T-type calcium channel regulators containing a piperazine core or a 1,4-diazepane core and methods of using same

Abstract

Disclosed herein are compounds for treating conditions regulated by calcium channel ion activity, including compounds containing a piperazine core, a 1,4-diazepane core, or a 1,5-diazepane core, and pharmaceutical compositions containing the compounds. 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) and compounds of formula (II) containing a piperazine core, including right- and left-handed substitutions. Also disclosed herein are compounds of formula (III) containing a 1,4-diazepane core, including compounds of formula (IV), including right- and left-handed substitutions.

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 326,682, 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 piperazine core or a 1,4-diazepane core, including left-sided and right-sided substitutions. Also 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, compounds of formula (I) and compounds of formula (II) are disclosed herein that include a piperazine core, including right- and left-handed substitutions. Compounds of formula (III) are also disclosed herein that include a 1,4-diazepane core, including right- and left-handed substitutions, including compounds of formula (IV).

[0007] In some aspects, the present disclosure provides a compound represented by formula (Ia): [ka] During the ceremony, B is absent or selected from the group consisting of -CH-, -CH-CH, -CH-CH-CH, -O-, -CH-O-, -O-CH-, and -CH-O-CH-; W1' and W2' are each independently selected from the group consisting of -H, deuterium, alkyl, and alkoxy, or W1' and W2' together form a carbocyclyl, heterocyclyl, or carbonyl (=O); S1' and S2' are each independently selected from the group consisting of -H and -CH3, or S1' and S2' together form a carbonyl; X2' is absent, -CH2-, -CHCH3-, or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; X1' is (i) [ka] (In the formula, R2' and R3' are each independently selected from the group consisting of -H, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocyclyl, and heterocyclyl, or R2' and R3' together form a cyclic ring; R4' and R5' are each independently selected from the group consisting of -H, deuterium, halo, CN, alkyl, and alkoxy, or R4' and R5' together form a carbonyl; R1' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, -OZ1', -NZ2'Z3', and -SO2Z7'; Z1' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl; Z2' and Z3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, -COZ'5, and -SO2Z6', or Z2' and Z3' together with the nitrogen to which they are attached form a heterocyclyl; Z5' is C 3-6 is a carbocyclyl, Z6' is C 1-6 is alkyl, or Z7' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl, or (ii) [ka] (In the formula, R6' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, and pharma- ceutically acceptable salts thereof.

[0008] In some aspects, the present disclosure provides a compound represented by formula (IIa): [ka] During the ceremony, The stereocenters marked with * are both in the S configuration or both in the R configuration, B is selected from the group consisting of -CH-, -CH-CH, -CH-CH-CH, -O-, -CH-O-, -O-CH-, and -CH-O-CH-; S1' and S2' are each independently selected from the group consisting of -H and -CH3, or S1' and S2' together form a carbonyl; X2' is absent, -CH2-, -CHCH3-, or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; X1' is (i) [ka] (In the formula, R2' and R3' are each independently selected from the group consisting of -H, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocyclyl, and heterocyclyl, or R2' and R3' together form a cyclic ring; R4' and R5' are each independently selected from the group consisting of -H, deuterium, halo, CN, alkyl, and alkoxy, or R4' and R5' together form a carbonyl; R1' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, -OZ1', -NZ2'Z3', and -SO2Z7'; Z1' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl; Z2' and Z3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, -COZ'5, and -SO2Z6', or Z2' and Z3' together with the nitrogen to which they are attached form a heterocyclyl; Z5' is C 3-6 is a carbocyclyl, Z6' is C 1-6 is alkyl, or Z7' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl, or (ii) [ka] (In the formula, R6' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, and pharma- ceutically acceptable salts thereof.

[0009] In some aspects, the present disclosure provides a compound represented by formula (IIIa): [ka] During the ceremony, One stereocenter indicated with an * is in the S configuration, and the other stereocenter indicated with an * is in the R configuration; B is -CH2-, -CH2-CH2, -CH2-CH2-CH2, -O-, -CH2-O-, -O-CH2-, or -CH2-O-CH2-; D is carbon or nitrogen; X1' is alkyl; X2' is -NHCO- or -CONH-; Compounds and pharma- ceutically acceptable salts thereof are provided, wherein X3' is aryl or heteroaryl.

[0010] In some aspects, the present disclosure provides a compound represented by formula (IVa): [ka] During the ceremony, The stereocenter marked with * is in the R or S configuration; X1' is alkyl; X2' is -O- or NR1R2, where R1 and R2 are each independently H or alkyl; Compounds and pharma- ceutically acceptable salts thereof are provided, wherein X3' is aryl or heteroaryl.

[0011] In some aspects, the present disclosure provides a compound represented by formula (Va): [ka] During the ceremony, the 1,4-diazepane core in the compound of formula (Va) optionally comprises a 2,7-CH2-bridge, a 2,7-CH2CH2-bridge, a 3,7-CH2-bridge, or a 3,7-CH2CH2-bridge; W1' and W2' are each independently hydrogen, deuterium, alkyl, and alkoxy, or W1' and W2' together form a carbocyclyl, heterocyclyl, or carbonyl (=O); W3 is hydrogen or carbonyl; S1' and S2' are each independently hydrogen or alkyl, or S1' and S2' together form a carbonyl; X2' is absent, -CH2-, -CHCH3-, or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; X1' is [ka] (In the formula, R1' is selected from the group consisting of hydrogen, alkyl, carbocyclyl, and heterocyclyl; R2' and R3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocyclyl, and heterocyclyl, or R2' and R3' together form a cyclic ring; R 11 ' is hydrogen or methyl; R 12 is selected from the group consisting of hydrogen, deuterium, and alkyl, or R 11 ' and R 12 ' together form an azetidine ring optionally containing at least one methyl substituent, R 13 is selected from the group consisting of hydrogen, deuterium, and alkyl, and pharma- ceutically acceptable salts thereof.

[0012] In some aspects, the present disclosure provides a compound represented by formula (VIa): [ka] During the ceremony, R1' and R2' are each hydrogen, or R1' and R2' together form a carbonyl; and pharma- ceutically acceptable salts thereof, wherein R3' is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxyl, amino, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, and trifluoromethoxy.

[0013] In some embodiments, R3' is isoquinoline. In some embodiments, R3' is naphspiridine.

[0014] In one aspect, the present disclosure provides a compound having the following structure: [ka] Also provided is a compound of the formula:

[0015] In one embodiment, a compound of formula (I) having a piperazine core, [ka] wherein n is selected from 0, 1, or 2; W1 and W2 are independently selected from -H or -CH2OCH3; or W1 and W2 together form an oxetane ring or =O; S1 and S2 are independently selected from -H or -CH3; X2 is absent or -CH2 - or -CONH-, X3 is a group represented by the formula (i) [ka] wherein A1 is selected from -CH, -CR6, or -N; R6 is absent, 1 or 2, and is independently selected from -H, -Cl, -F, -CHF2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -CN, cyclopropyl, or an aryl group; Formula (ii) [ka] (In the formula, R 10 is absent, 1 or 2 and is independently selected from -Cl, -F, -CH3, -CHF2, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -CN, cyclopropyl, or an aryl group; or adamantane ring, a phenyl group optionally containing one or two substituents independently selected from fluorine or chlorine, a pyrazole optionally containing at least one substituent selected from methyl (such as two methyl substituents), cyclopropyl, or tert-butyl, an indazole optionally containing at least one methyl substituent, a phenyl-pyrazole, where the pyrazole optionally contains at least one substituent selected from -CH2CH2(CH3)2, a phenyl-pyrazole, a phenyl-triazole, where the phenyl group is a salt right-side substitution of the piperazine core selected from phenyl-triazole, phenyl-imidazole, where the phenyl group optionally contains at least one substituent selected from chlorine or fluorine, such as chlorine and fluorine substituents, and the imidazole optionally contains at least one substituent selected from methyl or -CHCH(CH); X1, [ka] [ka] wherein R1 is selected from -H, deuterium, -CH3, -CHF2, -CH2CH3, -CF3, -F, -CH2OCH3, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; R2 is selected from -H, deuterium, -CH3, -CH2CH3, -CF3, or cyclopropyl; R3 is selected from -H or deuterium, or R2 and R3 together form a cyclic ring selected from cyclopropyl, cyclobutyl, or oxetane; R4 is selected from -CH3, -CH2CH3, -CF3, -CHF2, or CH2Oalkyl; R8 is selected from -H, -CH3, -CH2CH3, -CF3, -F, -CH2OCH3, cyclopropyl, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; R9 is selected from -H, -CH3, -CF3, -F, or CH2CH3, or R8 and R9 together form a cyclic ring selected from cyclopropyl, cyclobutyl, or oxetane; R 11 is selected from -H or -CH3; R 12 is selected from -H, -CH3, -CH2OH, -COOH, -CH2OCH3, -COOCH3, or R 11 and R 12 together form an azetidine ring optionally containing at least one methyl substituent; R 13 is selected from -H or -CH3; R 14 is selected from tetrahydropyran, phenyl, cyclopentane optionally containing an -OCH or -OH substituent, -C(CH), methoxycyclohexane, cyclohexane containing at least one substituent selected from -CH, -F, or =O; R 15 is selected from -OCH3 or -Cl; R 16 is selected from indole or tetrahydropyran optionally containing at least one methyl substituent; A2 is selected from -CH2, -CF2, -CHOH, or -O-; or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0016] In certain embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0017] In another embodiment, there is provided a compound of formula (II) having a piperazine core, [ka] wherein W1 is selected from -H, -CH3, -CH2CH3, -CF3, -F, -CH2OCH3, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; W2 is selected from -H, -CH3, -CH2CH3, or cyclopropyl; or W1 and W2 together form a cyclic ring, including cyclopropyl, cyclobutyl, oxetane, or W1 and W2 together are =O; S1 is selected from -H, -CH3, -CH2CH3, or -CF3; S2 is selected from -H or -CH3; X2 is absent or -CONH-; X3 is an adamantane ring or a group represented by formula (i) [ka] wherein R6 is absent, 1 or 2, and is independently selected from -H, -Cl, -F, -CHF2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -CN, cyclopropyl, or an aryl group; X1, [ka] wherein R1 is selected from -H, deuterium, -CH3, -CH2CH3, -CF3, -F, -CH2OCH3, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; R2 is selected from -H, deuterium, -CH3, -CH2CH3, -CF3, or cyclopropyl; R3 is selected from -H or deuterium, or R2 and R3 together form a cyclic ring selected from cyclopropyl, cyclobutyl, or oxetane; R 11 is selected from -H or -CH3; R 12 is selected from -H, deuterium, -CH3, -CH2OH, -COOH, -CH2OCH3, -COOCH3, or R 11 and R 12 together form an azetidine ring optionally containing at least one methyl substituent; R 13 is selected from -H, deuterium, or -CH3; A is a left-side substitution of the piperazine core, which may be selected from -CH, -N, or -CR6; or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0018] In certain embodiments, the compound of formula (II) is [ka] or a pharma- ceutically acceptable salt thereof.

[0019] In another embodiment, a compound of formula (III) having a 1,4 diazepane core, [ka] wherein the 1,4-diazepane core optionally includes a 2,7-CH2- bridge, a 2,7-CH2CH3 bridge, or a 3,7-CH2CH3 bridge; W1 is selected from -H, -CH3, -CH2CH3, -CF3, -F, -CH2OMe, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; W2 is selected from -H, -CH3, -CH2CH3, or cyclopropyl; or W1 and W2 together form a cyclic ring, including cyclopropyl, cyclobutyl, oxetane, or W1 and W2 together are =O; W3 is absent or =O; S1 is selected from -H, -CH3, -CH2CH3, or -CF3; S2 is selected from -H or -CH3; X2 is absent or -CONH-; X3 is a group represented by the formula (i) [ka] wherein R6 is absent, 1 or 2, and is independently selected from -H, -Cl, -F, -CHF2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -CN, cyclopropyl, or an aryl group; adamantane ring, and a phenyl group optionally containing one or two substituents independently selected from fluorine or chlorine; X1, [ka] wherein R1 is selected from -H, deuterium, -CH3, -CH2CH3, -CF3, -CHF2, -F, -CH2OCH3, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; R2 is selected from -H, -CH3, -CH2CH3, -CF3, or cyclopropyl; R3 is -H or R2 and R3 together form a cyclic ring selected from cyclopropyl, cyclobutyl, or oxetane; R 11is selected from -H or -CH3; R 12 is selected from -H, deuterium, -CH3, -CH2OH, -COOH, -CH2OCH3, -COOCH3, or R 11 and R 12 together form an azetidine ring optionally containing at least one methyl substituent; R 13 is selected from -H, deuterium, or -CH3; A is a left-handed substitution of the 1,4-diazepane core, which may be selected from -CH, -N, or -CR6; or a pharma- ceutically acceptable salt thereof is disclosed herein.

[0020] In certain embodiments, the compound of formula (III) is [ka] or a pharma- ceutically acceptable salt thereof.

[0021] In certain embodiments, the compound of formula (III) is a compound of formula (IV) having a 1,4-diazepane core, [ka] wherein W1, W2, S1, S2, X1, X2, and X3 are as defined for formula (III), or a pharma- ceutically acceptable salt thereof.

[0022] In certain embodiments, the compound of formula (IV) is [ka] or a pharma- ceutically acceptable salt thereof.

[0023] In certain embodiments of the compounds disclosed herein, S1 and S2 are -H and X2 is absent, and in certain embodiments, S1 and S2 are -H and X2 is -CONH-. According to certain embodiments, X1 is of formula (a), R2, R3, and R 11 Each of R, R 12 , and R 13 Each of is -CH3. In certain embodiments, X1 is of formula (a), and R1, R 12 , and R 13 Each of the formulas contains deuterium.

[0024] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV) or a pharma- ceutically acceptable salt thereof as disclosed herein 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.

[0025] 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), formula (II), formula (III), formula (IV) disclosed herein, or a pharma- ceutically acceptable salt thereof. 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.

[0026] In yet another aspect, disclosed herein is a compound of formula (I) disclosed herein, or its pharma- ceutically acceptable salt, or a pharmaceutical composition disclosed herein, for use in treating a disease or condition associated with abnormal function or activity of T-type calcium channel.In a particular aspect, the disease or condition associated with abnormal function or activity of T-type calcium channel is psychiatric disorder, pain, tremor, seizure, epilepsy, or epilepsy syndrome.In a particular embodiment, the disease or condition associated with abnormal function or activity of T-type calcium channel is tremor, such as essential tremor. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] 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.

[0028] 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.

[0029] 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 treatment and prophylactic treatment.

[0030] 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.

[0031] 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.

[0032] 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., a pediatric subject (e.g., an infant, a child, or an adolescent), or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)), 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.

[0033] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0034] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular 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 taken before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0035] 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.

[0036] 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, inside cover of Handbook of Chemistry and Physics, 75th Ed., and specific functional groups are generally defined as described herein. 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.

[0037] 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 exist 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.

[0038] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that a 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.

[0039] In the compositions provided herein, the enantiomerically pure compounds can be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R compound can 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 can 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 can 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 can 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 can be formulated with little or no excipients or carriers.

[0040] The compounds described herein may also include one or more isotopic substitutions. For example, H is: 1 H, 2 H (D or deuterium), and3 H may be in any isotopic form, including T or tritium, and C may be 12 C. 13 C, and 14 It may be in any isotopic form, including C, and O is 16 O and 18 It may be any isotopic form containing O, and so on.

[0041] 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 is also understood that, as described herein, any of the moieties defined below may be substituted with various substituents, and each definition is intended to include such substituted moieties within their scope as described below. Unless otherwise indicated, the term "substituted" is to be defined as described below. It is further understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can 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.

[0042] 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" means C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-6 Alkyl, C 2-5 Alkyl, C 2-4Alkyl, C 2-3 Alkyl, C 3-6 Alkyl, C 3-5 Alkyl, C 3-4 Alkyl, C 4-6 Alkyl, C 4-5 Alkyl, and C 5-6 Alkyl is intended to be included.

[0043] "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, an alkyl group has one carbon atom ("C alkyl"). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

[0044] The term "alkyl" encompasses alkyl groups that are unsubstituted or substituted with various substituents as described herein. For example, an alkyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, 6 or more) substituents as described herein. Exemplary substituents for an alkyl group include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, nitro (-NO2), amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C31, C42, C53, C64, C75, C86, C97, C11, C12, C13, C14, C15, C16, C17, C18, C21, C19, C22, C31, C42, C12, C13, C14, C15, C21, C16, C17, C22, C18, C19, C23, C24, C31, C12, C13, C25, C31, C14, C15, C26, C31, C15, C16, C17, C22, C31, C12, C13, C14, C15, C22, C16, C17, C23, C18, C19, C24, C31, C19, C23, C31, C19, C24, C31, C19, C23, C31, C24, C31 1-6 alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6 alkoxy), -COOCH3, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the alkyl group may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH3, and cyclopropyl.

[0045] "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, the alkenyl does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C 2-10In 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, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0046] The term "alkenyl" encompasses alkenyl groups that are unsubstituted or substituted with various substituents as described herein. Exemplary substituents for alkenyl groups include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, nitro (-NO2), amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C31, C42, C53, C64, C76, C86, C97, C98, C110, C120, C130, C140, C150, C160, C170, C180, C190, C190, C210, C220, C310, C42, C53, C64, C76, C86, C97, C120, C130, C140, C150, C160, C170, C180, C190, C190, C210, C190, C210, C220, C310, C310, C42, C53, C64, C76, C86, C97, C120 ... 1-6 alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6 alkoxy), -COOCH3, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the alkenyl group may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH3, and cyclopropyl.

[0047] "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 any double bonds. 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 2-9In 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, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups include, as well as, pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like.

[0048] The term "alkynyl" encompasses alkynyl groups that are unsubstituted or substituted with various substituents as described herein. Exemplary substituents for alkynyl groups include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, nitro (-NO2), amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C31, C42, C53, C64, C75, C86, C97, C98, C110, C120, C130, C140, C150, C160, C170, C180, C190, C191, C192, C193, C194, C195, C196, C197, C198, C206, C207, C208, C210, C211, C212, C213, C214, C215, C225, C230, C240, C250, C260, C271, C282, C293, C316, C316, C316, C42, C43, C44, C45, C53, C54, C55, C66, C67, C68, C79, C79, C81, C82, C93, C94, C95, C96, C97, C98, C105, C106, C107, C1 1-6alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6 alkoxy), -COOCH3, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, alkynyl groups can be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH3, and cyclopropyl.

[0049] The term "alkoxy" refers to alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. The term "alkoxy" encompasses alkoxy groups in which the alkyl, alkenyl, and alkynyl portions are unsubstituted or substituted with various substituents described herein.

[0050] The term "amino" refers to the group -NH2. The term "alkylamino" refers to the group -NHR1 where R1 is alkyl, e.g., methylamino or ethylamino. The term "dialkylamino" refers to the group -NR1R2 where R1 and R2 are both alkyl, e.g., dimethylamino, methylethylamino, or diethylamino.

[0051] "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 6-14In some embodiments, an aryl group has 6 ring carbon atoms ("C 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 with one or more carbocyclyl or heterocyclyl groups, where the radical or point of attachment is on the aryl ring, and in such cases 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. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0052] The term "aryl" encompasses aryl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for the aryl group include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, nitro (-NO2), amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C31, C42, C53, C64, C75, C86, C97, C98, C110, C120, C130, C140, C150, C160, C170, C180, C190, C191, C192, C193, C194, C195, C196, C197, C198, C201, C202, C203, C204, C205, C206, C207, C208, C210, C211, C212, C213, C214, C215, C225, C230, C240, C251, C252, C260, C271, C282, C293, C294, C316, C316, C316, C316, C316, C316, C42, C43, C44, C45, C46, ​​C47, C48, C53, C54, C55, C56, C65, C6 1-6alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6 alkoxy), -COOCH3, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the aryl group may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH3, and cyclopropyl. In some embodiments, the aryl group may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy, and cyclopropyl.

[0053] "Hetero", when used to describe a compound or a group present on a compound, means that one or more carbon atoms in the compound or group are replaced with a heteroatom, which is nitrogen, oxygen, or sulfur. Hetero can apply to any of the above mentioned 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.

[0054] "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 atom or at a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in either or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring defined above is fused with one or more aryl groups, where the point of attachment is on either the aryl or heteroaryl ring, and in such cases 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 with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl). Non-limiting examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, indazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, piperazine, benzofuran, quinazoline, benzisoxazole, quinolone, isoquinoline, and naphthyridine. The term "naphthyridine" includes 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,6-naphthyridine, and 2,7-naphthyridine.

[0055] The term "heteroaryl" encompasses heteroaryl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for heteroaryl groups include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, nitro (-NO2), amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C31, C42, C53, C64, C76, C86, C97, C98, C110, C120, C130, C140, C150, C160, C170, C180, C190, C190, C210, C220, C310, C42, C53, C64, C76, C86, C97 ...20, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, C120, 1-6 alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6 alkoxy), -COOCH3, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the heteroaryl moiety may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH3, and cyclopropyl.

[0056] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system ("5-8 membered heteroaryl") having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system ("5-6 membered heteroaryl") having ring carbon atoms and 1-4 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system. 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.

[0057] 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 3-6Carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-5 The carbocyclyl group is the aforementioned C 3-6 Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3-10 The carbocyclyl group is the aforementioned C 3-8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), 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, where the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to designate the number of carbons in the carbocyclic ring system.

[0058] The term "carbocyclyl" encompasses carbocyclyl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents of carbocyclyl groups include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C31, C42, C53, C64, C75, C86, C97, C98, C110, C120, C130, C140, C150, C160, C170, C180, C190, C190, C200, C210, C220, C310, C320, C43, C44, C55, C66, C77, C78, ​​C79, C81, C82, C83, C84, C85, C86, C97, C98, C99, C100, C111, C122, C132, C140, C150, C160, C171, C172, C173, C174, C175, C175, C176, C177, C178, C179, C179, C181, C182, C183, C184, C185, C186, C187, C188, C189, C191, C192, C193, C 1-6 alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6 alkoxy), -COOCH, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the carbocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH, and cyclopropyl.

[0059] "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 atom or at a 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 either 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 ring or the heterocyclyl ring, or 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 which case the number of ring members continues to designate the number of ring members in the heterocyclyl ring system.

[0060] The term "heterocyclyl" encompasses heterocyclyl moieties that are unsubstituted or substituted with various substituents as described herein. Exemplary substituents on heterocyclyl groups include halo (e.g., fluoro, chloro, and bromo), hydroxyl, cyano, amino (-NH2), alkylamino (e.g., methylamino or ethylamino), dialkylamino (e.g., dimethylamino or diethylamino), alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C31, C42, C53, C64, C75, C86, C97, C98, C110, C120, C130, C140, C150, C160, C170, C180, C190, C190, C210, C220, C31, C42, C53, C64, C75, C86, C97, C120 ... 1-6 alkyl), alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy, etc. 1-6alkoxy), -COOCH, carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclyl (e.g., oxirane, oxytane, tetrahydrofuran, etc.), aryl (e.g., phenyl), and heteroaryl (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the heterocyclyl group may be substituted with one or more substituents selected from the group consisting of fluoro, chloro, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, t-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH, and cyclopropyl.

[0061] 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 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 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 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 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0062] 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. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.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, and the like.

[0063] "Cyano" refers to -CN.

[0064] "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, a halo group is fluoro or chloro.

[0065] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0066] "Nitro" refers to -NO2.

[0067] In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen (e.g., carbon or nitrogen atom) present in a group is replaced with a permissible 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 specified, a "substituted" group has a substituent at one or more substitutable positions of 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.

[0068] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. -, H2PO4 - , HSO4 - , SO4 - , 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.).

[0069] 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 derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-butyl salts. + (C 1-4Representative alkali metal 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.

[0070] 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 release controlling polymer. For example, the release modifying polymer or release controlling 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).

[0071] The term "diluent" as used herein refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dibasic calcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol, and mannitol).

[0072] 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.

[0073] The term "lubricant" as used herein refers to an excipient used to prevent ingredients from clumping together and sticking to tablet punches or capsule filling machines. Lubricants are 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).

[0074] As used herein, the term "coating" refers to an excipient that protects tablet ingredients from deterioration due to moisture in the air and also makes large or unpleasant tasting tablets easier to swallow.

[0075] The embodiments disclosed herein are not intended to be limited in any way by the recitation of exemplary chemical groups and substituents above.

[0076] compound In one aspect, disclosed herein are compounds and compositions thereof for the modulation of T-type calcium channels and a disease, disorder, or condition 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, e.g., absence seizures, juvenile myoclonic epilepsy, status epilepticus, or genetic epilepsy).

[0077] In some aspects, the present disclosure provides a compound represented by formula (Ia): [ka] During the ceremony, B is absent or selected from the group consisting of -CH-, -CH-CH, -CH-CH-CH, -O-, -CH-O-, -O-CH-, and -CH-O-CH-; W1' and W2' are each independently selected from the group consisting of -H, deuterium, alkyl, and alkoxy, or W1' and W2' together form a carbocyclyl, heterocyclyl, or carbonyl (=O); S1' and S2' are each independently selected from the group consisting of -H and -CH3, or S1' and S2' together form a carbonyl; X2' is absent, -CH2-, -CHCH3-, or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; X1' is (i) [ka] (In the formula, R2' and R3' are each independently selected from the group consisting of -H, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocyclyl, and heterocyclyl, or R2' and R3' together form a cyclic ring; R4' and R5' are each independently selected from the group consisting of -H, deuterium, halo, CN, alkyl, and alkoxy, or R4' and R5' together form a carbonyl; R1' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, -OZ1', -NZ2'Z3', and -SO2Z7'; Z1' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl; Z2' and Z3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, -COZ'5, and -SO2Z6', or Z2' and Z3' together with the nitrogen to which they are attached form a heterocyclyl; Z5' is C 3-6 is a carbocyclyl, Z6' is C 1-6 is alkyl, or Z7' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl, or (ii) [ka] (In the formula, R6' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, and pharma- ceutically acceptable salts thereof.

[0078] In some embodiments of Formula (Ia), B is absent. In some embodiments of Formula (Ia), B is -CH2-. In some embodiments of Formula (Ia), B is -CH2-CH2-.

[0079] In some embodiments of Formula (Ia), W1' and W2' are both hydrogen.

[0080] In some embodiments of Formula (Ia), S1' and S2' are both hydrogen.

[0081] In some embodiments of Formula (Ia), R2' and R3' are both hydrogen.

[0082] In some embodiments of Formula (Ia), R4' and R5' together form a carbonyl.

[0083] In some embodiments of Formula (Ia), R 1 ' is -NZ 2 'Z 3 '.

[0084] In some embodiments of Formula (Ia), Z2' is hydrogen or methyl and Z3' is C 1-6 Alkyl, C 3-6 carbocyclyl or heterocyclyl, where C 1-6 Alkyl, C 3-6Each of the carbocyclyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxyl, halo, methoxy, trifluoromethyl, and -COOCH3. In some embodiments, Z2' is hydrogen and Z3' is C 1-6 In one embodiment, Z3' is t-butyl.

[0085] In some embodiments of Formula (Ia), Z2' is hydrogen and Z3' is cyclopropyl, cyclobutyl, or oxetane.

[0086] In some embodiments of Formula (Ia), R4' and R5' are each independently hydrogen, hydroxyl, or halo.

[0087] In some embodiments of Formula (Ia), R1' is -NZ2'Z3', Z2' is hydrogen and Z3' is -COZ5'.

[0088] In some embodiments of Formula (Ia), R 1 ' is alkyl, carbocyclyl, or heterocyclyl.

[0089] In some embodiments of Formula (Ia), X2' is -CONH-.

[0090] In some embodiments of formula (Ia), X3' is aryl or heteroaryl, where each of the aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, and t-butyl. In some embodiments of formula (Ia), X3' is selected from the group consisting of phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran, quinazoline, phenyl-imidazole, phenyl-triazole, phenyl-pyrazole, and an adamantane ring. In one embodiment, X3' is phenyl optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro, cyano, methyl, methoxy, difluoromethoxy, and trifluoromethoxy. In one embodiment, X3' is benzimidazole optionally substituted with two substituents selected from the group consisting of chloro and fluoro.

[0091] In some embodiments, the compound of formula (Ia) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is.

[0092] In some aspects, the present disclosure provides a compound represented by formula (IIa): [ka] During the ceremony, The stereocenters marked with * are both in the S configuration or both in the R configuration, B is selected from the group consisting of -CH-, -CH-CH, -CH-CH-CH, -O-, -CH-O-, -O-CH-, and -CH-O-CH-; S1' and S2' are each independently selected from the group consisting of -H and -CH3, or S1' and S2' together form a carbonyl; X2' is absent, -CH2-, -CHCH3-, or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; X1' is (i) [ka] (In the formula, R2' and R3' are each independently selected from the group consisting of -H, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocyclyl, and heterocyclyl, or R2' and R3' together form a cyclic ring; R4' and R5' are each independently selected from the group consisting of -H, deuterium, halo, CN, alkyl, and alkoxy, or R4' and R5' together form a carbonyl; R1' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, -OZ1', -NZ2'Z3', and -SO2Z7'; Z1' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl; Z2' and Z3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, -COZ'5, and -SO2Z6', or Z2' and Z3' together with the nitrogen to which they are attached form a heterocyclyl; Z5' is C 3-6 is a carbocyclyl, Z6' is C 1-6 is alkyl, or Z7' is selected from the group consisting of alkyl, carbocyclyl, and heterocyclyl, or (ii) [ka] (In the formula, R6' is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, and pharma- ceutically acceptable salts thereof.

[0093] In some embodiments of formula (IIa), both stereocenters designated * are in the S configuration. In some embodiments of formula (IIa), both stereocenters designated * are in the R configuration.

[0094] In some embodiments of Formula (IIa), B is -CH2-. In some embodiments of Formula (IIa), B is -CH2-CH2-.

[0095] In some embodiments of Formula (IIa), S1' and S2' are both hydrogen.

[0096] In some embodiments of Formula (IIa), R2' and R3' are both hydrogen.

[0097] In some embodiments of Formula (IIa), R4' and R5' together form a carbonyl.

[0098] In some embodiments of formula (IIa), R is -NZZ. In some embodiments, Z is hydrogen or methyl and Z is C 1-6 Alkyl, C 3-6 carbocyclyl or heterocyclyl, where C 1-6 Alkyl, C 3-6 Each of the carbocyclyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxyl, halo, methoxy, trifluoromethoxy, and -COOCH3. In some embodiments, Z2' is hydrogen and Z3' is C 1-6 In one embodiment, Z3' is t-butyl.

[0099] In some embodiments of Formula (IIa), Z2' is hydrogen and Z3' is cyclopropyl, cyclobutyl, or oxetane.

[0100] In some embodiments of Formula (IIa), R4' and R5' are each independently hydrogen, hydroxyl, or halo.

[0101] In some embodiments of formula (IIa), R1' is -NZ2'Z3', Z2' is hydrogen, and Z3' is -COZ5'. In some embodiments of formula (IIa), R1' is alkyl, carbocyclyl, or heterocyclyl.

[0102] In some embodiments of Formula (IIa), X2' is -CONH-.

[0103] In some embodiments of formula (IIa), X3' is aryl or heteroaryl, where each of the aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, and t-butyl. In some embodiments, X3' is selected from the group consisting of phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran, quinazoline, phenyl-imidazole, phenyl-triazole, phenyl-pyrazole, bicycloheptane, bicyclooctane, and an adamantane ring. In one embodiment, X3' is phenyl optionally substituted with two substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, difluoromethoxy, and trifluoromethoxy.

[0104] In some embodiments, the compound of formula (IIa) is [ka] [ka] [ka] [ka] [ka] [ka] It is.

[0105] In some aspects, the present disclosure provides a compound represented by formula (IIIa): [ka] During the ceremony, One stereocenter indicated with an * is in the S configuration, and the other stereocenter indicated with an * is in the R configuration; B is -CH2-, -CH2-CH2, -CH2-CH2-CH2, -O-, -CH2-O-, -O-CH2-, or -CH2-O-CH2-; D is carbon or nitrogen; X1' is alkyl; X2' is -NHCO- or -CONH-; Compounds and pharma- ceutically acceptable salts thereof are provided, wherein X3' is aryl or heteroaryl.

[0106] In some embodiments of Formula (IIIa), C is -CH2-O-CH2-.

[0107] In some embodiments of Formula (IIIa), X1' is t-butyl.

[0108] In some embodiments of Formula (IIIa), X3' is phenyl or benzimidazole, where phenyl and benzimidazole are each optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro, and difluoromethoxy.

[0109] In some embodiments, the compound of formula (IIIa) is [ka] It is.

[0110] In some aspects, the present disclosure provides a compound represented by formula (IVa): [ka] During the ceremony, The stereocenter marked with * is in the R or S configuration; X1' is alkyl; X2' is -O- or NR1R2, where R1 and R2 are each independently H or alkyl; Compounds and pharma- ceutically acceptable salts thereof are provided, wherein X3' is aryl or heteroaryl.

[0111] In some embodiments, the compound of formula (IVa) is [ka] It is.

[0112] In some aspects, the present disclosure provides a compound represented by formula (Va): [ka] During the ceremony, the 1,4-diazepane core in the compound of formula (Va) optionally comprises a 2,7-CH2-bridge, a 2,7-CH2CH2-bridge, a 3,7-CH2-bridge, or a 3,7-CH2CH2-bridge; W1' and W2' are each independently hydrogen, deuterium, alkyl, and alkoxy, or W1' and W2' together form a carbocyclyl, heterocyclyl, or carbonyl (=O); W3 is hydrogen or carbonyl; S1' and S2' are each independently hydrogen or alkyl, or S1' and S2' together form a carbonyl; X2' is absent, -CH2-, -CHCH3-, or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl; X1' is [ka] (In the formula, R1' is selected from the group consisting of hydrogen, alkyl, carbocyclyl, and heterocyclyl; R2' and R3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocyclyl, and heterocyclyl, or R2' and R3' together form a cyclic ring; R11 ' is hydrogen or methyl; R 12 is selected from the group consisting of hydrogen, deuterium, and alkyl, or R 11 ' and R 12 ' together form an azetidine ring optionally containing at least one methyl substituent, R 13 is selected from the group consisting of hydrogen, deuterium, and alkyl, and pharma- ceutically acceptable salts thereof.

[0113] In some embodiments, the compound of formula (Va) is also represented by formula (Vb): [ka] wherein W1', W2', S1', S2', X1', X2', and X3' are as defined for formula (Va).

[0114] In some embodiments of Formula (Va) or Formula (Vb), X3' is selected from the group consisting of a phenyl, a benzimidazole, and an adamantane ring, wherein the phenyl and the benzimidazole are each optionally substituted with one or two substituents selected from chloro and fluoro.

[0115] In some embodiments, the compound of formula (Va) is [ka] It is.

[0116] In some aspects, the present disclosure provides a compound represented by formula (VIa): [ka] During the ceremony, R1' and R2' are each hydrogen, or R1' and R2' together form a carbonyl; Also provided are compounds, and pharma- ceutically acceptable salts thereof, wherein R3' is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxyl, amino, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, and trifluoromethoxy.

[0117] In some embodiments, R3' is isoquinoline. In some embodiments, R3' is naphspiridine.

[0118] In some embodiments, the compound of formula (VIa) is [ka] It is.

[0119] In one aspect, the present disclosure provides a compound having the following structure: [ka] Also provided is a compound of the formula:

[0120] In some embodiments, the compounds disclosed herein include compounds of formula (I) or formula (II) having a piperazine core, and in certain embodiments, the compounds disclosed herein include compounds of formula (III), including compounds of formula (IV), a 1,4-diazepane core. In certain embodiments disclosed herein, a compound selected from formula (I), formula (II), or formula (III), [ka] [ka] [ka] wherein the 1,4-diazepane core of formula (III) optionally includes a 2,7-CH2- bridge, a 2,7-CH2CH3 bridge, or a 3,7-CH2CH3 bridge; n is selected from 0, 1, or 2; W1 and W2 are independently selected from -H, -CH3, -CH2CH3, -CF3, -F, -CH2OCH3, -CH2CF3, -CH2OCF3, cyclopropyl, or -CH2Ocyclopropyl; or W1 and W2 together form a cyclic ring, including cyclopropyl, cyclobutyl, oxetane, or W1 and W2 together are =O; S1 and S2 are independently selected from -H, -CH3, -CH2CH3, or -CF3; X2 is absent, -CH2 or -CONH-; X3 is a group represented by the formula (i) [ka] wherein A1 is selected from -CH, -CF2, -COH, -N, -O, or -CR6; R6 is absent, 1 or 2, and is independently selected from -H, -Cl, -F, -CF2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -CN, cyclopropyl, or an aryl group; Formula (ii) [ka] (In the formula, R 10 is absent, 1 or 2 and is independently selected from -Cl, -F, -CH3, -CF3, -CHF2, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -OCHF2, -CN, cyclopropyl, or an aryl group; or adamantane ring, a phenyl group optionally containing one or two substituents independently selected from fluorine or chlorine, a pyrazole optionally containing at least one substituent selected from methyl (such as two methyl substituents), cyclopropyl, or tert-butyl, an indazole optionally containing at least one methyl substituent, a phenyl-pyrazole, where the pyrazole optionally contains at least one substituent selected from -CH2CH2(CH3)2, a phenyl-pyrazole, a phenyl-triazole, where the phenyl group optionally contains a chlorine substituent and a right-side substitution of a piperazine or 1,4-diazepane core selected from phenyl-triazole, phenyl-imidazole, where the phenyl group optionally contains at least one substituent selected from chlorine or fluorine, such as a chlorine and fluorine substituent, and the imidazole optionally contains at least one substituent selected from methyl or -CHCH(CH); X1, [ka] wherein R1 is selected from -H, deuterium, -CH3, -CH2CH3, -CF3, -F, -CH2OCH3, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; R2 is selected from -H, deuterium, -CH3, -CH2CH3, -CF3, or cyclopropyl; R3 is selected from -H or deuterium, or R2 and R3 together form a cyclic ring selected from cyclopropyl, cyclobutyl, or oxetane; R4 is selected from -CH3, -CH2CH3, -CF3, -F, or CH2Oalkyl; R8 is selected from -H, -CH3, -CH2CH3, -CF3, -F, -CH2OCH3, cyclopropyl, -CH2CF3, -CH2OCF3, or -CH2Ocyclopropyl; R9 is selected from -H, -CH3, -CF3, -F, or CH2CH3, or R8 and R9 together form a cyclic ring selected from cyclopropyl, cyclobutyl, or oxetane; R 11 is selected from -H or -CH3; R 12 is selected from -H, deuterium, -CH3, -CH2OH, -COOH, -CH2OCH3, -COOCH3, or R 11 and R 12 together form an azetidine ring optionally containing at least one methyl substituent; R 13 is selected from -H, deuterium, or -CH3; R 14 is selected from tetrahydropyran, phenyl, cyclopentane optionally containing an -OCH or -OH substituent, -C(CH), methoxycyclohexane, cyclohexane containing at least one substituent selected from -CH, -F, or =O; R 15 is selected from -OCH3 or -Cl; R 16 is selected from indole or tetrahydropyran optionally containing at least one methyl substituent; A2 is selected from -CH2, -CF2, -CHOH, or -O-; or a pharma- ceutically acceptable salt thereof.

[0121] In certain embodiments, X1 is of formula (a), and R1, R2, R3, R 11 , R 12 , and R 13is -H. In certain embodiments, S1 and S2 are -H. In certain embodiments, X2 is absent, and in certain embodiments, X2 is -CONH. In certain embodiments, X3 is formula (i), and in certain embodiments of formula (i), R6 is 2 and includes one each of fluorine and chlorine.

[0122] In certain embodiments, the compounds disclosed herein are compounds of formula (I) having the structure depicted below: [ka] [ka] [ka] [ka] [ka] or a pharma- ceutically acceptable salt thereof.

[0123] In certain embodiments, the compounds disclosed herein are compounds of formula (II) having the structure depicted below: [ka] or a pharma- ceutically acceptable salt thereof.

[0124] In certain embodiments, the compounds disclosed herein are compounds of formula (III) having the structure depicted below: [ka] or a pharma- ceutically acceptable salt thereof.

[0125] In certain embodiments, the compounds disclosed herein are compounds of formula (III) and compounds of formula (IV) [ka] wherein W1, W2, S1, S2, X1, X2, and X3 are as defined above for formula (III), or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compounds disclosed herein are compounds of formula (IV), having the structure depicted below: [ka] or a pharma- ceutically acceptable salt thereof.

[0126] composition In one aspect, the compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) disclosed herein, or pharma- ceutically acceptable salts 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.

[0127] In some embodiments, a composition that can be used in the methods described herein can be a pharmaceutical composition comprising a compound of Formula (I), (II), (III), or (IV) disclosed herein, or a pharma- ceutically acceptable salt thereof, and an excipient that functions to modulate the release rate of the compound of Formula (I), (II), (III), or (IV) disclosed herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition can be a swellable core technology formulation.

[0128] 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), Formula (II), Formula (III), or Formula (IV) 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), Formula (II), or Formula (III) disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0129] 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, ...5% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 30% by weight, about 40% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about 50% by weight, about %, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 40% by weight of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) 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), Formula (II), Formula (III), or Formula (IV) disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0130] In some embodiments, the dosage form may comprise, for example, about 4% to about 25% by weight, such as 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), Formula (II), Formula (III), or Formula (IV) disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0131] In some embodiments, a dosage form that can be used in the methods described herein can be a dosage form or composition that contains from 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 disclosed herein or a pharma- ceutically acceptable salt thereof.

[0132] In other embodiments, a dosage form that can be used in the methods described herein 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), Formula (II), Formula (III), or Formula (IV) disclosed herein, or a pharma- ceutical acceptable salt thereof, and, for example, when administered to a subject, a compound of Formula (I), Formula (II), and a release modifying polymer (e.g., a release controlling polymer, a hydrophilic matrix polymer such as 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 (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof.

[0133] 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), Formula (II), Formula (III), or Formula (IV) 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), 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), of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) disclosed herein, or a pharma- ceutically acceptable salt thereof.

[0134] In some embodiments, the dosage form comprises about 55 mg to about 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).

[0135] 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 (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) of microcrystalline cellulose. 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).

[0136] 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.

[0137] In some embodiments, upon administration to a subject, about 80% of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof disclosed herein is released within 7 hours. In certain embodiments, about 80% of the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof disclosed herein 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.

[0138] 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.

[0139] In other embodiments, the dosage form is administered to a patient once a day. In certain embodiments, the dosage form is administered to a patient twice a day. 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.

[0140] In some embodiments, a dosage form that can be used in the methods described herein can be an oral dosage form (e.g., a microparticle) comprising about 15 mg to 25 mg of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, and about 55 mg to 65 mg of an HPMC polymer.

[0141] In other embodiments, a dosage form that can be used in the methods described herein can be an oral dosage form (e.g., a microparticle) comprising about 14% to about 25% by weight of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, and about 53% to about 64% by weight of an HPMC polymer.

[0142] In certain embodiments, a dosage form that can be used in the methods described herein can be an oral dosage form (e.g., a microparticle) comprising about 3 mg to 8 mg of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, and about 55 mg to 65 mg of an HPMC polymer.

[0143] In some embodiments, a dosage form that can be used in the methods described herein can be an oral dosage form (e.g., a microparticle) comprising about 3% to about 8% by weight of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, and about 53% to about 64% by weight of an HPMC polymer.

[0144] In other embodiments, a 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), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, and a release modifying polymer (e.g., a release controlling polymer, e.g., an HPMC polymer as a hydrophilic matrix polymer).

[0145] In some embodiments, the composition comprises about 0.9% to about 40% by weight of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), 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), Formula (II), or Formula (III), or a pharma- ceutically acceptable salt thereof.

[0146] 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), Formula (II), Formula (III), or Formula (IV), 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), Formula (II), Formula (III), or Formula (IV), 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), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof.

[0147] 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.

[0148] 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), Formula (II), Formula (III), or Formula (IV), 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.

[0149] 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), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, wherein the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, is released immediately after administration to a subject.

[0150] In other embodiments, a dosage form that can be used in the methods described herein can be an immediate release oral capsule comprising about 15 mg to about 20 mg of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, about 75 mg to 85 mg of a diluent, about 2 mg to 10 mg of a binder, about 1% to about 5% of a disintegrant, and about 0.1 mg to 5 mg of a lubricant.

[0151] 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).

[0152] In some embodiments, the dosage form is administered to the subject once daily (e.g., one 20 mg tablet once daily, two 20 mg tablets once daily, or three 20 mg tablets once daily). In some embodiments, the dosage form is administered to the subject twice daily (e.g., one 10 mg tablet twice daily, one 20 mg tablet twice daily, two 20 mg tablets twice daily, or three 20 mg tablets twice daily). In some embodiments, the dosage form is administered to the subject every other day. In certain embodiments, about 1 mg to about 60 mg, such as about 20 mg to about 40 mg, of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, is administered to the subject daily. In other embodiments, about 15 mg to 25 mg of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, is administered to a subject daily. In certain embodiments, about 30 mg to 40 mg of a compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof, is administered to a subject daily.

[0153] The compounds provided according to the present invention are usually administered in the form of pharmaceutical compositions. Thus, the present invention provides pharmaceutical compositions comprising one or more of the compounds described or their pharma- ceutically acceptable salts as active ingredients, 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 (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)).

[0154] The pharmaceutical compositions may be administered in either single or multiple doses by any of the accepted modes of administration of drugs having utilities similar to those described, for example, in the patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as, for example, a stent or an arterially inserted cylindrical polymer.

[0155] 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).

[0156] 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.

[0157] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose.The formulation may additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.

[0158] 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 that include polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are provided 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.

[0159] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for human subjects and other mammals as a unitary dosage, each unit containing a predetermined amount of active substance 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 medicament-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, taking into account 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.

[0160] 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 said to be homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, which allows the composition to be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0161] The tablets or pills disclosed herein can 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 tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former.These two components can be separated by an enteric layer that functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be released in a delayed manner.Various materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0162] Methods of 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), formula (II), formula (III), or formula (IV) 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) 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.

[0163] 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.

[0164] Epilepsy and epilepsy syndromes The compositions described herein are useful for treating 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.

[0165] 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 cry or make some kind of noise, stiffen for a few seconds to a minute, and then rhythmically move their arms and legs. The eyes may be open and / or the person may not appear to be breathing and may 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, eyelid myoclonic) seizures, and epileptic spasms. Partial or focal seizures involve only a part of the brain and therefore only one part of the body. Symptoms can vary, depending on the part of the brain that has abnormal electrical activity.

[0166] Epilepsy as referred to herein includes generalized, partial, complex partial (e.g., seizures that involve 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.

[0167] The compositions described herein may also be useful for treating epilepsy syndromes.Severe syndromes with diffuse brain dysfunction caused at least in part by some forms 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.

[0168] In some embodiments, the epilepsy syndrome includes 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.

[0169] 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, non-convulsive seizures characterized by the sudden onset of loss of consciousness and unresponsiveness, usually lasting 10-30 seconds, and with a rapid return to normal consciousness without postictal confusion. Seizures are characterized by the sudden onset and disappearance of generalized spike-and-wave discharges of 1-6 Hz (e.g., 3 Hz) 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 teenage years. However, in a minority of patients, absence seizures may persist into adulthood, where absence seizures are often refractory to medication, and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures are usually extremely disabling and are accompanied by significant psychosocial impairments, particularly by disqualifying affected individuals from obtaining a driver's license or pursuing occupations and hobbies where seizure-related periods of unconsciousness pose a safety risk (Wirrell et al., 1997).

[0170] Although there is a common perception that absence seizures are relatively "easily" treated, randomized controlled trials in patients with childhood absence epilepsy have shown 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 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 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.

[0171] There is abundant evidence that low-threshold (T-type) calcium channels are involved 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), formula (II), formula (III) 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 resistant to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0172] 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.

[0173] In some embodiments, the methods described herein further comprise identifying a subject having absence seizures.

[0174] 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 includes epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile 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 migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0175] 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 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 migratory 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.

[0176] 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 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 migratory partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy), comprising administering to a subject in need thereof a composition described herein.

[0177] The compositions of the invention can also be used to treat epileptic encephalopathy, where the subject is either: Mutations in one or more of NT1, 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.

[0178] In some embodiments, the methods described herein include administering to the patient an effective amount of any of the following: 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, MEF 2C, 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.

[0179] The compositions of the invention can also be used to treat epileptic encephalopathy, where the subject is receiving treatment with 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, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCN T1, 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, S ERPINI1, 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,Mutations in one or more of 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.

[0180] In some embodiments, the methods described herein involve the use of 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, DYRK, 1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRI N2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, L IAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNK P, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SI K1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX 1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H,The method further includes identifying subjects having a mutation in one or more of 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.

[0181] The compositions disclosed herein can also be used to treat epileptic encephalopathy, where a subject is receiving any of the following: 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, FOL R1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1, KCNJ10, KC NMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3, NR2F1, NRXN1, PACS1, PCDH19, PIGA 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.

[0182] In some embodiments, the methods described herein are directed to a method 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, FR RS1L, 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 subjects 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.

[0183] The compositions disclosed herein can also be used to treat epileptic encephalopathy, where a subject has a gene encoding 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, KCN J10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC1 Mutations in one or more of the following genes: 3A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0184] In some embodiments, the methods described herein are directed to the use of 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, P OLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A5, SLC25A22, SLC 2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0185] 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).

[0186] Clinical depression, also known as major depression, major depressive disorder (MDD), severe 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 activities that are normally enjoyable. Some people with clinical depression may 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 perform daily activities, making them feel like life is not worth living.

[0187] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, feelings of restlessness, difficulty sleeping, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of disconnection from the baby and / or fetus, and loss of interest in previously enjoyed activities.

[0188] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after giving birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0189] In some embodiments, subjects with PND have experienced depression or depressive symptoms during pregnancy. This depression is referred to herein as perinatal depression. In some embodiments, subjects who experience perinatal depression are at increased risk of experiencing PND.

[0190] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positive mood, significant weight gain, or increased appetite. Patients with AD may also have significant social impairment as a result of excessive sleep or somnolence (hypersomnia), heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0191] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), an inability to respond to pleasurable stimuli, a depressed mood that is more pronounced than sadness or loss, excessive weight loss, or excessive feelings of guilt.

[0192] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0193] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit aimless or bizarre movements.

[0194] Seasonal Affective Disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0195] Dysthymia refers to conditions related to unipolar depression that manifest with the same physical and cognitive problems. These tend to be less severe but last longer (e.g., at least two years).

[0196] Dual depression refers to a significant depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0197] Depressive personality disorder (DPD) refers to a personality disorder that has depressive features.

[0198] 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.

[0199] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0200] Bipolar disorder or manic-depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may feel or act unusually happy, energetic, or irritable. They often make ill-considered decisions with little consideration for the consequences. There is usually a decreased need for sleep. During periods of depression, there may be crying episodes, poor eye contact with others, and a negative outlook on life. The risk of suicide for those with the disorder is high at over 6% over a 20-year period, while 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.

[0201] 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.

[0202] Treatment-resistant depression refers to a state in which 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 then 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).

[0203] Postoperative depression refers to feelings of depression that occur after surgery (e.g., as a result of having to face one's mortality). For example, an individual may experience a persistent feeling of sadness or emptiness, a loss of pleasure or interest in hobbies and activities that they normally enjoy, or a persistent feeling of worthlessness or hopelessness.

[0204] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein).

[0205] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts of suicide or an abnormal obsession with suicide. The spectrum of suicidal ideation varies widely, for example, from flashes of thought to extensive thinking, detailed plans, role-playing, and / or unfinished attempts. Symptoms may include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless in situations, increasing alcohol or drug use, doing dangerous or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0206] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, 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, suicidal thoughts, 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 mental status examination).

[0207] 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.

[0208] 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 score 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 in the HAM-D total score from baseline after administration of the compositions described herein (e.g., 12, 24, or 48 hours, or 24, 48, 72, or 96 hours or more after administration, or 1 day, 2 days, 14 days, 21 days, or 28 days, or 1 week, 2 weeks, 3 weeks, or 4 weeks, or 1 month, 2 months, 6 months, or 10 months, or 1 year, 2 years, or lifetime).

[0209] In some embodiments, the subject has a mild depressive disorder, e.g., a mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., a moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., a severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., a 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 between 14 and 18 (including borderlines). In some embodiments, the subject's baseline HAM-D total score is between 19 and 22 (including borderlines). 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.

[0210] In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (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 or less. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within the first day or within the 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 effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within 14 days of initiating treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic effect (e.g., as determined by a statistically significant reduction in HAM-D total score) within 21 days of initiating 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.

[0211] 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 of 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).

[0212] The therapeutic effect on major depressive disorder can be determined by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score exhibited 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, 8 hours or less. The MADRS is a 10-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 a reduction from baseline in the MADRS score at the end of the treatment period (e.g., 14 days after administration).

[0213] pain The compounds and compositions described herein may be useful for treating 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.

[0214] 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), Formula (II), Formula (III), or Formula (IV), or a pharma- ceutically acceptable salt thereof).

[0215] 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 mellitus, 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 as physiological tremor, strong physiological tremor, essential tremor syndrome (including classic essential tremor), primary orthostatic tremor, task-specific and position-specific tremor, dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, toxin- or drug-induced tremor, and psychogenic tremor. Tremor can be familial tremor.

[0216] In some embodiments, subjects treated with compounds of the present disclosure have a clinical diagnosis of essential tremor. In some embodiments, subjects treated with compounds of the present disclosure have essential tremor but not intention tremor.

[0217] Tremor is an involuntary rhythmic vibration of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0218] 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, caused by tumor, stroke, or other focal lesion disease (e.g., multiple sclerosis) or neurodegenerative disease.

[0219] Dystonic tremors occur in individuals suffering from dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful postural or malpositioning. Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and can often be relieved by complete rest or certain sensory manipulations.

[0220] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild and non-progressive in some tremors, beginning on one side of the body, but typically slowly progressive, affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors can decrease with age, but the severity can increase. Emotional excitement, stress, fever, physical exhaustion, or hypoglycemia can induce tremors and / or increase their severity. Symptoms generally develop over time and can be visible after onset, and can be persistent.

[0221] Orthostatic tremor is characterized by rapid (e.g., greater than 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.

[0222] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is typically seen as a "pill-rolling" movement of the hand that may also involve the jaw, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. The movement may begin in one leg or on one side of the body and progress to involve the other side.

[0223] Red tremor is characterized by a slow, coarse tremor that can be present at rest, in position, and on purpose. It is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0224] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor.

[0225] The efficacy of the compounds or compositions disclosed herein for treating essential tremor can be measured by methods known 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 these references are incorporated herein in their entirety.

[0226] 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 about a 40% average reduction 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 at least a 35% average reduction in symptom severity as measured by TETRAS performance score compared to baseline.

[0227] ataxia Ataxia, including both cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally associated with loss or incoordination. Patients with ataxia may have difficulty regulating the force, range, direction, speed, and rhythm involved in body position, balance, and limb movement. Trunk ataxia, for example, may increase postural tilt and cause an inability to maintain the center of gravity over a base of support. Primary or secondary symptoms of leg ataxia and ataxic gait and tremor may be accompanied by speech disorders, dysphagia, abnormal breathing and speech, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, which may substantially interfere with activities of daily living.

[0228] As described above, ataxia can result from a wide variety of underlying diseases and conditions in patients, 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 insufficiency, cerebellar hypoplasia (endosteal sclerosis), cerebellar morphea, cerebellar malformation ... malformation (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, spinal column conditions, autonomic neuropathy, disequilibrium syndrome, paresthesia, endocrine disorders, disorders caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptics), fragile X / tremor ataxia syndrome, Friedreich's ataxia, frontal lobe Dysfunction, genetic disorders, central nervous system granulomatous vasculitis, Hallervorden-Spatz syndrome, hereditary motor and sensory neuropathies, hydrocephalus (e.g., hypotonic or normal), 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 dystrophies, myoclonic ataxia neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, parkinsonism (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe brain injury (e.g., caused by head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infection, or brain tumor), spastic hemiparesis, spastic paraplegia23,Spastic paraplegiaGlaucomaPrecocious puberty,SPG,Spinocerebellar ataxia,Spinocerebellar ataxia(muscular atrophy-deafness),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 4),Spinocerebellar ataxia(autosomal recessive 5), spinocerebellar ataxia (autosomal recessive, with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph 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 / tremor ataxia syndrome.

[0229] Tinnitus Provided herein is a method for treating tinnitus in a subject in need thereof, comprising administering a compound or composition disclosed herein. Tinnitus is a condition in which an affected person perceives sound in one or both ears or in the head in the absence of external sound. Often referred to as "ringing" in the ear, tinnitus can occur intermittently or consistently, with a perceived loudness ranging from low to painfully loud. However, the perceived loudness of tinnitus can vary from patient to patient, and one patient may perceive an objective measure of tinnitus loudness as painful, while another patient may perceive the same loudness as insignificant.

[0230] 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 central disorder of hypersomnia, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Klein-Levin syndrome, hypersomnia due to a medical disorder, hypersomnia due to a drug or substance, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0231] 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).

[0232] Anticonvulsants Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0233] Painkillers Analgesics are therapeutic agents used to relieve pain.Examples of analgesics include opiates and morphine-like drugs, such as fentanyl and morphine; paracetamol; NSAIDs; and COX-2 inhibitors.In view of the ability of the compounds disclosed herein to treat pain by inhibiting T-type calcium channels (e.g., Cav3.1, Cav3.2, and Cav3.3), combination with analgesics is particularly envisioned.

[0234] Drugs used to treat tremors 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.

[0235] The present disclosure will be more fully understood with reference to the following examples. EXAMPLES

[0236] The invention will now be described with reference to the following examples, which are provided for illustrative purposes only, and the invention is not limited to these examples, but rather includes all variations that become evident as a result of the teachings provided herein.

[0237] Materials and Methods General Experimental Details Purification by chromatography refers to purification using a Biotage® Isolera™ One purification system. When the product was 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.

[0238] NMR spectra were obtained on a Bruker Ascend™ 400 MHz, 5 mm BBFO probe H, C, F, P, single Z gradient, 2 channel instrument running TopSpin 4.1.

[0239] Compound names were generated in the standard manner using the structure naming functionality of ChemDraw Professional 20.

[0240] Abbreviation DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA N,N-Diisopropylethylamine DMF N,N-Dimethylformamide DPPA Diphenylphosphoryl azide FA Formic Acid HATU 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate K2CO3 Potassium Carbonate MeCN Acetonitrile PE Petroleum Ether TFA Trifluoroacetic acid THF Tetrahydrofuran

[0241] Analytical LC-MS conditions Method 1: Column: HALO C18, 2.7 μm, 3.0 mm × 30 mm; Mobile phase: MeCN (0.05%HCOOH)-water (0.05%HCOOH); Gradient: 5% to 95% MeCN over 1.4 min, hold for 0.6 min, total run time 2.5 min; Flow rate: 1.8mL / min; Column temperature: 50°C; Wavelength: 214nm and 254nm PDA; Shimadzu LCMS 2020 Mass Spectrometer.

[0242] Method 2: Column: XBridge C18, 3.5 μm, 2.1 mm × 50 mm; Mobile phase: MeCN-water (0.1% NH4OH); Gradient: 5% to 95% MeCN over 1.8 min, 0.7 min hold, total run time 3.0 min; Flow rate: 1.0 mL / min; Column temperature: 50 °C; Wavelengths: 214 nm and 254 nm PDA. Shimadzu LCMS 2020 mass spectrometer.

[0243] Analytical HPLC conditions Method A: Column: ZORBAX ECLIPES PLUS C18, 1.8 μm, 4.6 mm × 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: 2.0mL / min; Wavelength range: 190nm~800nm; Equipment: SHIMADZU LC-2030C 3D Plus.

[0244] Method B: Column: XBridge BEH C18, 2.5 μm, 3.0 mm × 30 mm; Mobile phase: water (0.1%NH3 / H2O)-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: 1.5mL / min; Wavelength range: 190nm~800nm; Equipment: SHIMADZU LC-2030C 3D Plus.

[0245] HNMR conditions for analysis HNMR: BRUKER 400, temperature: 25℃

[0246] Example 1: Preparation of 2-[4-[2-(tert-butylamino)-2-oxo-ethyl]piperazin-1-yl]-N-[(5-isobutyl-1-phenyl-pyrazol-3-yl)methyl]acetamide (Compound 1) Scheme 1: [ka] General method 1: Step 1: Preparation of tert-butyl 4-[2-(tert-butylamino)-2-oxo-ethyl]piperazine-1-carboxylate (Intermediate 3) [ka] To a solution of N-tert-butyl-2-chloro-acetamide (120 mg, 0.80 mmol) (Intermediate 2) in MeCN (10 mL) was added K2CO3 (167 mg, 1.20 mmol) and 1-Boc-piperazine (150 mg, 0.80 mmol) (Intermediate 1). The reaction solution was stirred at room temperature for 12 h. The resulting mixture was filtered and the filtrate was concentrated to dryness. The residue was taken up in DCM (10 mL) and washed with water (2 x 10 mL) followed by saturated brine solution (10 mL). The organic layer was separated, dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by C18 column chromatography to give tert-butyl 4-[2-(tert-butylamino)-2-oxo-ethyl]piperazine-1-carboxylate (210 mg, yield: 87%) as an off-white solid.

[0247] MS Observation (ESI+): [(M+H) + ]:300.1. R t :1.63 minutes (method 2)

[0248] Step 2: Preparation of N-tert-butyl-2-piperazin-1-yl-acetamide hydrochloride (Intermediate 4) [ka] To a solution of tert-butyl 4-[2-(tert-butylamino)-2-oxo-ethyl]piperazine-1-carboxylate (210 mg, 0.70 mmol) (Intermediate 3) in DCM (2 mL) was added 4M HCl in dioxane (2 mL). The reaction solution was stirred at room temperature for 5 h and then concentrated in vacuo to give the title compound N-tert-butyl-2-piperazin-1-yl-acetamide hydrochloride (205 mg, 68% yield) as an off-white solid.

[0249] MS Observation (ESI+): [(M+H) + ]:200.2. R t :0.33 minutes (method 1)

[0250] Step 3: Preparation of 2-chloro-4-(3-chloro-5-fluoro-phenyl)oxazole (Intermediate 6) [ka] 5-Isobutyl-1-phenyl-pyrazole-3-carboxylic acid (800 mg, 3.20 mmol) (Intermediate 5) was dissolved in dry THF (10 mL) and cooled to 0° C. Lithium aluminum hydride (186 mg, 4.90 mmol) was added in small portions. The reaction mixture was refluxed for 4 h, then cooled to 0° C. and quenched by the addition of water (3 mL), followed by 15% aqueous NaOH (1.5 mL) and water (3 mL). After stirring at room temperature for 15 min, the solids were removed by filtration. The filtrate was concentrated to dryness to give the crude product, which was used in the next step without further purification.

[0251] Step 4: Preparation of (5-isobutyl-1-phenyl-pyrazol-3-yl)methanamine (Intermediate 7) [ka] To a solution of (5-isobutyl-1-phenyl-pyrazol-3-yl)methanol (800 mg, 3.40 mmol) (Intermediate 6) and DPPA (1.2 g, 4.5 mmol) in THF (10 mL) was added DBU (1.0 mL, 10 mmol) at room temperature. The resulting solution was stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature and then treated with water (10 mL) and PPh3 (1.36 g, 5.20 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated to dryness, the residue was taken up in DCM (10 mL) and the organics were washed with water (2×10 mL) followed by saturated brine solution (10 mL). The organics were then separated, dried (Na2SO4) and then concentrated in vacuo. The crude was purified by silica gel column chromatography eluting with 1% MeOH in DCM to give the title compound (5-isobutyl-1-phenyl-pyrazol-3-yl)methanamine (650 mg, 73% yield) as a yellow solid.

[0252] MS Observation (ESI+): [(M+H) + ]:230.0. R t :1.27 minutes (method 2)

[0253] Step 5: Preparation of 2-chloro-N-[(5-isobutyl-1-phenyl-pyrazol-3-yl)methyl]acetamide (Intermediate 8) [ka] To a cooled solution of (5-isobutyl-1-phenyl-pyrazol-3-yl)methanamine (150 mg, 0.65 mmol) (Intermediate 7) and DIPEA (0.10 mL, 0.78 mmol) in DCM (9 mL) at 0° C. was added dropwise a solution of acetyl chloride (57 μL, 0.71 mmol) in DCM (1 mL). The resulting mixture was allowed to stir at 0° C. for 30 min, then allowed to warm to room temperature and stirred for an additional 2 h. The resulting mixture was concentrated to dryness, the residue was taken up in DCM (10 mL) and the organics were washed with water (2×10 mL) followed by saturated brine solution (10 mL). The organic layer was separated, dried (Na2SO4) and then concentrated in vacuo. The crude was then purified by silica gel column chromatography eluting with 1% MeOH in DCM to give the title compound 2-chloro-N-[(5-isobutyl-1-phenyl-pyrazol-3-yl)methyl]acetamide (155 mg, 77% yield) as a yellow solid.

[0254] MS Observation (ESI+): [(M+H) + ]:306.0. R t :1.66 minutes (method 2)

[0255] Step 6: Preparation of 2-[4-[2-(tert-butylamino)-2-oxo-ethyl]piperazin-1-yl]-N-[(5-isobutyl-1-phenyl-pyrazol-3-yl)methyl]acetamide (compound 1) [ka] To a solution of N-tert-butyl-2-piperazin-1-yl-acetamide hydrochloride (98 mg, 0.42 mmol) (Intermediate 4) in MeCN (2 mL) was added K2CO3 (136 mg, 0.98 mmol) and 2 2-chloro-N-[(5-isobutyl-1-phenyl-pyrazol-3-yl)methyl]acetamide (100 mg, 0.32 mmol) (Intermediate 8). The reaction solution was stirred at 50° C. for 12 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The resulting oil was purified by silica gel column chromatography eluting with 1-2% MeOH in DCM to give the title compound 2-[4-[2-(tert-butylamino)-2-oxo-ethyl]piperazin-1-yl]-N-[(5-isobutyl-1-phenyl-pyrazol-3-yl)methyl]acetamide (40 mg, 24% yield, 95% purity) as a yellow oil.

[0256] MS Observation (ESI+): [(M+H) + ]:469.3. R t :1.71 minutes (method 2)

[0257] HPLC:R t :3.17 minutes (method B)

[0258] 1 H NMR(400MHz,DMSO)δ 8.10(t,J=4.0Hz,1H),7.56-7.48(m,2H),7.43-7.40(m,3H),7.11(s,1H),6.14(s,1H),4.29(d,4.0Hz,2H),2.96(s,2H) ,2.80(s,2H),2.53-2.51(m,3H),2.46(s,6H),2.42-2.34(m,1H),1.78-1.68(m,1H),1.26(s,9H),0.79(d,J=6.6Hz,6H).

[0259] The following compounds listed in Table 1 below were prepared similarly. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0260] Example 2: Preparation of N-tert-butyl-2-[4-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazin-1-yl]acetamide (Compound 31) Scheme 2: [ka] General method 2: Step 1: Preparation of 2-[(2-bromoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (Intermediate 10) [ka] To a solution of 2-bromo-1H-imidazole (1 g, 6.80 mmol) (Intermediate 9) in THF (20 mL) was added NaH (490 mg, 20.4 mmol) dropwise. The mixture was stirred at 0° C. for 30 min and then treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.45 mL, 8.16 mmol) with continued stirring for 2 h. The reaction was quenched by addition of EtOH and then concentrated to dryness, the residue was taken up in DCM (40 mL) and the organics were washed with water (25 mL) followed by saturated brine solution (20 mL). The organic layer was separated, dried (Na2SO4) and then concentrated to dryness. The crude was then purified by flash column chromatography eluting with 10% EtOAc in PE. The desired fractions were concentrated to give 2-[(2-bromoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (1.4 g, 71% yield, 95% purity) as a colorless oil.

[0261] MS Observation (ESI+): [(M+H) + ]:277.0. R t :1.17 minutes (method 1)

[0262] Step 2: Preparation of 2-bromo-3-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (Intermediate 11) [ka] To a solution of n-BuLi (1.17 mL, 2.81 mmol) in THF (1.5 mL) was added dropwise at −20° C. a solution of 2,2,6,6-tetramethylpiperidine (397 mg, 2.81 mmol) in THF (1 mL) under N2. The reaction mixture was stirred at −20° C. for 30 min. 2-[(2-bromoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (600 mg, 2.16 mmol) (Intermediate 10) in THF (2 mL) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 45 min. DMF (15 g, 21.64 mmol) was added and the reaction was allowed to warm to room temperature. It was then stirred for 16 h. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl and then extracted with EtOAc (3×10 mL). The combined organic extracts were washed with water (2×10 mL), then with saturated brine solution (10 mL), then separated, dried (Na2SO4), then concentrated to dryness. The crude was then purified by flash column chromatography eluting with EtOAc in PE to give 2-bromo-3-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (300 mg, 41% yield, 90% purity) as a yellow oil.

[0263] MS Observation (ESI+): [(M-14+H) + ]:291.0. R t :1.01 minutes (method 2)

[0264] Step 3: Preparation of tert-butyl 4-[[2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine-1-carboxylate (Intermediate 12) [ka] To a solution of 2-bromo-3-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (240 mg, 0.79 mmol) (Intermediate 11) in MeOH (3 mL) was added 1-Boc-piperazine (175.7 mg, 0.94 mmol) (Intermediate 1) and AcOH (1 drop). The mixture was stirred at 45° C. for 16 h and treated with NaBH(OAc)3 (500 mg, 2.36 mmol). The reaction mixture was stirred at 45° C. for 4 h. The reaction was concentrated to dryness, the residue was taken up in DCM (20 mL) and the organics were washed with water (2×10 mL) followed by saturated brine solution (15 mL). The organic layer was separated, dried (Na2SO4) and then concentrated to dryness. The crude was then purified by C18 atmospheric pressure chromatography to give tert-butyl 4-[[2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine-1-carboxylate (222 mg, 53% yield, 90% purity) as a pale yellow oil.

[0265] MS Observation (ESI+): [(M+H) + ]:475.2. R t :2.07 minutes (method 2)

[0266] Step 4: Preparation of tert-butyl 4-[[2-(3-chloro-5-fluoro-phenyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine-1-carboxylate (Intermediate 14) [ka] To a solution of tert-butyl 4-[[2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine-1-carboxylate (100 mg, 0.21 mmol) (Intermediate 12) in a 20% 1,4-dioxane aqueous mixture (3.0 mL) was added (3-chloro-5-fluoro-phenyl)boronic acid (44 mg, 0.25 mmol) (Intermediate 13), Pd(PPh3)4 (24 mg, 0.02 mmol), and Na2CO3 (45 mg, 0.42 mmol). The reaction mixture was stirred at 80° C. for 16 h. The reaction was concentrated to dryness, the residue was taken up in DCM (15 mL), and the organics were washed with water (2×8 mL) followed by saturated brine solution (10 mL). The organics were then separated, dried (Na2SO4), and then concentrated to dryness. The crude was then purified by flash column chromatography eluting with 10% EtOAc in PE to give tert-butyl 4-[[2-(3-chloro-5-fluoro-phenyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine-1-carboxylate (79 mg, 64% yield, 90% purity) as a pale yellow oil.

[0267] MS Observation (ESI+): [(M+Na) + ]:557.2. R t :1.48 minutes (method 2)

[0268] Step 5: Preparation of 1-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazine hydrochloride (Intermediate 15) [ka] To a solution of tert-butyl 4-[[2-(3-chloro-5-fluoro-phenyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine-1-carboxylate (102 mg, 0.19 mmol) (Intermediate 14) in DCM (0.5 mL) was added 4 M HCl in dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 2 h and then concentrated in vacuo to give 1-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazine hydrochloride (113 mg, 88% yield, 50% purity) as a yellow solid.

[0269] MS Observation (ESI+): [(M+H) + ]:295.1. R t :0.65 minutes (method 1)

[0270] Step 6: Preparation of N-tert-butyl-2-[4-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazin-1-yl]acetamide (compound 31) [ka] To a solution of 1-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazine hydrochloride (93 mg, 0.28 mmol) (Intermediate 15) in MeCN (1.5 mL) was added N-tert-butyl-2-chloro-acetamide (42 mg, 0.28 mmol) (Intermediate 2) and DIPEA (0.24 mL, 1.40 mmol). The reaction mixture was stirred at 40° C. for 16 h, then concentrated to dryness, the residue was taken up in DCM (20 mL) and the organics were washed with water (2×10 mL) followed by saturated brine solution (15 mL). The organics were then separated, dried (Na2SO4) and then concentrated to dryness. The crude was then purified by C18 ambient pressure chromatography (0.05% NH3 in MeCN / H2O, 1 to 95% MeCN over 25 min) to give N-tert-butyl-2-[4-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazin-1-yl]acetamide (42 mg, 36% yield, 98.8% purity) as a yellow solid.

[0271] MS Observation (ESI+): [(M+H) + ]:408.1. R t :1.36 minutes (method 2)

[0272] 1 H NMR(400MHz,DMSO)δ 12.20(s,1H),7.76(d,J=1.8Hz,1H),7.66(t,J=1.6Hz,1H),7.53(d,J=10.2Hz,1H), 7.20-7.14(m,1H),7.12(s,1H),3.53(s,2H),2.81(s,2H),2.47(s,8H),1.26(s,9H).

[0273] The following compounds listed in Table 2 below were prepared similarly. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16]

[0274] Example 3: Preparation of N-tert-butyl-2-[4-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazin-1-yl]acetamide (Compound 61) Scheme 3: [ka] General method 3: Step 1: Preparation of tert-butyl 4-(2-hydrazino-2-oxo-ethyl)piperazine-1-carboxylate (Intermediate 17) [ka] A solution of tert-butyl 4-(2-ethoxy-2-oxo-ethyl)piperazine-1-carboxylate (200 mg, 0.73 mmol) (Intermediate 16) and hydrazine hydrate (0.18 mL, 3.67 mmol) in EtOH (10 mL) was stirred for 16 h at 80° C. The mixture was concentrated in vacuo to give the crude product tert-butyl 4-(2-hydrazino-2-oxo-ethyl)piperazine-1-carboxylate (190 mg) as a white solid, which was used in the next step without further purification.

[0275] MS Observation (ESI+): [(M+H) + ]:259.0. R t :0.89 minutes (method 2)

[0276] Step 2: Preparation of tert-butyl 4-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine-1-carboxylate (Intermediate 19) [ka] A solution of tert-butyl 4-(2-hydrazino-2-oxo-ethyl)piperazine-1-carboxylate (190 mg, 0.74 mmol) (Intermediate 17), 3-chloro-5-fluoro-benzonitrile (172 mg, 1.10 mmol) (Intermediate 18), K2CO3 (20 mg, 0.14 mmol) in 1-butanol (15 mL) was stirred for 5 h at 150° C. The reaction was concentrated to dryness and the residue was taken up in DCM (5 mL) and the organics washed with water (2×5 mL) followed by saturated brine solution (5 mL). The organics were dried (Na2SO4), concentrated and purified by flash column chromatography eluting with 2% MeOH in DCM to give tert-butyl 4-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine-1-carboxylate (160 mg, 55% yield) as an off-white solid.

[0277] MS Observation (ESI+): [(M+H) + ]:396.1. R t :1.00 minutes (method 1)

[0278] Step 3: Preparation of 1-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine hydrochloride (Intermediate 20) [ka] To a solution of tert-butyl 4-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine-1-carboxylate (150 mg, 0.38 mmol) (Intermediate 19) in DCM (3 mL) was added 4M HCl in dioxane (3 mL). The reaction solution was stirred at room temperature for 2 h and then concentrated in vacuo to give the title compound 1-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine hydrochloride (125 mg, quant.) as a yellow solid, which was used in the next step without further purification.

[0279] MS Observation (ESI+): [(M+H) + ]:296.0. R t :0.74 minutes (method 1)

[0280] Step 4: Preparation of N-tert-butyl-2-[4-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazin-1-yl]acetamide (compound 61) [ka] A solution of 1-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine hydrochloride (125 mg, 0.38 mmol) (Intermediate 20), N-tert-butyl-2-chloro-acetamide (61.93 mg, 0.41 mmol) (Intermediate 2), and TEA (0.26 mL, 1.88 mmol) in MeCN (3 mL) was stirred for 5 h at 50° C. The reaction was concentrated to dryness and the residue was taken up in DCM (5 mL) and the organics were washed with water (2×5 mL) followed by saturated brine solution (15 mL). The organics were dried (Na2SO4) and concentrated to give the crude product N-tert-butyl-2-[4-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazin-1-yl]acetamide (45 mg, 29% yield, >99% purity) as an off-white solid.

[0281] MS Observation (ESI+): [(M+H) + ]:409.2. R t :0.85 minutes (method 1)

[0282] HPLC:R t :2.33 minutes (method A)

[0283] 1H NMR(400MHz,DMSO)δ 14.19(s,1H),7.83(s,1H),7.70(d,J=9.0Hz,1H),7.50(d,J=8.6Hz,1H) ,7.12(s,1H),3.68(s,2H),2.81(s,2H),2.49-2.39(m,8H),1.26(s,9H).

[0284] Example 4 Preparation of N-(tert-butyl)-2-(3-((4-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)acetamide (Compound 62) Scheme 4: [ka] General method 4: Step 1: Preparation of 4-chloro-2-(chloromethyl)-6-fluoro-1H-benzo[d]imidazole (Intermediate 22) [ka] To a solution of 3-chloro-5-fluoro-benzene-1,2-diamine (2.0 g, 12.45 mmol) (Intermediate 21) 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) and the organics were washed with water (2×13 mL) followed by saturated brine solution (13 mL). The organics were then separated, dried (Na2SO4) and then concentrated in vacuo. The crude material 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.

[0285] MS Observation (ESI+): [(M+H) + ]:218.9. R t :0.83 minutes (method 1)

[0286] Step 2: Preparation of tert-butyl 3-((4-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Intermediate 24) [ka] 4-Chloro-2-(chloromethyl)-6-fluoro-1H-benzimidazole (120 mg, 0.55 mmol) (Intermediate 22), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (99 mg, 0.50 mmol) (Intermediate 23), and K2CO3 (207 mg, 1.5 mmol) were added sequentially to a 10 mL round-bottom flask. MeCN (2 mL) was added and the reaction mixture was stirred at 50 °C for 4 h. After cooling to room temperature, the reaction mixture was washed with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were washed with saturated aqueous brine solution (2 x 3 mL) and the organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 30% EtOAc in PE to give tert-butyl 3-[(4-chloro-6-fluoro-1H-benzimidazol-2-yl)methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (140 mg, 70% yield, 95% purity).

[0287] MS Observation (ESI+): [(M+H) + ]:381.1. Rt: 1.66 minutes (method 2)

[0288] Step 3: Preparation of 3-((4-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane (Intermediate 25) [ka] To a 4M aqueous HCl solution (3 mL) was added tert-butyl 3-[(4-chloro-6-fluoro-1H-benzimidazol-2-yl)methyl]-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (140 mg, 0.37 mmol) (Intermediate 24) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was adjusted to pH 8 with saturated aqueous Na2CO3 and the resulting mixture was extracted with DCM (3 x 10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to give the crude product 4-chloro-2-(3,6-diazabicyclo[3.1.1]heptane-3-ylmethyl)-6-fluoro-1H-benzimidazole (66 mg, 60% yield, 95% purity) as a yellow oil.

[0289] MS Observation (ESI+): [(M+H) + ]:281.2. Rt: 0.45 minutes (method 1)

[0290] Step 4: Preparation of N-(tert-butyl)-2-(3-((4-chloro-6-fluoro-1H-benzo[d]imidazol-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)acetamide (compound 62) [ka] To a solution of 4-chloro-2-(3,6-diazabicyclo[3.1.1]heptan-3-ylmethyl)-6-fluoro-1H-benzimidazole (66 mg, 0.24 mmol) (Intermediate 25) in MeCN (1 mL) was added DIPEA (0.12 mL, 0.71 mmol) and N-tert-butyl-2-chloro-acetamide (39 mg, 0.26 mmol) (Intermediate 2). The reaction solution was stirred at 50° C. for 2 hours, then filtered and the filtrate was concentrated in vacuo. The resulting oil was purified by silica gel column chromatography eluting with 1-5% MeOH in DCM to give the title compound N-tert-butyl-2-[3-[(4-chloro-6-fluoro-1H-benzimidazol-2-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-6-yl]acetamide (28 mg, 30% yield, 97.7% purity) as an off-white solid.

[0291] MS Observation (ESI+): [(M+H) + ]:394.2. R t :0.71 minutes (method 1)

[0292] 1 H NMR(400MHz,DMSO)δ 7.28(s,1H),7.22-7.16(m,2H),3.97(s,2H),3.47(d,J=5.2Hz,2H),3.01(d,J=11. 2Hz, 2H), 2.85-2.81 (m, 4H), 2.38-2.33 (m, 1H), 1.94 (d, J=6.4Hz, 1H), 1.24 (s, 9H).

[0293] The following compounds listed in Table 3 below were prepared similarly. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

[0294] Example 5 Preparation of N-tert-butyl-2-[3-[(4-chloro-7-fluoro-1H-benzimidazol-2-yl)methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]acetamide (Compound 185) Scheme 5: [ka] General method 5: Step 1: Preparation of tert-butyl 8-[2-(tert-butylamino)-2-oxo-ethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Intermediate 27) [ka] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (3.0 g, 14.13 mmol) (Intermediate 26) in MeCN (30 mL) was added N-tert-butyl-2-chloro-acetamide (2.11 g, 14.13 mmol) (Intermediate 2) and K2CO3 (3.91 g, 28.26 mmol). The reaction mixture was stirred at 40° C. for 16 h. The reaction was concentrated to dryness and the residue was taken up in EtOAc (200 mL) and the organics were washed with water (150 mL) followed by saturated brine solution (120 mL). The organics were then separated, dried (Na2SO4) and then concentrated in vacuo. The crude was purified by flash column chromatography eluting with 35% EtOAc in PE to give tert-butyl 8-[2-(tert-butylamino)-2-oxo-ethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.2 g, 86% yield, 95% purity) as a yellow solid.

[0295] MS Observation (ESI+): [(M+H) + ]:326.2. R t :0.78 minutes (method 1)

[0296] Step 2: Preparation of N-tert-butyl-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)acetamide; hydrochloride salt (Intermediate 28) [ka] A solution of tert-butyl 8-[2-(tert-butylamino)-2-oxo-ethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (4.2 g, 12.91 mmol) (Intermediate 27) in 4 M HCl in dioxane (60 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo to give N-tert-butyl-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)acetamide; hydrochloride (3.8 g, 12 mmol, 95% yield, 85% purity) as a yellow solid.

[0297] MS Observation (ESI+): [(M+H) + ]:226.0. R t :0.38 minutes (method 1)

[0298] Step 3: Preparation of N-tert-butyl-2-[3-[(4-chloro-7-fluoro-1H-benzimidazol-2-yl)methyl]-3,8 diazabicyclo[3.2.1]octan-8-yl]acetamide (compound 185) [ka] To a solution of N-tert-butyl-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)acetamide; hydrochloride (100 mg, 0.38 mmol) (Intermediate 28) in MeCN (2 mL) was added 4-chloro-2-(chloromethyl)-7-fluoro-1H-benzimidazole (84 mg, 0.38 mmol) (Intermediate 29) and K2CO3 (158 mg, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated to dryness and the residue was taken up in DCM (10 mL) and the organics were washed with water (2 x 8 mL) followed by saturated brine solution (10 mL). The organics were then separated, dried (Na2SO4) and then concentrated in vacuo. The crude was then purified by prep-HPLC (0.05% NH3 in MeCN / H2O, 15% to 95% MeCN over 15 min) to give the target product as an off-white solid: N-tert-butyl-2-[3-[(4-chloro-7-fluoro-1H-benzimidazol-2-yl)methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]acetamide (42 mg, 26% yield, 95.1% purity).

[0299] MS Observation (ESI+): [(M+H) + ]:408.3. R t :1.58 minutes (method 2)

[0300] 1 H NMR(400MHz,DMSO)δ 7.41(s,1H),7.04(s,1H),6.86(s,1H),3.67(s,2H),3.03(s,2H),2.74(s,2H),2. 62(d,J=9.8Hz,2H),2.38(d,J=10.0Hz,2H),1.73(s,4H),1.24(d,J=10.2Hz,9H).

[0301] The following compounds listed in Table 4 below were prepared similarly. [Table 4-1] [Table 4-2]

Table 4-3

Table 4-4

Table 4-5

Table 4-6

Table 4-7

Table 4-8

Table 4-9

Table 4-10

Table 4-11

Table 4-12

Table 4-13

Table 4-14

Table 4-15

Table 4-16

Table 4-17

Table 4-18

Table 4-19

Table 4-20

Table 4-21

Table 4-22

Table 4-23

Table 4-24

Table 4-25

Table 4-26

Table 4-27

Table 4-28

Table 4-29

Table 4-30

Table 4-31

Table 4-32

Table 4-33

Table 4-34

Table 4-35

Table 4-36

Table 4-37

Table 4-38

Table 4-39

Table 4-40

Table 4-41

Table 4-42

Table 4-43

Table 4-44

Table 4-45

Table 4-46

Table 4-47

Table 4-48

Table 4-49

Table 4-50

Table 4-51

Table 4-52

Table 4-53

Table 4-54

Table 4-55

Table 4-56

Table 4-57

Table 4-58

Table 4-59

Table 4-60

Table 4-61

Table 4-62

Table 4-63

Table 4-64

Table 4-65

Table 4-66

Table 4-67

Table 4-68

Table 4-69

Table 4-70

Table 4-71

Table 4-72

Table 4-73

Table 4-74

Table 4-75

Table 4-76

Table 4-77

Table 4-78

Table 4-79

Table 4-80

Table 4-81

Table 4-82

Table 4-83

Table 4-84

Table 4-85

Table 4-86

Table 4-87

Table 4-88

Table 4-89

Table 4-90

Table 4-91

Table 4-92

Table 4-93

Table 4-94

Table 4-95

Table 4-96

Table 4-97

Table 4-98

Table 4-99

Table 4-100

Table 4-101

Table 4-102

Table 4-103

Table 4-104

[0302] Example 6. Preparation of additional compounds of the present disclosure The following additional compounds, listed in Table 5 below, were prepared by the methods disclosed herein. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7]

[0303] Example 7. In vitro Cav3.1 single point and IC50 (VDB) data Certain compounds (as indicated) were tested for human Cav3.1 calcium channel activity using the patch clamp assay disclosed herein.

[0304] 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 SyncroPatch 384PE 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, 1 mM MgCl2, 6 mM CaCl2, 5 mM glucose, and 10 mM HEPES (pH=7.4, osmolality approximately 300 mOsm). The extracellular solution was used as a wash, reference, and compound delivery solution. The internal solution contained 110 mM CsF, 10 mM CsCl, 10 mM NaCl, 10 mM EGTA, 10 mM HEPES (pH=7.2, osmolality approximately 295 mOsm).

[0305] Compound plates were made up at 2x concentrations in extracellular solution. Compounds were diluted 1:2 when added to recording wells. The amount of DMSO in the extracellular solution was kept constant at the level used for the highest test concentration. For Cav3.1 voltage clamp experiments, data were sampled at 10KHz. After seal-passaging in whole-cell configuration, cells were held at -120mV. Cav3.1 currents were evoked using a 100ms step to -20mV (to measure resting-state block), followed by a 1600ms step to -65mV and a second 100ms step to -20mV (to measure voltage-dependent block). Voltage protocols were applied every 15s in the absence and presence of the compound under investigation. 2.5mM nickel 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 fluid 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 Table 6 below, human Cav3.1 inhibition data for compounds are presented at a given single point concentration and, in some instances, their IC 50 It was decided. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8]

Table 6-9

Claims

1. A compound represented by formula (Ia), 【Chemical 86】 During the ceremony, B is -CH ２ -, -CH ２ -CH ２ , -CH ２ -CH ２ -CH ２ , -O-, -CH ２ -O-, -O-CH ２ , and -CH ２ -O-CH ２ selected from the group consisting of W １ 'and W ２ Each of these is independently selected from the group consisting of -H, deuterium, alkyl, and alkoxy, or W １ 'and W ２ 'together form a carbocyclyl, heterocyclyl, or carbonyl (=O), S １ 'and S ２ ' are independent of each other, -H and -CH ３ Selected from the group consisting of S １ 'and S ２ 'together form a carbonyl group, X ２ ' is absent, -CH ２ -ien-CHCH ３ -, or -CONH-, X ３ ' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl, X １ 'but, (i) 【Chemistry 87】 (In the formula, R ２ 'and R ３ Each of these is independently selected from the group consisting of -H, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocykryl, and heterocyclyl, or R ２ 'and R ３ 'together form a ring-shaped ring, R ４ 'and R ５ Each of these is independently selected from the group consisting of -H, deuterium, halo, CN, alkyl, and alkoxy, or R ４ 'and R ５ 'together form a carbonyl group, R １ 'Alkyl, carbocyrill, heterocyclyl, -OZ １ ', -NZ ２ 'Z ３ ', and -SO ２ Z ７ Selected from the group consisting of ', Z １ ' is selected from the group consisting of alkyl, carbocykryl, and heterocyclyl, Z ２ 'and Z ３ 'Each of these independently consists of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, and -COZ'. ５ , and -SO ２ Z ６ Selected from the group consisting of ', or Z ２ 'and Z ３ 'But together with the nitrogen they are bound to, they form a heterocycline. Z ５ 'But, C ３－６ It is carbocyclyl, Z ６ 'But, C １－６ Alkyl or Z ７ ' is selected from the group consisting of alkyl, carbocyryl, and heterocyclyl), or (ii) 【Chemical 88】 (In the formula, R ６ A compound selected from the group consisting of alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl compounds, and a pharmaceutically acceptable salt thereof.

2. B is -CH ２ The compound according to claim 1, wherein B is -CH2-CH2-.

3. W １ 'and W ２ ' Both are hydrogen, and / or Both S1' and S2' are hydrogen, and / or Both R2' and R3' are hydrogen, and / or Both R2' and R3' are hydrogen, and R4' and R5' together form a carbonyl group. The compound according to claim 1.

4. R １ 'ga-NZ ２ 'Z ３ The compound according to claim 3.

5. Z ２ ' is hydrogen or methyl, Z ３ ' is C １－６ Alkyl, C ３－６ Carbocyclyl or heterocyclyl, where C １－６ Alkyl, C ３－６ Each of the carbocyclyl and heterocyclyl compounds is methyl, trifluoromethyl, hydroxyl, halo, methoxy, trifluoromethyl, and -COOCH ３ The compound according to claim 4, which is optionally substituted with one or more substituents selected from the group consisting of the following.

6. Z ２ ' is hydrogen, Z ３ ' is C １－６ The compound according to claim 5, wherein Z2' is alkyl, or Z3' is hydrogen and Z3' is t-butyl, or Z2' is hydrogen and Z3' is cyclopropyl, cyclobutyl, or oxetane.

7. R ４ 'and R ５ The compound according to claim 1, wherein each of the elements is independently hydrogen, hydroxyl, or halo.

8. R １ 'ga-NZ ２ 'Z ３ ' and Z ２ ' is hydrogen, Z ３ 'ga-coz ５ The compound according to claim 7, wherein 'R1' is an alkyl, carbocykryl, or heterocyclyl.

9. X ２ The compound according to claim 1, wherein ' is -CONH-.

10. X ３ ' is an aryl or heteroaryl, where each aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, and t-butyl, or The X3' is selected from the group consisting of phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran, quinazoline, phenyl-imidazole, phenyl-triazole, phenyl-pyrazole, and an adamantane ring, or X3' is a phenyl molecule optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro, cyano, methyl, methoxy, difluoromethoxy, and trifluoromethoxy, or X3' is a benzimidazole in which two substituents selected from the group consisting of chloro and fluoro are optionally substituted. The compound according to claim 1.

11. The aforementioned compound, 【Chemistry 89-1】 【Chemistry 89-2】 【Chemistry 89-3】 【Chemistry 89-4】 【Chemistry 89-5】 【Chemistry 89-6】 【Chemistry 89-7】 【Chemistry 89-8】 【Chemistry 89-9】 【Chemistry 89-10】 【Chemistry 89-11】 【Chemistry 89-12】 【Chemistry 111-13】 【Chemistry 111-14】 A compound according to claim 1, selected from the group consisting of the following. 【Request Item 12】 【Chemistry 112-1】 【Chemistry 112-2】 【Chemistry 112-3】 A compound selected from the group consisting of the following.

13. A compound represented by formula (IIa), 【Chemistry 90】 During the ceremony, The solid centers indicated by * are either both in an S configuration or both in an R configuration. B is -CH ２ -ien-CH ２ -CH ２ ien-CH ２ -CH ２ -CH ２ , -O-, -CH ２ -O-, -O-CH ２ -, and -CH ２ -O-CH ２ - Selected from the group consisting of, S １ ’ and S ２ ’ are each independently selected from the group consisting of -H and -CH ３ or S １ ’ and S ２ ’ together form a carbonyl, X ２ ' is absent, -CH ２ -ien-CHCH ３ -, or -CONH-, X ３ ' is selected from the group consisting of carbocyclic, heterocyclic, aryl, and heteroaryl, X １ 'but, (i) 【Chemistry 91】 (In the formula, R ２ 'and R ３ Each of these is independently selected from the group consisting of -H, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocykryl, and heterocyclyl, or R ２ 'and R ３ 'together form a ring-shaped ring, R ４ 'and R ５ Each of these is independently selected from the group consisting of -H, deuterium, halo, CN, alkyl, and alkoxy, or R ４ 'and R ５ 'together form a carbonyl group, R １ 'Alkyl, carbocyrill, heterocyclyl, -OZ １ ', -NZ ２ 'Z ３ ', and -SO ２ Z ７ Selected from the group consisting of ', Z １ ' is selected from the group consisting of alkyl, carbocykryl, and heterocyclyl, Z ２ 'and Z ３ 'Each of these independently consists of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, and -COZ'. ５ , and -SO ２ Z ６ Selected from the group consisting of ', or Z ２ 'and Z ３ 'But together with the nitrogen they are bound to, they form a heterocycline. Z ５ 'But, C ３－６ It is carbocyclyl, Z ６ 'But, C １－６ Alkyl or Z ７ ' is selected from the group consisting of alkyl, carbocyryl, and heterocyclyl), or (ii) 【Chemistry 92】 (In the formula, R ６ A compound selected from the group consisting of alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl compounds, and a pharmaceutically acceptable salt thereof.

14. B is -CH ２ The compound according to claim 13, wherein B is - or B is -CH2-CH2-.

15. S １ 'and S ２ Both R2' and R3' are hydrogen, or S1' and S2' are hydrogen and R4' and R5' together form a carbonyl group. The compound according to claim 13.

16. R １ 'ga-NZ ２ 'Z ３ The compound according to claim 14, wherein R1' is -NZ2'Z3', Z2' is hydrogen or methyl, and Z3' is C1-6 alkyl, C3-6 carbocykyl, or heterocyclyl, where each of C1-6 alkyl, C3-6 carbocykyl, and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxyl, halo, methoxy, trifluoromethoxy, and -COOCH3.

17. Z ２ ' is hydrogen, Z ３ ' is C １－６ The compound according to claim 16, wherein Z2' is alkyl, or Z3' is hydrogen and Z3' is t-butyl, or Z2' is hydrogen and Z3' is cyclopropyl, cyclobutyl, or oxetane.

18. R ４ 'and R ５ The compound according to claim 15, wherein each of the ' is independently hydrogen, hydroxyl, or halo, or R4' and R5' are independently hydrogen, hydroxyl, or halo, and R1' is -NZ2'Z3', Z2' is hydrogen, and Z3' is -COZ5'.

19. R １ The compound according to claim 18, wherein ' is an alkyl, carbocykryl, or heterocyclyl.

20. X ２ The compound according to claim 13, wherein ' is -CONH-.

21. X ３ ' is an aryl or heteroaryl, where each aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl, and t-butyl, or X3' is selected from the group consisting of phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran, quinazoline, phenyl-imidazole, phenyl-triazole, phenyl-pyrazole, bicycloheptane, bicyclooctane, and adamantane ring, or X3' is a phenyl molecule optionally substituted with two substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, difluoromethoxy, and trifluoromethoxy. The compound according to claim 13.

22. The aforementioned compound, 【Chemistry 93-1】 【Chemistry 93-2】 【Chemistry 93-3】 【Chemistry 93-4】 【Chemistry 93-5】 【Chemistry 93-6】 【Chemistry 93-7】 A compound according to claim 13, selected from the group consisting of the following.

23. A compound represented by formula (IIIa), 【Chemical 94】 During the ceremony, One of the solid centers indicated by * is in an S configuration, and the other solid center indicated by * is in an R configuration. B is -CH ２ -ien-CH ２ -CH ２ ien-CH ２ -CH ２ -CH ２ , -O-, -CH ２ -O-, -O-CH ２ -, and -CH ２ -O-CH ２ - and D is carbon or nitrogen, X １ ' is alkyl, X ２ ' is -NHCO- or -CONH-, X ３ Compounds in which ' is aryl or heteroaryl, and pharmaceutically acceptable salts thereof.

24. C is -CH ２ -O-CH ２ The compound according to claim 23, wherein X1' is t-butyl and / or X3' is phenyl or benzimidazole, where phenyl and benzimidazole are each optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro and difluoromethoxy.

25. The aforementioned compound, 【Chemistry 95-1】 【Chemistry 95-2】 A compound according to claim 23, selected from the group consisting of the following.

26. A compound represented by formula (IVa), 【Chemistry 96】 During the ceremony, The center of the solid indicated by * is in either the R configuration or the S configuration. X １ ' is alkyl, X ２ 'But, -O- or NR １ R ２ And in the formula, R １ and R ２ Each of them is independently H or alkyl, X ３ Compounds in which ' is aryl or heteroaryl, and pharmaceutically acceptable salts thereof.

27. The aforementioned compound, 【Chemistry 97】 A compound according to claim 26, selected from the group consisting of the following.

28. A compound represented by formula (Va), 【Chem.98】 During the ceremony, The 1,4-diazepan core in the compound of formula (Va) is 2,7-CH ２ -Bridge, 2,7-CH ２ CH ２ -Bridged, 3,7-CH ２ -Cross-linked, or 3,7-CH ２ CH ２ -Optionally includes cross-linking, W １ 'and W ２ ' is independently hydrogen, deuterium, alkyl, and alkoxy, or W １ 'and W ２ 'together form a carbocyclyl, heterocyclyl, or carbonyl (=O), W ３ However, it is hydrogen or carbonyl, S １ 'and S ２ Each of these is independently hydrogen or alkyl, or S １ 'and S ２ 'together form a carbonyl group, X ２ ' is absent, -CH ２ -ien-CHCH ３ -, or -CONH-, X ３ ' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl, and heteroaryl, X １ 'but, 【Chem.99】 (In the formula, R １ ' is selected from the group consisting of hydrogen, alkyl, carbocykryl, and heterocyclyl, R ２ 'and R ３ Each of these is independently selected from the group consisting of hydrogen, deuterium, alkyl, hydroxyl, alkoxy, halo, carbocykryl, and heterocyclyl, or R ２ 'and R ３ 'together form a ring-shaped ring, R １１ ' is hydrogen or methyl, R １２ However, it is selected from the group consisting of hydrogen, deuterium, and alkyl, or R １１ 'and R １２ Together, they form an azetidine ring containing at least one methyl substituent optionally. R １３ Compounds and pharmaceutically acceptable salts thereof, wherein the compound is selected from the group consisting of hydrogen, deuterium, and alkyl.

29. The aforementioned compound is represented by formula (Vb), 【Chemistry 100】 During the ceremony, W １ ', W ２ ', S １ ', S ２ ', X １ ', X ２ ', and X ３ The compound according to claim 28, wherein the compound is as defined in claim 28.

30. X ３ The compound according to claim 28, wherein ' is selected from the group consisting of phenyl, benzimidazole, and an adamantane ring, where phenyl and benzimidazole are each optionally substituted with one or two substituents selected from chloro and fluoro.

31. The aforementioned compound, 【Chemistry 101】 A compound according to claim 28, selected from the group consisting of the following.

32. A compound represented by formula (VIa), 【Chemical Engineering 102】 During the ceremony, R １ 'and R ２ Each of these is either hydrogen or R １ 'and R ２ 'together form a carbonyl group, R ３ Compounds in which ' is an aryl or heteroaryl compound optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxyl, amino, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, and trifluoromethoxy, and pharmaceutically acceptable salts thereof.

33. R ３ The compound according to claim 32, wherein ' is isoquinoline or naphthpiridine.

34. The aforementioned compound, 【Chemistry 103】 A compound according to claim 32, selected from the group consisting of the following.

35. The following structure: 【Chemical 104】 A compound of [unclear].

36. A pharmaceutical composition comprising a compound according to any one of claims 1 to 35 and a pharmaceutically acceptable carrier.

37. 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 a compound according to any one of claims 1 to 35, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 35 and a pharmaceutically acceptable carrier.

38. The disease or condition associated with abnormal function or activity of T-type calcium channels is selected from the group consisting of mental disorders, pain, tremors, seizures, epilepsy, and epileptic syndromes, or The disease or condition associated with abnormal function or activity of T-type calcium channels is a tremor, or The disease or condition associated with abnormal function or activity of T-type calcium channels is essential tremor. A composition for use or pharmaceutical composition according to claim 37.

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