9H).

[0210] Example 10: Preparation of N-(3-chloro-5-fluoro-phenyl)-2-[2-[2-(1,1-dimethylpropylamino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptan-6-yl]acetamide [ka] General method 2: Step 1: Preparation of 6-[2-(3-chloro-5-fluoro-anilino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Intermediate 10) [ka]

[0211] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.0 g, 10.4 mmol) (Intermediate 8) in MeCN (30 mL) was added 2-chloro-N-(3-chloro-5-fluoro-phenyl)acetamide (2.54 g, 11.5 mmol) (Intermediate 9) and K 2 CO 3 (4.31 g, 31.2 mmol) was added. The reaction mixture was stirred at 40° C. for 6 h. The reaction was concentrated in vacuo and the residue was taken up in EtOAc (100 mL). The organic layer was washed with water (2×150 mL) and saturated brine solution (100 mL), then separated and dried (Na 2 SO 4) and concentrated in vacuo. The resulting residue was purified by flash column chromatography eluting with 10% EtOAc in PE to give tert-butyl 6-[2-(3-chloro-5-fluoro-anilino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3.7 g, 83% yield, 90% purity) as a yellow solid. MS observed (ESI+): [(M+H) + ]:385.7. R t :1.77 minutes (method 2).

[0212] Step 2: Preparation of N-(3-chloro-5-fluoro-phenyl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)acetamide (Intermediate 11) [ka]

[0213] To a solution of tert-butyl 6-[2-(3-chloro-5-fluoro-anilino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (3.7 g, 9.64 mmol) (Intermediate 10) in DCM (30 mL) was added TFA (10 mL, 71 mmol). The reaction mixture was stirred at room temperature for 2 h and then concentrated to dryness. The pH of the residue was adjusted to 8-9 and then extracted with 10% DCM / MeOH (5 x 45 mL). The combined organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C. for 1 hour, filtered and concentrated in vacuo to give N-(3-chloro-5-fluoro-phenyl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)acetamide (2.2 g, 6.97 mmol, 72.4% yield, 90% purity) as a yellow oil. MS observed (ESI+): [(M+H) + ]:284.0. R t :0.70 minutes (method 1).

[0214] Step 3: Preparation of N-(3-chloro-5-fluoro-phenyl)-2-[2-[2-(1,1-dimethylpropylamino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptan-6-yl]acetamide (Example 10) [ka]

[0215] A solution of N-(3-chloro-5-fluoro-phenyl)-2-(2,6-diazaspiro[3.3]heptan-2-yl)acetamide (60 mg, 0.21 mmol) (Intermediate 11) in MeCN (1 mL) was mixed with 2-chloro-N-(1,1-dimethylpropyl)acetamide (38 mg, 0.23 mmol) (Intermediate 12) and K 2 CO 3 (88 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The residue was taken up in DCM (10 mL) and the organic layer was washed with water (2×8 mL) followed by saturated brine solution (10 mL). The organic layer was separated and dried (Na 2 SO 4 ), and then concentrated in vacuo. The resulting residue was purified by preparative HPLC (15% to 95% [MeCN / H 2 0.05%NH in O 3 ]) to give the title compound N-(3-chloro-5-fluoro-phenyl)-2-[2-[2-(1,1-dimethylpropylamino)-2-oxo-ethyl]-2,6-diazaspiro[3.3]heptan-6-yl]acetamide (33 mg, 37% yield, 97.3% purity) as a white solid after lyophilization.

[0216] MS Observation (ESI+): [(M+H) + ]:411.4. R t :1.68 minutes (method 2). 1 H NMR (400MHz, DMSO-d6)δ 10.01(s,1H),7.62(s,1H),7.58-7.50(m,1H),7.11-7.08(m,1H),6.86(s,1H),3.36(s,4H),3. 30(s,4H),3.19(s,2H),2.88(s,2H),1.62(q,J=7.4Hz,2H),1.19(s,6H),0.75(t,J=7.4Hz,3H).

[0217] The following compounds listed in Table 2 were similarly prepared and certain compounds (as indicated) were tested for human Cav3.1 calcium channel activity by the methods disclosed in Example 1. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0218] Examples 11 to 29 1 H NMR (400 MHz, DMSO-d6) δ data was as follows:

[0219] Example 11:10.02(s,1H),7.64-7.59(m,1H),7.58-7.51(m,1H),7.14-7.00( m,2H),3.37(s,4H),3.35(s,4H),3.20(s,2H),2.93(s,2H),1.24(s,9H).

[0220] Example 12: 6.99(s,1H),6.85(s,1H),3.26(s,8H),2.85(d,J=3.1Hz,4H),2.00(s,3H),1.89(d,J=2.6Hz,6H),1.61(s,6H),1.24(s,9H).

[0221] Example 13: 10.00(s,1H),7.71(s,1H),7.62(s,1H),7.56-7.53(m,1H),7.11 -7.08(m,1H),3.36-3.35(m,6H),3.25(s,4H),3.19(s,2H),1.28(s,9H).

[0222] Example 14: 10.03 (s, 1H), 7.62 (s, 1H), 7.55 (dt, J = 11.2, 2.0 Hz, 1H), 7.49 (s, 1H), 7.09 (dt, J = 8.6, 2.0 Hz, 1H), 3.36 (s, 4H), 3.30 (s, 4H), 3.19 (s, 2H), 2.88 (s, 2H), 2.24-2.17 (m, 2H), 1.90-1.82 (m, 2H), 1.78-1.69 (m, 2H), 1.33 (s, 3H).

[0223] Example 15: 10.03 (s, 1H), 7.99 (s, 1H), 7.96-7.94 m, 2H), 7.62 (s, 1H), 7.56-7.52 (m, 4H), 7.11-7.08 (m, 1H), 3.46 (s, 2H), 3.37 (s, 4H), 3.30 (s, 4H), 3.20 (s, 2H).

[0224] Example 16: 10.03 (s, 1H), 7.62 (s, 1H), 7.56-7.53 (m, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.11-7.08 (m, 1H), 4.04-3.89 (m, 1H), 3.36 (s, 5H), 3.29 (s, 5H), 3.19 (s, 2H), 2.91 (s, 2H), 1.78-1.72 (m, 2H), 1.67-1.57 (m, 2H), 1.53-1.46 (m, 2H), 1.42-1.31 (m, 2H).

[0225] Example 17: 10.39 (s, 1H), 7.55-7.45 (m, 4H), 7.42-7.32 (m, 1H), 7.01 (s, 1H), 6.56 (s, 1H), 3.03 (s, 2H), 2.94-2.93 (m, 4H), 2.31 (s, 4H), 1.93-1.90 (m, 2H), 1.68-1.65 (m, 2H), 1.47-1.31 (m, 4H), 1.26 (s, 9H).

[0226] Example 18: 12.23 (s, 1H), 10.01 (s, 1H), 7.62 (s, 1H), 7.56-7.51 (m, J=9.0 Hz, 2H), 7.41-7.39 (m, 1H), 7.15-7.07 (m, 3H), 3.74 (s, 2H), 3.38 (s, 4H), 3.35 (s, 4H), 3.20 (s, 2H).

[0227] Example 19: 10.00 (s, 1H), 7.67 (s, 1H), 7.62 (s, 1H), 7.55 (dt, J = 11.2, 2.0 Hz, 1H), 7.09 (dt, J = 8.6, 2.0 Hz, 1H), 3.55 (s, 2H), 3.34 (s, 4H), 3.32 (s, 4H), 3.19 (s, 2H), 1.18 (s, 9H).

[0228] Example 20: 10.01 (s, 1H), 7.62 (s, 1H), 7.54 (d, J = 11.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 3.33 (s, 4H), 3.19 (s, 2H), 3.16 (s, 4H), 2.35-2.26 (m, 2H), 1.73-1.65 (m, 3H), 1.58-1.52 (m, 2H), 1.49-1.44 (m, 2H), 1.26-1.21 (m, 2H), 1.06-0.98 (m, 2H).

[0229] Example 21: 10.06 (s, 1H), 8.20 (s, 2H), 7.61 (s, 1H), 7.54 (dt, J = 11.2, 2.0 Hz, 1H), 7.10 (dt, J = 8.6, 2.0 Hz, 1H), 3.62 (s, 4H), 3.41 (s, 4H), 3.22 (s, 2H), 2.68-2.67 (m, 2H), 1.32-1.16 (m, 2H), 0.86 (s, 9H).

[0230] Example 22: 10.00 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.56-7.53 (m, 1H), 7.11-7.08 (m, 1H), 3.34 (s, 4H), 3.31 (s, 2H), 3.23 (s, 4H), 3.19 (s, 2H), 2.34 (s, 3H).

[0231] Example 23: 12.34 (d, J = 37.8 Hz, 1H), 10.00 (s, 1H), 7.93-7.87 (m, 2H), 7.62 (s, 1H), 7.55 (d, J = 11.2 Hz, 1H), 7.43-7.39 (m, 2H), 7.33-7.29 (m 1H), 7.11-7.07 (m, 1H), 6.91 (d, J = 72.5 Hz, 1H), 3.45 (d, J = 30.6 Hz, 2H), 3.35 (s, 4H), 3.25 (s, 2H), 3.22 (s, 2H), 3.19 (s, 2H).

[0232] Example 24: 10.00 (s, 1H), 7.62 (s, 1H), 7.56-7.53 (m, 1H), 7.22-7.18 (m, 1H), 7.12-7.08 (m, 1H), 6.82-6.78 (m, 3H), 3.73 (s, 3H), 3.46 (s, 2H), 3.36 (s, 4H), 3.21 (s, 4H), 3.19 (s, 2H).

[0233] Example 25: 10.00 (s, 1H), 7.62 (s, 1H), 7.54 (d, J = 11.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.29 (s, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 3.50 (s, 2H), 3.36 (s, 4H), 3.23 (s, 4H), 3.19 (s, 2H).

[0234] Example 26: 10.01 (s, 1H), 7.62 (s, 1H), 7.54 (d, J = 11.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 3.33 (s, 4H), 3.19 (s, 2H), 3.13 (s, 4H), 2.30 (t, J = 7.2 Hz, 2H), 1.95-1.93 (m, 2H), 1.82-1.78 (m, 1H), 1.72-1.69 (m, 4H), 1.19-1.14 (m, 2H), 1.11-1.09 (m, 2H).

[0235] Example 27: 9.99 (s, 1H), 7.62 (s, 1H), 7.54 (d, J = 11.2 Hz, 1H), 7.46-7.39 (m, 4H), 7.09 (d, J = 8.6 Hz, 1H), 7.01 (t, 56.0 Hz, 1H), 3.56 (s, 2H), 3.37 (s, 4H), 3.24 (s, 4H), 3.19 (s, 2H).

[0236] Example 28: 10.00 (s, 1H), 8.54 (s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.62 (s, 1H), 7.55 (d, J = 11.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 3.67 (s, 2H), 3.37 (d, J = 1.8 Hz, 8H), 3.20 (s, 2H).

[0237] Example 29: 11.42-11.32 (m, 1H), 10.00 (s, 1H), 7.62 (s, 1H), 7.54 (d, J=11.2 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.69-6.47 (m, 1H), 3.37-3.33 (m, 4H), 3.30 (s, 2H), 3.20-3.16 (m, 6H), 1.23 (s, 9H).

[0238] Example 30: 10.00 (s, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.62 (s, 1H), 7.55 (dt, J = 11.2, 2.0 Hz, 1H), 7.09 (dt, J = 8.6, 2.0 Hz, 1H), 3.54 (s, 2H), 3.34 (s, 4H), 3.30 (s, 4H), 3.19 (s, 2H), 2.04 (d, J = 1.2 Hz, 3H).

[0239] Example 31: 12.69 (s, 1H), 7.51 (s, 1H), 7.21 (s, 2H), 3.75 (s, 2H), 3.34 (s, 8H), 3.00 (s, 2H), 1.47 (s, 6H).

[0240] Example 32: 12.70 (s, 1H), 7.20 (d, J = 9.3 Hz, 2H), 6.98 (s, 1H), 3.75 (s, 2H), 3.41 (s, 4H), 3.35 (s, 4H), 3.01 (s, 2H), 1.62 (q, J = 7.4 Hz, 2H), 1.18 (s, 6H), 0.75 (t, J = 7.5 Hz, 3H).

[0241] Example 33: 12.72 (s, 1H), 7.20 (d, J=9.7 Hz, 2H), 3.74 (s, 2H), 3.31 (s, 4H), 3.20 (s, 4H), 2.37-2.28 (m, 2H), 1.16-1.07 (m, 2H), 0.84 (s, 9H).

[0242] Example 34: 12.73 (s, 1H), 7.21 (d, J = 9.7 Hz, 2H), 3.83 (s, 2H), 3.76 (s, 2H), 3.33 (s, 4H), 2.82 (s, 2H), 1.70 (s, 3H), 1.60-1.44 (m, 4H), 1.34 (d, J = 4.6 Hz, 2H), 1.23 (s, 2H), 1.05 (s, 2H).

[0243] Example 35: 12.73 (s, 1H), 7.21 (d, J = 9.8 Hz, 2H), 3.76 (s, 5H), 3.40 (s, 4H), 2.71 (s, 2H), 1.26 (dd, J = 15.8, 7.0 Hz, 3H), 1.11 (dd, J = 11.1, 5.6 Hz, 2H), 0.85 (s, 9H).

[0244] Example 36: 7.20 (ddd, J = 12.0, 9.3, 2.1 Hz, 2H), 3.73 (s, 2H), 3.30 (s, 4H), 3.15 (s, 4H), 2.18 (d, J = 6.8 Hz, 2H), 1.94 (d, J = 7.8 Hz, 2H), 1.79-1.65 (m, 4H), 1.33 (s, 1H), 1.16-0.98 (m, 2H).

[0245] Example 37: 12.20(d,J=46.2Hz,1H),7.27(dd,J=51.9,7.8Hz,1H),7.00(dd,J=9.1,5.9Hz,2H),6.90(d,J=6. 5Hz,1H),3.71(d,J=8.9Hz,2H),3.30(d,J=11.1Hz,8H),2.86(s,2H),2.47(d,J=6.0Hz,3H),1.23(s,9H).

[0246] Example 38: 12.34 (d, J = 61.7 Hz, 1H), 7.13-6.97 (m, 2H), 6.81 (t, J = 11.9 Hz, 1H), 3.71 (s, 2H), 3.33 (s, 8H), 2.93 (s, 2H), 2.47 (d, J = 5.7 Hz, 3H), 1.23 (s, 9H).

[0247] Example 39: 12.78 (s, 1H), 7.47 (s, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.00 (s, 1H), 3.76 (s, 2H), 3.33 (s, 4H), 3.29 (s, 4H), 2.86 (s, 2H), 1.24 (s, 9H).

[0248] Example 40: 7.15-7.10 (m, 1H), 6.88-6.82 (m, 1H), 6.81 (t, J=72 Hz, 1H), 3.81 (s, 2H), 3.48-3.43 (m, 8H), 3.01 (s, 2H), 1.32 (s, 9H).

[0249] Example 41: 10.93 (s, 1H), 8.09 (s, 1H), 7.35-7.31 (m, 1H), 7.27 (t, J=73.2 Hz, 1H), 7.23 (s, 1H), 6.94-6.88 (m, 1H), 4.47-4.18 (m, 10H), 3.91 (s, 2H), 1.27 (s, 9H).

[0250] Example 42: 7.02 (s, 1H), 5.42 (s, 1H), 3.78 (s, 4H), 3.29 (s, 4H), 2.86 (s, 2H), 1.98 (s, 3H), 1.87-1.86 (m, 6H), 1.64-1.51 (m, 6H), 1.24 (s, 9H).

[0251] Example 43: 8.77 (s, 1H), 7.45-7.44 (m, 1H), 7.42-7.37 (m, 1H), 7.06 (s, 1H), 6.94-6.90 (m, 1H), 4.03 (s, 4H), 3.36 (s, 4H), 2.90 (s, 2H), 1.25 (s, 9H).

Claims

1. A compound of formula (IA) having a diazaspiroheptane core, 【Chemistry 25】 In the formula, X １ but, 【Chemistry 26】 Selected from the group consisting of, wherein, R １ is selected from the group consisting of -H, -CH ３ , -CH ２ OCH ３ , -CF ３ , -CH ２ CH ３ , and -(CH ２ ) ２ OCH ３ and is selected from the group consisting of: R ２ However, it is -H, R ３ However, it is -H, R ４ However, -H and -CH ３ Selected from the group consisting of R １ and R ４ Together, they form a cyclopropane, cyclobutane, cyclopentane, or oxetane ring. R ５ However, -H, -CH ３ CF ３ ien-CH ２ OH, -COOCH ３ , -COOH, and -CH ２ OCH ３ Selected from the group consisting of, R ６ However, -H and -CH ３ Selected from the group consisting of R ５ and R ６ Together they form an azetidine, pyrrolidine, morpholine, or piperidine ring, and these each are -CH ３ -OH, -CF ３ It optionally includes at least one substituent selected from the group consisting of , and -F, R ７ However, -Cl, -F, -CF ３ ien-CH ３ , -OCHF ２ , and -OCH ３ Selected from the group consisting of, R ８ However, benzene, -CH ３ Selected from the group consisting of , and tert-butyl, R ９ However, at least one -F or -CH ３ Selected from the group consisting of cyclohexane containing substituents and optionally substituted with -O-, and benzimidazole, R １０ However, -C(CH ３ ) ３ , cyclopentyl, -(CH ２ ) C (CH ３ ) ３ Cyclohexane, -OCH, which is optionally substituted with -N- and optionally contains at least one substituent selected from the group consisting of -F and =O. ３ Alternatively, cyclopentane, tert-butyl, -CF containing an optional -OH substituent. ３ Selected from the group consisting of , and cyclopropyls optionally containing a methyl substituent, Each A １ These are independently selected from the group consisting of -CH and -N, Each A ２ These are independently selected from the group consisting of -CH, -N, and -O, and A ３ However, -O, CH ２ , and CF ２ Selected from the group consisting of, X ２ However, -CH ２ CONH-, -CH ２ -ien-CH ２ NHKCO-, -CH ２ NHCOCH ２ -ien-CH ２ NHCO (CH ２ ) ２ -, -NHCO-, -NHCH ２ CONH-,-N(CH ３ )CH ２ CONH-, -CH ２ N(CH ３ )CO-, -CONH-, -CONHCH ２ -, CONHCH ２ C (CH ２ CH ３ ) ２ -, and -CH ２ Selected from the group consisting of NH-, and X ３ but, (i) Adamantane ring, (ii) Benzofuran, (iii) Halogen, -CH ３ , -CF ３ ,-CHF ２ , -OCHF ２ , -CN, -OCH(CH ３ ) ２ ien-CH ２ CH ３ , -OCH ２ CHF ２ , -OCH ３ A phenyl group having at least one substituent optionally selected independently from the group consisting of , and cyclopentane, (iv) 1,4-CH ２ CH ２ Cyclohexane containing optional crosslinks, (v) Optionally, at least one substituent independently selected from the group consisting of fluorine, chlorine, cyclohexane, -CH ３ , -OCHF ２ , benzene optionally containing a halogen substituent, isobutyl, cyclopropyl, tert-butyl, methylpyrazole, -CH(CH ３ ), ２ and methylpiperidine, and containing an imidazole or benzimidazole, (vi) Methylpyrazole, cyclopropyl, and -CH ３ A pyridine comprising at least one substituent independently selected from the group consisting of the following, (vii) Naphthalene, and (viiii) A compound selected from the group consisting of isoquinolines containing at least one halogen substituent, or a pharmaceutically acceptable salt thereof.

2. A compound of formula (I) having a diazaspiroheptane core, 【Chemistry 27】 In the formula, X １ but, 【Chemistry 28】 Selected from the group consisting of, wherein, R １ is selected from the group consisting of -H, -CH ３ , -CH ２ OCH ３ , -CF ３ , -CH ２ CH ３ , and -(CH ２ ) ２ OCH ３ ; R ２ However, it is -H, R ３ However, it is -H, R ４ However, -H and -CH ３ Selected from the group consisting of R １ and R ４ Together they form a cyclobutane, cyclopentane, or oxetane ring. R ５ However, -H, -CH ３ ien-CH ２ OH, -COOCH ３ , -COOH, and -CH ２ OCH ３ Selected from the group consisting of, R ６ However, -H and -CH ３ Selected from the group consisting of R ５ and R ６ Together they form an azetidine, pyrrolidine, morpholine, or piperidine ring, and these each are -CH ３ -OH, -CF ３ It optionally includes at least one substituent selected from the group consisting of , and -F, R ７ However, -Cl, -F, -CF ３ ,-CHF ２ ien-CH ３ , -OCHF ２ , and -OCH ３ Selected from the group consisting of, R ８ However, benzene, -CH ３ Selected from the group consisting of , and tert-butyl, R ９ However, at least one -F or -CH ３ The substituents include optionally -O-, benzimidazole, and -CO(CH ２ ) ２ C (CH ３ ) ３ Selected from the group consisting of cyclohexane substituted with, R １０ However, cyclohexane, -OCH, which is optionally substituted with -N- and optionally contains at least one substituent selected from the group consisting of -F and =O. ３ Alternatively, cyclopentane, tert-butyl, and -CF containing an optional -OH substituent. ３ Selected from the group consisting of, Each A １ These are independently selected from the group consisting of -CH and -N, Each A ２ These are independently selected from the group consisting of -CH, -N, and -O, and A ３ However, -O, CH ２ , and CF ２ Selected from the group consisting of, X ２ However, -CH ２ CONH-, -CH ２ -ien-CH ２ NHKCO-, -CH ２ NHCOCH ２ -ien-CH ２ NHCO (CH ２ ) ２ -, -NHCO-, -NHCH ２ CONH-,-N(CH ３ )CH ２ CONH-, -CH ２ N(CH ３ )CO-, -CONH-, -CONHCH ２ -, CONHCH ２ C (CH ２ CH ３ ) ２ -, and -CH ２ Selected from the group consisting of NH-, and X ３ but, (i) Adamantane ring, (ii) Benzofuran, (iii) Halogen, -CH ３ , -CF ３ ,-CHF ２ , -OCHF ２ , -CN, -OCH(CH ３ ) ２ ien-CH ２ CH ３ , -OCH ２ CHF ２ , -OCH ３ A phenyl group having at least one substituent optionally selected independently from the group consisting of , and cyclopentane, (iv) 1,4-CH ２ CH ２ Cyclohexane containing optional crosslinks, (v) Optionally, chlorine, cyclohexane, -CH ３ benzene, isobutyl, cyclopropyl, tert-butyl, methylpyrazole, -CH(CH) containing halogen substituents as optional ３ ) ２ Imidazole or benzimidazole comprising at least one substituent independently selected from the group consisting of , and methylpiperidine, (vi) Methylpyrazole, cyclopropyl, and -CH ３ A pyridine comprising at least one substituent independently selected from the group consisting of the following, (vii) Naphthalene, and (viiii) A compound selected from the group consisting of isoquinolines containing at least one halogen substituent as optional, or a pharmaceutically acceptable salt thereof.

3. X １ The compound according to claim 1 or 2, wherein the compound is of formula (a).

4. In equation (a), R １ , R ４ , and R ５ Each of them is -CH ３ The compound according to claim 3.

5. R ２ , R ３ , and R ６ The compound according to claim 3, wherein each of them is -H.

6. X ２ However, -CH ２ CONH- or -CH ２ - The compound according to claim 1 or claim 2.

7. X ２ However, -CH ２ The compound according to claim 1 or claim 2, wherein it is CONH-.

8. X ３ The compound according to claim 1 or claim 2, wherein the ring is an adamantane ring.

9. X ３ The compound according to claim 1 or claim 2, wherein the group is a phenyl group.

10. The compound according to claim 9, wherein the phenyl group comprises at least one halogen substituent.

11. The compound according to claim 10, wherein the at least one halogen is fluorine or chlorine.

12. The compound according to claim 11, wherein the at least one halogen comprises fluorine and chlorine.

13. The compound according to claim 1 or claim 2, wherein the compound comprises at least one deuterium atom.

14. The above-mentioned at least one deuterium is X １ The compound according to claim 13.

15. The aforementioned compound, 【Chemistry 29-1】 【Chemistry 29-2】 A compound according to claim 2 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

16. The aforementioned compound, 【Transformation 30】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

17. A pharmaceutical composition comprising the compound according to claim 1 or claim 2 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to claim 17, further comprising a release-regulating polymer.

19. The pharmaceutical composition according to claim 18, wherein the release-regulating polymer is hydroxypropyl methylcellulose, ethylcellulose, or a polyacrylate polymer.

20. A composition or pharmaceutical composition for use in treating a disease or condition related to abnormal function or activity of T-type calcium channels in a subject requiring such treatment, comprising the compound described in claim 1 or claim 2, or a pharmaceutical composition comprising the compound described in claim 1 or claim 2 and a pharmaceutically acceptable carrier.

21. The composition for use or pharmaceutical composition according to claim 20, wherein the disease or condition related to the abnormal function or activity of T-type calcium channels is a mental disorder, pain, tremor, seizure, epilepsy, or epileptic syndrome.

22. The composition for use or pharmaceutical composition according to claim 21, wherein the disease or condition associated with abnormal function or activity of T-type calcium channels is tremor.

23. The composition for use or pharmaceutical composition according to claim 22, wherein the disease or condition associated with abnormal function or activity of T-type calcium channels is essential tremor.

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