Modulators of T-type calcium channels comprising piperazine or 1, 4-diazepane core and methods of use thereof

Abstract

Disclosed herein are compounds and pharmaceutical compositions comprising such compounds for the treatment of conditions modulated by calcium channel ion activity, including compounds comprising a piperazine core, a 1, 4-diazepane core, or a 1, 5-diazepane core. Also disclosed herein are methods of using the compounds to treat diseases or conditions associated with aberrant function or activity of T-type calcium channels.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 326,682, filed on April 1, 2022, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] Disclosed herein are compounds for treating conditions associated with calcium channel activity and, in particular, T-type calcium channel activity. Specifically, disclosed herein are compounds comprising a piperazine nucleus or a 1,4-diazepane nucleus, wherein the compounds comprise levorotatory and dextrorotatory substitutions. Also disclosed herein are methods for treating conditions associated with T-type calcium channel activity by administering the compounds disclosed herein. Background Art

[0004] Calcium enters cells through voltage-gated calcium channels, mediating a variety of cellular and physiological responses, including excitation-contraction coupling, hormone secretion, and gene expression. In neurons, calcium channels directly affect membrane potential and contribute to electrical properties, as well as regulating 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.

[0005] For example, T-type calcium channel modulators having a piperidinyl core are disclosed in PCT Publication No. 2009 / 146540, published on December 10, 2009, and U.S. Pat. Nos. 8,377,968 (published on February 19, 2013), 8,569,344 (published on October 29, 2013), and 9,096,522 (published on August 4, 2015), the entire contents of which are incorporated herein by reference.

[0006] 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, tremor (e.g., essential tremor), epilepsy or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy). Therefore, additional compounds that selectively modulate T-type calcium channels in mammals can be used to treat such disease states. Summary of the invention

[0007] The present disclosure provides compounds for treating conditions associated with calcium channel activity and specifically T-type calcium channel activity. Specifically, compounds of formula (I) and formula (II) containing left-handed and right-handed substitutions containing piperazine nuclei are disclosed herein. Compounds of formula (III) containing left-handed and right-handed substitutions containing 1,4-diazepane nuclei are also disclosed herein, including compounds of formula (IV).

[0008] In some aspects, the present disclosure provides a compound represented by formula (Ia):

[0009]

[0010] in:

[0011] B is absent or selected from the group consisting of: -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 -;

[0012] W 1 ' and W 2 ' are each 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);

[0013] S 1 ′ and S 2 ' are each independently selected from -H and -CH 3 The group, or S 1 ′ and S 2 ' together to form a carbonyl group;

[0014] X 2 'Does not exist, is -CH 2 -、-CHCH 3 -or-CONH-;

[0015] X 3 ' is selected from the group consisting of: carbocyclyl, heterocyclyl, aryl and heteroaryl;

[0016] X 1 'Selected from the group consisting of:

[0017] (i)

[0018]

[0019] in.

[0020] R 2 ' and R 3 ' are each independently selected from the group consisting of: -H, deuterium, alkyl, hydroxy, alkoxy, halo, carbocyclyl and heterocyclyl; or R2 ' and R 3 'Together they form a ring-like ring;

[0021] R 4 ′ and R μ ' are each independently selected from the group consisting of: -H, deuterium, halo, CN, alkyl and alkoxy; or R 4 ' and R μ 'Together they form a carbonyl group;

[0022] R 1 'Selected from the group consisting of: alkyl, carbocyclic, heterocyclic, -OZ 1 '、-NZ 2 'Z 3 'and-SO 2 Z 7 ';

[0023] Z 1 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups;

[0024] Z 2 ′ and Z 3 'Each independently selected from the group consisting of: hydrogen, deuterium, alkyl, carbocyclic group, heterocyclic group, -COZ' 5 and-SO 2 Z 6 '; or where Z 2 ' and Z 3 ' together with the nitrogen to which it is bonded, forms a heterocyclic group;

[0025] Z 5 ′ is C 3-6 Carbocyclic group;

[0026] Z 6 ′ is C 1-6 Alkyl; or

[0027] Z 7 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups; or

[0028] (ii)

[0029]

[0030] in

[0031] R 6 ' is selected from the group consisting of: alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; and pharmaceutically acceptable salts thereof.

[0032] In some aspects, the present disclosure provides a compound represented by formula (IIa):

[0033]

[0034] in:

[0035] The stereocenters indicated by * are all in S configuration or all in R configuration;

[0036] B chooses from -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 - the groups formed;

[0037] S 1 ′ and S 2 ' are each independently selected from -H and -CH 3 The group, or S 1 ′ and S 2 ' together to form a carbonyl group;

[0038] X 2 'Does not exist, is -CH 2 -、-CHCH 3 -or-CONH-;

[0039] X 3 ' is selected from the group consisting of: carbocyclyl, heterocyclyl, aryl and heteroaryl;

[0040] X 1 'Selected from the group consisting of:

[0041] (i)

[0042]

[0043] in.

[0044] R 2 ' and R 3 ' are each independently selected from the group consisting of: -H, deuterium, alkyl, hydroxy, alkoxy, halo, carbocyclyl and heterocyclyl; or R 2 ' and R 3 'Together they form a ring-like ring;

[0045] R 4 ′ and R 5 ' are each independently selected from the group consisting of: -H, deuterium, halo, CN, alkyl and alkoxy; or R 4 ' and R 5'Together they form a carbonyl group;

[0046] R 1 'Selected from the group consisting of: alkyl, carbocyclic, heterocyclic, -OZ 1 '、-NZ 2 'Z 3 'and-SO 2 Z 7 ';

[0047] Z 1 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups;

[0048] Z 2 ′ and Z 3 'Each independently selected from the group consisting of: hydrogen, deuterium, alkyl, carbocyclic group, heterocyclic group, -COZ' 5 and-SO 2 Z 6 '; or where Z 2 ' and Z 3 'Together with the nitrogen to which it is bonded, it forms a heterocyclic group;

[0049] Z 5 ′ is C 3-6 Carbocyclic group;

[0050] Z 6 ′ is C 1-6 Alkyl; or

[0051] Z 7 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups; or

[0052] (ii)

[0053]

[0054] in

[0055] R 6 ' is selected from the group consisting of: alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; and pharmaceutically acceptable salts thereof.

[0056] In some aspects, the present disclosure provides a compound represented by formula (IIIa):

[0057]

[0058] in.

[0059] One stereocenter indicated by * is in the S configuration, and the other stereocenter indicated by * is in the R configuration;

[0060] B is -CH 2 -、-CH2 -CH 2 、-CH 2 -CH 2 -CH 2 、-O-、-CH 2 -O-, -O-CH 2 -and-CH 2 -O-CH 2 -;

[0061] D is carbon or nitrogen;

[0062] X 1 ' is an alkyl group,

[0063] X 2 'is -NHCO- or -CONH-; and

[0064] X 3 ' is aryl or heteroaryl; and pharmaceutically acceptable salts thereof.

[0065] In some aspects, the present disclosure provides a compound represented by formula (IVa):

[0066]

[0067] in:

[0068] Stereocenters indicated by * are in R or S configuration;

[0069] X 1 ' is an alkyl group;

[0070] X 2 ' is -O- or NR 1 R 2 , where R 1 and R 2 are each independently H or alkyl; and

[0071] X 3 ' is aryl or heteroaryl; and pharmaceutically acceptable salts thereof.

[0072] In some aspects, the present disclosure provides a compound represented by formula (Va):

[0073]

[0074] in:

[0075] The 1,4-diazepane nucleus of the compound of formula (Va) optionally comprises 2,7-CH 2 -bridge, 2,7-CH 2 CH 2 -bridge, 3,7-CH 2-bridge or 3,7-CH 2 CH 2 -bridge;

[0076] W 1 ' and W 2 ' are each independently hydrogen, deuterium, alkyl and alkoxy; or W 1 ' and W 2 'together form a carbocyclyl, heterocyclyl or carbonyl (=O);

[0077] W 3 is hydrogen or carbonyl;

[0078] S 1 ′ and S 2 ' are each independently hydrogen or alkyl, or S 1 ′ and S 2 ' together to form a carbonyl group;

[0079] X 2 'Does not exist, is -CH 2 -、-CHCH 3 -or-CONH-;

[0080] X 3 ' is selected from the group consisting of: carbocyclyl, heterocyclyl, aryl and heteroaryl;

[0081] X 1 'yes

[0082]

[0083] in.

[0084] R 1 ' is selected from the group consisting of hydrogen, alkyl, carbocyclyl and heterocyclyl;

[0085] R 2 ′ and R 3 ' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, hydroxy, alkoxy, halo, carbocyclyl and heterocyclyl; or R 2 ′ and R 3 ' together form an annular ring;

[0086] R 11 ' is hydrogen or methyl;

[0087] 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 comprising at least one methyl substituent;

[0088] R 13Selected from the group consisting of hydrogen, deuterium and alkyl; and pharmaceutically acceptable salts thereof.

[0089] In some aspects, the present disclosure provides a compound represented by formula (VIa):

[0090]

[0091] in

[0092] R 1 ′ and R 2 ' are each hydrogen, or R 1 ′ and R 2 ' together to form a carbonyl group; and

[0093] R 3 ' is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, amino, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy; and pharmaceutically acceptable salts thereof.

[0094] In some embodiments, R 3 ' is isoquinoline. In some embodiments, R 3 ' is naphthyridine.

[0095] In one aspect, the present disclosure also provides a compound having the following structure:

[0096]

[0097] In one aspect, disclosed herein is a compound of formula (I) having a piperazine core:

[0098]

[0099] wherein n is selected from 0, 1 or 2;

[0100] W 1 and W 2 Independently selected from -H or -CH 2 OCH 3 ,or

[0101] W 1 and W 2 together to form an oxetane cyclic ring or =O;

[0102] S 1 and S 2 Independently selected from -H or -CH 3 ;

[0103] X 2 Does not exist, is -CH 2 -or-CONH-;

[0104] X 3 is a dextrorotatory substitution of a piperazine nucleus selected from formula (i):

[0105]

[0106] Among them A 1 Selected from -CH, -CR 6 or -N, and

[0107] R 6 is absent, is 1 or 2, and is independently selected from -H, -Cl, -F, -CHF 2 、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-OCF 3 、-OCHF 2 , -CN, cyclopropyl or aryl;

[0108] Formula (ii)

[0109]

[0110] Where R 10 is absent, is 1 or 2, and is independently selected from -Cl, -F, -CH 3 , -CHF 2 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-OCF 3 、-OCHF 2 , -CN, cyclopropyl or aryl; or

[0111] adamantane ring; phenyl, the phenyl optionally comprising 1 or 2 substituents independently selected from fluorine or chlorine; pyrazole, the pyrazole optionally comprising at least one substituent selected from methyl (such as two methyl substituents), cyclopropyl or tert-butyl; indazole, the indazole optionally comprising at least one methyl substituent; phenylpyrazole, wherein the pyrazole optionally comprises at least one substituent selected from -CH 2 CH 2 (CH 3 ) 2phenyltriazole, wherein the phenyl group optionally comprises at least one substituent selected from chlorine or fluorine, such as a chlorine substituent and a fluorine substituent; phenylimidazole, wherein the phenyl group optionally comprises at least one substituent selected from chlorine or fluorine, such as a chlorine substituent and a fluorine substituent, and wherein the imidazole optionally comprises at least one substituent selected from methyl or -CH 2 CH 2 (CH 3 ) 2 benzofuran; quinazoline; or benzisoxazole; and

[0112] X 1 is a levorotatory substitution of a piperazine nucleus selected from:

[0113]

[0114]

[0115] Where R 1 Selected from -H, deuterium, -CH 3 , -CHF 2 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 、-CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0116] R 2 Selected from -H, deuterium, -CH 3 、-CH 2 CH 3 , -CF 3 or cyclopropyl;

[0117] R 3 Selected from -H or deuterium, or R 2 and R 3 together form a cyclic ring selected from cyclopropyl, cyclobutyl or oxetane;

[0118] R 4 Selected from -CH 3 、-CH 2 CH 3 , -CF 3 , -CHF 2 or CH 2 O alkyl;

[0119] R 8 Selected from -H, -CH3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 , cyclopropyl, -CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0120] R 9 Selected from -H, -CH 3 , -CF 3 , -F or CH 2 CH 3 , or R 8 and R 9 together form a cyclic ring selected from cyclopropyl, cyclobutyl or oxetane;

[0121] R 11 Selected from -H or -CH 3 ;

[0122] R 12 Selected from -H, -CH 3 、-CH 2 OH, -COOH, -CH 2 OCH 3 、-COOCH 3 , or R 11 and R 12 together form an azetidine ring optionally comprising at least one methyl substituent;

[0123] R 13 Selected from -H or -CH 3 ;

[0124] R 14 Selected from tetrahydropyran, phenyl, optionally containing -OCH 3 or -OH-substituted cyclopentane, -C(CH 3 ) 3 , methoxycyclohexane, containing at least one selected from -CH 3 , -F or =O substituted cyclohexane;

[0125] R 15 Selected from -OCH 3 or -Cl;

[0126] R 16 is selected from indole or tetrahydropyran optionally comprising at least one methyl substituent; and

[0127] A2 Selected from -CH 2 , -CF 2 , -CHOH or -O-,

[0128] or a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments, the compound of formula (I) is selected from:

[0130]

[0131]

[0132]

[0133]

[0134]

[0135] or a pharmaceutically acceptable salt thereof.

[0136] In another aspect, disclosed herein is a compound of formula (II) having a piperazine core:

[0137]

[0138] Where W 1 Selected from -H, -CH 3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 、-CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0139] W 2 Selected from -H, -CH 3 、-CH 2 CH 3 or cyclopropyl; or

[0140] W 1 and W 2 Together they form a cyclic ring including cyclopropyl, cyclobutyl, oxetane, or W 1 and W 2 Together is = O;

[0141] S 1 Selected from -H, -CH 3 、-CH 2 CH3 or -CF 3 ;

[0142] S 2 Selected from -H or -CH 3 ;

[0143] X 2 Not present or -CONH-;

[0144] X 3 is a right-handed substitution selected from an adamantane ring or a piperazine nucleus of formula (i):

[0145]

[0146] Where R 6 is absent, is 1 or 2, and is independently selected from -H, -Cl, -F, -CHF 2 、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-OCF 3 、-OCHF 2 , -CN, cyclopropyl or aryl; and

[0147] X 1 is a levorotatory substitution of the piperazine nucleus which may be selected from:

[0148]

[0149] Where R 1 Selected from -H, deuterium, -CH 3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 、-CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0150] R 2 Selected from -H, deuterium, -CH 3 、-CH 2 CH 3 , -CF 3 or cyclopropyl;

[0151] R 3 Selected from -H or deuterium, or R 2 and R3 together form a cyclic ring selected from cyclopropyl, cyclobutyl or oxetane;

[0152] R 11 Selected from -H or -CH 3 ;

[0153] R 12 Selected from -H, deuterium, -CH 3 、-CH 2 OH, -COOH, -CH 2 OCH 3 、-COOCH 3 , or R 11 and R 12 together form an azetidine ring optionally comprising at least one methyl substituent;

[0154] R 13 Selected from -H, deuterium or -CH 3 ;and

[0155] A is selected from -CH, -N or -CR 6 ;

[0156] or a pharmaceutically acceptable salt thereof.

[0157] In certain embodiments, the compound of formula (II) is selected from:

[0158]

[0159] or a pharmaceutically acceptable salt thereof.

[0160] In another aspect, disclosed herein is a compound of formula (III) having a 1,4-diazepane nucleus:

[0161]

[0162] wherein the 1,4-diazepane nucleus optionally comprises 2,7-CH 2 -bridge, 2,7-CH 2 CH 3 Bridge or 3,7-CH 2 CH 3 bridge;

[0163] W 1 Selected from -H, -CH 3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OMe, -CH 2 CF 3 、-CH 2 OCF3 or -CH 2 O Cyclopropyl,

[0164] W 2 Selected from -H, -CH 3 、-CH 2 CH 3 or cyclopropyl, or

[0165] W 1 and W 2 Together they form a cyclic ring including cyclopropyl, cyclobutyl, oxetane, or W 1 and W 2 Together is = O;

[0166] W 3 Does not exist or =O;

[0167] S 1 Selected from -H, -CH 3 、-CH 2 CH 3 or -CF 3 ;

[0168] S 2 Selected from -H or -CH 3 ;

[0169] X 2 Not present or -CONH-;

[0170] X 3 is a dextrorotatory substitution of a 1,4-diazepane nucleus which may be selected from the group consisting of formula (i):

[0171]

[0172] Where R 6 is absent, is 1 or 2, and is independently selected from -H, -Cl, -F, -CHF 2 、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-OCF 3 、-OCHF 2 , -CN, cyclopropyl or aryl;

[0173] an adamantane ring and a phenyl group optionally comprising 1 or 2 substituents independently selected from fluorine or chlorine; and

[0174] X 1 is a levorotatory substitution of a 1,4-diazepane nucleus which may be selected from:

[0175]

[0176] Where R 1 Selected from -H, deuterium, -CH 3 、-CH 2 CH 3 , -CF 3 , -CHF 2 、-F、-CH 2 OCH 3 、-CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0177] R 2 Selected from -H, -CH 3 、-CH 2 CH 3 , -CF 3 or cyclopropyl;

[0178] R 3 Yes -H, or R 2 and R 3 together form a cyclic ring selected from cyclopropyl, cyclobutyl or oxetane;

[0179] R 11 Selected from -H or -CH 3 ;

[0180] R 12 Selected from -H, deuterium, -CH 3 、-CH 2 OH, -COOH, -CH 2 OCH 3 、-COOCH 3 , or R 11 and R 12 together form an azetidine ring optionally comprising at least one methyl substituent;

[0181] R 13 Selected from -H, deuterium or -CH 3 ;and

[0182] A is selected from -CH, -N or -CR 6 ;

[0183] or a pharmaceutically acceptable salt thereof.

[0184] In certain embodiments, the compound of formula (III) is selected from:

[0185]

[0186] or a pharmaceutically acceptable salt thereof.

[0187] In certain embodiments, the compound of formula (III) comprises a compound of formula (IV) having a 1,4-diazepane core:

[0188]

[0189] Where W 1 , W 2 , S 1 , S 2 , X 1 , X 2 and X 3 As defined in formula (III), or a pharmaceutically acceptable salt thereof.

[0190] In certain embodiments, the compound of formula (IV) is:

[0191]

[0192] or a pharmaceutically acceptable salt thereof.

[0193] In certain embodiments of the compounds disclosed herein, S 1 and S 2 is -H, and X 2 does not exist, and in some embodiments, S 1 and S 2 is -H, and X 2 According to certain embodiments, X 1 is formula (a), and R 2 , R 3 and R 11 Each of is -H, and R 1 , R 12 and R 13 Each of the - is -CH 3 In certain embodiments, X 1 is formula (a), and R 1 , R 12 and R 13 Each of which contains deuterium.

[0194] On the other hand, disclosed herein is a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV) or a pharmaceutically acceptable salt thereof as disclosed herein and a pharmaceutically acceptable carrier. In certain aspects, the pharmaceutical composition further comprises a modified release polymer, such as hydroxypropyl methylcellulose, ethyl cellulose or a polyacrylate polymer.

[0195] On the other hand, disclosed herein is a method for treating a disease or condition related to abnormal function or activity of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof. In some aspects, the disease or condition related to abnormal function or activity of a T-type calcium channel is a mental disorder, pain, tremor, epileptic seizure, epilepsy, or epilepsy syndrome. In certain embodiments, the disease or condition related to abnormal function or activity of a T-type calcium channel is tremor, such as essential tremor.

[0196] On the other hand, disclosed herein is a compound of formula (I) as disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as disclosed herein, which is used to treat a disease or condition related to the abnormal function or activity of a T-type calcium channel. In some aspects, the disease or condition related to the abnormal function or activity of a T-type calcium channel is a mental disorder, pain, tremor, epileptic seizure, epilepsy or epilepsy syndrome. In certain embodiments, the disease or condition related to the abnormal function or activity of a T-type calcium channel is a tremor, such as essential tremor. DETAILED DESCRIPTION

[0197] Disclosed herein are compounds and compositions that can be used to prevent and / or treat 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 can also be used to prevent and / or treat mental disorders. For example, mental disorders can include mood disorders such as depression, major depressive disorder, and mood disorders (e.g., mild depression); bipolar disorder (e.g., I and / or II); anxiety disorders (e.g., generalized anxiety disorder (GAD) and social anxiety disorder); stress; post-traumatic stress disorder (PTSD); and obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD)). Methods for modulating the function of T-type calcium channels and enhancing their effectiveness are also proposed.

[0198] definition

[0199] In order to make the present disclosure easier to understand, some terms are first defined below. The following terms and other definitions of other terms can be set forth in the specification. If the definition of the term set forth below is inconsistent with the definition in the application or patent incorporated by reference, the definition set forth in the present application should be used to understand the meaning of the term.

[0200] As used herein, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response. As will be appreciated by one of ordinary skill in the art, an effective amount of a compound as disclosed herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatments.

[0201] As used herein, and unless otherwise indicated, 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 the disease, disorder, or condition. A therapeutically effective amount of a compound refers to 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 symptoms or causes of a disease or condition, or enhances the efficacy of another therapeutic agent.

[0202] As used herein, the term "refractory" refers to a disease, disorder, or condition that does not readily yield or respond to therapy or treatment, or is not controlled by therapy or treatment. In some embodiments, the diseases, disorders, or conditions described herein are refractory (e.g., refractory epilepsy or refractory absence seizures) and are unresponsive to standard therapy or treatment.

[0203] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, or adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0204] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0205] As used herein, and unless otherwise indicated, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is suffering from a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").

[0206] As used herein, the terms "in some embodiments," "in other embodiments," etc. refer to embodiments of all aspects of the present disclosure, unless the context clearly dictates otherwise.

[0207] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inside cover, and specific functional groups are generally defined as described 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 Modem Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004.

[0208] The compounds described herein may contain one or more asymmetric centers and may therefore exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including a racemic mixture and a mixture enriched in one or more stereoisomers. Isomers may be separated from the mixture 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 may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates 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 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). In certain embodiments, the compounds described herein may be a single isomer substantially free of other isomers, or alternatively as a mixture of various isomers.

[0209] As used herein, a pure enantiomer 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 the compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.2%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% by weight of the enantiomer. In certain embodiments, weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0210] In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure R-compounds. In certain embodiments, the enantiomerically pure R-compound in such a composition may, for example, comprise at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound by the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipients and about 10% enantiomerically pure S-compounds. In certain embodiments, the enantiomerically pure S-compound in such a composition may, for example, comprise at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound by the total weight of the compound. In certain embodiments, the active ingredient may be formulated with very little or no excipient or carrier.

[0211] The compounds described herein may also contain one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O; etc.

[0212] The following terms are intended to have the meanings presented below, and can be used to understand the description and expected scope of the present disclosure. When describing certain aspects of the present disclosure, the present disclosure may include compounds, pharmaceutical compositions containing such compounds, and methods using such compounds and compositions, unless otherwise specified, the following terms, if present, have the following meanings. It should also be understood that when described herein, any part defined below can be substituted by various substituents, and the corresponding definition is intended to include such substituted parts within its scope as set forth below. Unless otherwise specified, the term "substituted" will be defined as set forth below. It should also be understood that when used herein, the terms "groups" and "radicals" can be considered interchangeable. The articles "a" and "an" can be used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. As an example, "an analog" means an analog or more than one analog.

[0213] When a range of values ​​is listed, it is intended that every value and subrange within the range be included. For example, “C 1-6 The term "alkyl" is intended to encompass C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0214] "Alkyl" refers to a group such as a straight-chain 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 (“C1-6 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 1 carbon atom (“C 1 C 1-6 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.

[0215] The term "alkyl" encompasses alkyl groups that are unsubstituted or substituted with a variety of substituents as described herein. For example, an alkyl group can be substituted with one or more (e.g., one, two, three, four, five, six or more) substituents as described herein. Exemplary substituents for alkyl groups include halo (e.g., fluoro, chloro, and bromo); hydroxy; cyano; nitro (-NO 2 ); amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3 ; carbocyclic groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic groups (e.g., ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl groups (e.g., phenyl) and heteroaryl groups (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the alkyl group may be replaced by one or more selected from fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH 3 and cyclopropyl are substituted by a substituent group,

[0216] "Alkenyl" refers to a straight or branched chain hydrocarbon radical 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). 2-20 In some embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2-10In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 One or more carbon-carbon double bonds may be located internally (such as in 2-butenyl) or terminally (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadiene (C 4 ) etc. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 Alkenyl and pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ) and the like. Other examples of alkenyl groups include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 )wait.

[0217] The term "alkenyl" encompasses alkenyl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for alkenyl groups include halo (e.g., fluoro, chloro, and bromo); hydroxy; cyano; nitro (-NO 2 ); amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3; carbocyclic groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic groups (e.g., ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl groups (e.g., phenyl) and heteroaryl groups (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the alkenyl group may be replaced by one or more selected from fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH 3 and cyclopropyl are substituted by a substituent group,

[0218] "Alkynyl" refers to a straight or branched chain hydrocarbon radical ("C-carbon") 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). 2-20 In some embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 The carbon-carbon triple bond(s) may 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 (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) etc. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 Alkynyl and pentynyl (C 5 ), hexynyl (C 6 ) and the like. Other examples of alkynyl groups include heptynyl (C 7 ), octynyl (C8 )wait.

[0219] The term "alkynyl" encompasses alkynyl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for alkynyl groups include halo (e.g., fluoro, chloro, and bromo); hydroxy; cyano; nitro (-NO 2 ); amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3 ; carbocyclic groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic groups (e.g., ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl groups (e.g., phenyl) and heteroaryl groups (e.g., pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the alkynyl group may be replaced by one or more selected from fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH 3 and cyclopropyl are substituted by a substituent group,

[0220] The term "alkoxy" refers to alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, propoxy, butoxy and pentoxy. The term "alkoxy" encompasses alkoxy groups in which the alkyl, alkenyl and alkynyl moieties are unsubstituted or substituted with a variety of substituents as described herein.

[0221] The term "amino" refers to -NH 2 The term "alkylamino" refers to -NHR 1 Group, where R 1 is an alkyl group, for example, methylamino or ethylamino. The term "dialkylamino" refers to -NR 1 R 2 Group, where R 1 and R 2 Both are alkyl groups, for example, dimethylamino, methylethylamino or diethylamino.

[0222] "Aryl" refers to a group having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons in common in the ring array) ("C 6-14In some embodiments, an aryl group has six ring carbon atoms (“C 6 In some embodiments, an aryl group has ten ring carbon atoms (“C 10 In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical 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, phenanthe ... The aryl group includes s-indacene, indane, indene, naphthalene, octaacene, octaphene, octalene, ovalene, pentadiene, pentacene, cyclopentadiene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Specifically, the aryl group includes phenyl, naphthyl, indenyl and tetrahydronaphthyl.

[0223] The term "aryl" encompasses aryl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for aryl groups include halo (e.g., fluoro, chloro, and bromo); hydroxy; cyano; nitro (-NO 2 ); amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3; carbocyclic group (for example, cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic group (for example, ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl (for example, phenyl) and heteroaryl (for example, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, aryl can be selected from one or more fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH 3 In some embodiments, the aryl group may be substituted with one or more substituents selected from the group consisting of fluorine, chlorine, hydroxyl, cyano, methyl, difluoromethyl, trifluoromethyl, methoxy and cyclopropyl.

[0224] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen or sulfur heteroatoms. Hetero can be applied to the above-mentioned alkyl groups, such as alkyl, for example, heterocycloalkyl; alkenyl, for example, heteroalkenyl; alkynyl, for example, heteroalkynyl; carbocyclyl, for example, heterocyclyl; aryl, for example, any of heteroaryl, and similar groups having 1 to 5, and specifically 1 to 3 heteroatoms, etc.

[0225] "Heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the ring array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom when valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused to one or more aryls, wherein the point of attachment is located on an aryl or heteroaryl ring, and in such cases, the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. One of the rings does not contain a heteroatom bicyclic heteroaryl (e.g., indolyl, quinolyl, carbazolyl, etc.), and the point of attachment can be located at any ring, that is, a ring with a heteroatom (e.g., 2-indolyl) or a ring that does not contain a heteroatom (e.g., 5-indolyl). Non-limiting examples of heteroaryl include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, indazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, piperazine, benzofuran, quinazoline, benzisoxazole, quinolinone, isoquinoline and naphthyridine. The term "naphthyridine" encompasses 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,6-naphthyridine, and 2,7-naphthyridine.

[0226] 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); hydroxy; cyano; nitro (-NO 2 ); amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3; carbocyclic group (for example, cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic group (for example, ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl (for example, phenyl) and heteroaryl (for example, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the heteroaryl portion can be selected from one or more fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH 3 and cyclopropyl.

[0227] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 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.

[0228] "Carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 "Carbocyclyl"). Exemplary C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C6 ), cyclohexadienyl (C 6 ) etc. Exemplary C 3-5 Carbocyclic groups include but are not limited to the aforementioned C 3-6 Carbocyclic and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptyl (C 7 ), bicyclo[2.2.2]octyl (C 8 ) etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the aforementioned C 3-8 Carbocyclic and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) etc. As illustrated by the foregoing examples, in certain embodiments, the carbocyclyl is a monocyclic ring ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic carbocyclyl"), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the carbocyclyl system.

[0229] The term "carbocyclyl" encompasses carbocyclyl groups that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for carbocyclyl groups include halo (e.g., fluoro, chloro, and bromo); hydroxy; cyano; amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3; carbocyclic group (for example, cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic group (for example, ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl (for example, phenyl) and heteroaryl (for example, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the carbocyclic group can be selected from one or more fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH 3 and cyclopropyl.

[0230] "Heterocyclyl" or "heterocycle" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. A heterocyclyl may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system.

[0231] The term "heterocyclyl" encompasses heterocyclyl moieties that are unsubstituted or substituted with a variety of substituents as described herein. Exemplary substituents for heterocyclyl include halo (e.g., fluoro, chloro, and bromo); hydroxy; cyano; amino (-NH 2 ); alkylamino (e.g., methylamino or ethylamino); dialkylamino (e.g., dimethylamino or diethylamino); alkyl (e.g., C 1-6 alkyl, such as methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.); alkoxy (e.g., C 1-6 Alkoxy (e.g., methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, difluoroethoxy, trifluoroethoxy), -COOCH 3 ; carbocyclic group (for example, cyclopropyl, cyclobutyl, cyclopentyl, etc.), heterocyclic group (for example, ethylene oxide, propylene oxide, tetrahydrofuran, etc.); aryl (for example, phenyl) and heteroaryl (for example, pyrazole, imidazole, pyrrole, pyridine, pyrimidine, oxazole, etc.). In some embodiments, the heterocyclic group can be selected from one or more fluorine, chlorine, hydroxyl, cyano, amino, methyl, difluoromethyl, trifluoromethyl, tert-butyl, methoxy, difluoromethoxy, trifluoromethoxy, -COOCH3 and cyclopropyl.

[0232] In some embodiments, heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl”). In some embodiments, heterocyclyl is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In some embodiments, 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen and sulfur.

[0233]

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

[0234] "Cyano" refers to -CN.

[0235] "Halo" or "halogen" refers to a fluorine atom (ie, F or -F), a chlorine atom (ie, C or -Cl), a bromine atom (ie, B or -Br), and an iodine atom (ie, I or -I). In certain embodiments, the halo group is fluorine or chlorine.

[0236] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0237] "Nitro" refers to -NO 2 .

[0238] In general, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with 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 (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents may be the same or different at each position.

[0239] "Counter ions" or "anionic counter ions" are negatively charged groups associated with cationic quaternary amino groups to maintain electronic neutrality. Exemplary counter ions include halide ions (e.g., F - , Cl - Br - ,I - ), NO 3 - , ClO 4 - OH - , H 2 PO 4 - , HSO 4 - 、SO 4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanesulfonate, propionate, benzoate, glyceride, lactate, tartrate, glycolate, etc.).

[0240] The term "pharmaceutically acceptable salt" refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, and are 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., who describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0241] The term "modified release polymer" refers to a polymer used in formulations (e.g., tablets and capsules) to change the release rate of a drug after administration to a subject. For example, a modified release polymer is used to dissolve a drug over time so that it is released more slowly and more steadily into the bloodstream. For example, a modified release polymer is a controlled release polymer. For example, a modified release polymer or a controlled release polymer is an HPMC polymer. In some embodiments, a modified release polymer can include a hydrophilic matrix polymer (e.g., hydroxypropyl methylcellulose, hydroxy-propyl methylcellulose (HPMC)), a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel), or a polyacrylate polymer (e.g., RL100, RS100).

[0242] As used herein, the term "diluent" refers to an excipient used to increase weight and improve content uniformity. For example, diluents include cellulose derivatives (e.g., microcrystalline cellulose), starch (e.g., hydrolyzed starch and partially pregelatinized starch), anhydrous lactose, lactose monohydrate, dicalcium phosphate (DCP), sugar alcohols (e.g., sorbitol, xylitol and mannitol)).

[0243] As used herein, the term "glidant" refers to an excipient used to promote powder flow by reducing inter-particle friction and cohesion. For example, glidants include fumed silica (e.g., colloidal silicon dioxide), talc, and magnesium carbonate.

[0244] As used herein, the term "lubricant" refers to an excipient used to prevent ingredients from agglomerating and sticking to a tablet punch or capsule filling machine. Lubricants are also used to ensure that tablet formation and discharge can occur under low friction between the solid and the die wall. For example, lubricants include magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, and fats (e.g., vegetable stearin).

[0245] As used herein, the term "coating" refers to excipients that protect tablet ingredients from deterioration due to moisture in the air and make large or bad-tasting tablets easier to swallow.

[0246] The embodiments disclosed herein are not intended to be limited in any way by the exemplary list of chemical groups and substituents described above.

[0247] Compound

[0248] In one aspect, compounds and compositions thereof are disclosed for use in modulating T-type calcium channels, and diseases, disorders or conditions associated with abnormal function thereof (e.g., psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)); pain; tremor, such as essential tremor; epilepsy or epileptic seizures, such as absence seizures, juvenile myoclonic epilepsy, grand mal epilepsy or hereditary epilepsy).

[0249] In some aspects, the present disclosure provides a compound represented by formula (Ia):

[0250]

[0251] in:

[0252] B is absent or selected from the group consisting of: -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 -;

[0253] W 1 ' and W 2 ' are each 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);

[0254] S 1 ′ and S 2 ' are each independently selected from -H and -CH 3 The group, or S 1 ′ and S 2 ' together to form a carbonyl group;

[0255] X 2 'Does not exist, is -CH 2 -、-CHCH 3 -or-CONH-;

[0256] X 3 ' is selected from the group consisting of: carbocyclyl, heterocyclyl, aryl and heteroaryl;

[0257] X 1 'Selected from the group consisting of:

[0258] (i)

[0259]

[0260] in.

[0261] R 2 ' and R 3 ' are each independently selected from the group consisting of: -H, deuterium, alkyl, hydroxy, alkoxy, halo, carbocyclyl and heterocyclyl; or R 2 ' and R 3 'Together they form a ring-like ring;

[0262] R 4 ′ and R μ ' are each independently selected from the group consisting of: -H, deuterium, halo, CN, alkyl and alkoxy; or R 4 ' and R μ 'Together they form a carbonyl group;

[0263] R 1 'Selected from the group consisting of: alkyl, carbocyclic, heterocyclic, -OZ 1 '、-NZ 2 'Z 3 'and-SO 2 Z 7 ';

[0264] Z 1 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups;

[0265] Z 2 ′ and Z 3 'Each independently selected from the group consisting of: hydrogen, deuterium, alkyl, carbocyclic group, heterocyclic group, -COZ' 5 and-SO 2 Z 6 '; or where Z 2 ' and Z 3 ' together with the nitrogen to which it is bonded, forms a heterocyclic group;

[0266] Z 5 ′ is C 3-6 Carbocyclic group;

[0267] Z 6 ′ is C 1-6 Alkyl; or

[0268] Z 7 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups; or

[0269] (ii)

[0270]

[0271] in

[0272] R 6 ' is selected from the group consisting of: alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; and pharmaceutically acceptable salts thereof.

[0273] In some embodiments of Formula (Ia), B is absent. In some embodiments of Formula (Ia), B is -CH 2 -. In some embodiments of Formula (Ia), B is -CH 2 -CH 2 -.

[0274] In some embodiments of Formula (Ia), W 1 ' and W 2 'Both are hydrogen.

[0275] In some embodiments of Formula (Ia), S 1 ′ and S 2 'Both are hydrogen.

[0276] In some embodiments of Formula (Ia), R 2 ' and R 3 'Both are hydrogen.

[0277] In some embodiments of Formula (Ia), R 4 ' and R μ 'Together they form a carbonyl group.

[0278] In some embodiments of Formula (Ia), R 1 'Yes-NZ 2 'Z 3 '.

[0279] In some embodiments of Formula (Ia), Z 2 ' is hydrogen or methyl; and Z 3 'It's C 1-6 Alkyl, C 3-6 A carbocyclic or heterocyclic group, wherein C 1-6 Alkyl, C 3-6 Each of the carbocyclyl and heterocyclyl groups is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxy, halo, methoxy, trifluoromethyl, and -COOCH 3 In some embodiments, Z 2 ' is hydrogen, and Z 3 ′ is C 1-6 In one embodiment, Z 3 ' is tert-butyl.

[0280] In some embodiments of Formula (Ia), Z 2 ' is hydrogen, and Z 3' is cyclopropyl, cyclobutyl or oxetane.

[0281] In some embodiments of Formula (Ia), R 4 ' and R μ ' are each independently hydrogen, hydroxy or halo.

[0282] In some embodiments of Formula (Ia), R 1 'Yes-NZ 2 'Z 3 ', Z 2 ' is hydrogen, and Z 3 ' is -COZ 2 '.

[0283] In some embodiments of Formula (Ia), R 1 ' is an alkyl group, a carbocyclic group or a heterocyclic group.

[0284] In some embodiments of Formula (Ia), X 2 'It's -CONH-.

[0285] In some embodiments of Formula (Ia), X 3 ' is aryl or heteroaryl, wherein each of the aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl and tert-butyl. In some embodiments of Formula (Ia), X 3 ' is selected from the group consisting of: phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran; quinazoline phenylimidazole, phenyltriazole, phenylpyrazole and adamantane ring. In one embodiment, X 3 ' is phenyl optionally substituted by one or two substituents selected from the group consisting of chloro, fluoro, cyano, methyl, methoxy, difluoromethoxy and trifluoromethoxy. In one embodiment, X 3 ' is a benzimidazole optionally substituted with two substituents selected from the group consisting of chlorine and fluorine.

[0286] In some embodiments, the compound of formula (Ia) is:

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300] In some aspects, the present disclosure provides a compound represented by formula (IIa):

[0301]

[0302] in:

[0303] The stereocenters indicated by * are all in S configuration or all in R configuration;

[0304] B chooses from -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 - the groups formed;

[0305] S 1 ′ and S 2 ' are each independently selected from -H and -CH 3 The group, or S 1 ′ and S 2 ' together to form a carbonyl group;

[0306] X 2 'Does not exist, is -CH 2 -、-CHCH 3 -or-CONH-;

[0307] X 3 ' is selected from the group consisting of: carbocyclyl, heterocyclyl, aryl and heteroaryl;

[0308] X1 ' is selected from the group consisting of:

[0309] (i)

[0310]

[0311] in:

[0312] R 2 ' and R 3 ' are each independently selected from the group consisting of: -H, deuterium, alkyl, hydroxy, alkoxy, halo, carbocyclyl and heterocyclyl; or R 2 ' and R 3 'Together they form a ring-like ring;

[0313] R 4 ′ and R μ ' are each independently selected from the group consisting of: -H, deuterium, halo, CN, alkyl and alkoxy; or R 4 ' and R μ 'Together they form a carbonyl group;

[0314] R 1 ' is selected from the group consisting of: alkyl, carbocyclic, heterocyclic, -OZ 1 '、-NZ 2 ′Z 3 'and-SO 2 Z 7 ';

[0315] Z 1 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups;

[0316] Z 2 ′ and Z 3 'Each independently selected from the group consisting of: hydrogen, deuterium, alkyl, carbocyclic group, heterocyclic group, -COZ' 5 and-SO 2 Z 6 '; or where Z 2 ' and Z 3 'Together with the nitrogen to which it is bonded, it forms a heterocyclic group;

[0317] Z 5 ′ is C 3-6 Carbocyclic group;

[0318] Z 6 ′ is C 1-6 Alkyl; or

[0319] Z 7 ' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups; or

[0320] (ii)

[0321]

[0322] in

[0323] R 6 ' is selected from the group consisting of: alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; and pharmaceutically acceptable salts thereof.

[0324] In some embodiments of Formula (IIa), the stereocenters indicated by * are all in the S configuration. In some embodiments of Formula (IIa), the stereocenters indicated by * are all in the R configuration.

[0325] In some embodiments of Formula (IIa), B is -CH 2 -. In some embodiments of Formula (IIa), B is -CH 2 -CH 2 -.

[0326] In some embodiments of Formula (IIa), S 1 ′ and S 2 'Both are hydrogen.

[0327] In some embodiments of Formula (IIa), R 2 ' and R 3 'Both are hydrogen.

[0328] In some embodiments of Formula (IIa), R 4 ' and R 5 'Together they form a carbonyl group.

[0329] In some embodiments of Formula (IIa), R 1 'Yes-NZ 2 'Z 3 '. In some embodiments, Z 2 ' is hydrogen or methyl; and Z 3 ′ is C 1-6 Alkyl, C 3-6 A carbocyclic or heterocyclic group, wherein C 1-6 Alkyl, C 3-6 Each of the carbocyclyl and heterocyclyl groups is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxy, halo, methoxy, trifluoromethoxy, and -COOCH 3 In some embodiments, Z 2 ' is hydrogen, and Z 3 ′ is C 1-6 In one embodiment, Z 3 ' is tert-butyl.

[0330] In some embodiments of Formula (IIa), Z2 ' is hydrogen, and Z 3 ' is cyclopropyl, cyclobutyl or oxetane.

[0331] In some embodiments of Formula (IIa), R 4 ' and R 5 ' are each independently hydrogen, hydroxy or halo.

[0332] In some embodiments of Formula (IIa), R 1 'Yes-NZ 2 'Z 3 ', Z 2 ' is hydrogen, and Z 3 'Yes-COZ 5 '. In some embodiments of Formula (IIa), R 1 ' is an alkyl group, a carbocyclic group or a heterocyclic group.

[0333] In some embodiments of Formula (IIa), X 2 'It's -CONH-.

[0334] In some embodiments of Formula (IIa), X 3 ' is aryl or heteroaryl, wherein each of the aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl and tert-butyl. In some embodiments, X 3 ' is selected from the group consisting of: phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran; quinazoline phenylimidazole, phenyltriazole, phenylpyrazole, bicycloheptane, bicyclooctane and adamantane ring. In one embodiment, X 3 ' is phenyl optionally substituted with two substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, difluoromethoxy and trifluoromethoxy.

[0335] In some embodiments, the compound of formula (IIa) is:

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] In some aspects, the present disclosure provides a compound represented by formula (IIIa):

[0343]

[0344] in:

[0345] One stereocenter indicated by * is in the S configuration, and the other stereocenter indicated by * is in the R configuration;

[0346] 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 -;

[0347] D is carbon or nitrogen;

[0348] X 1 ' is an alkyl group,

[0349] X 2 'is -NHCO- or -CONH-; and

[0350] X 3 ' is aryl or heteroaryl; and pharmaceutically acceptable salts thereof.

[0351] In some embodiments of Formula (IIIa), C is -CH 2 -O-CH 2 -.

[0352] In some embodiments of Formula (IIIa), X 1 ' is tert-butyl.

[0353] In some embodiments of Formula (IIIa), X 3 ' is phenyl or benzimidazole, wherein phenyl and benzimidazole are each optionally substituted with one or two substituents selected from the group consisting of chlorine, fluorine and difluoromethoxy.

[0354] In some embodiments, the compound of formula (IIIa) is:

[0355]

[0356] In some aspects, the present disclosure provides a compound represented by formula (IVa):

[0357]

[0358] in:

[0359] Stereocenters indicated by * are in R or S configuration;

[0360] X 1 ' is an alkyl group;

[0361] X 2 ' is -O- or NR 1 R 2 , where R 1 and R 2 are each independently H or alkyl; and

[0362] X 3 ' is aryl or heteroaryl; and pharmaceutically acceptable salts thereof.

[0363] In some embodiments, the compound of formula (IVa) is:

[0364]

[0365] In some aspects, the present disclosure provides a compound represented by formula (Va):

[0366]

[0367] in:

[0368] The 1,4-diazepane nucleus of the compound of formula (Va) optionally comprises 2,7-CH 2 -bridge, 2,7-CH 2 CH 2 -bridge, 3,7-CH 2 -bridge or 3,7-CH 2 CH 2 -bridge;

[0369] W 1 ' and W 2 ' are each independently hydrogen, deuterium, alkyl and alkoxy; or W 1 ' and W 2 'together form a carbocyclyl, heterocyclyl or carbonyl (=O);

[0370] W 3 is hydrogen or carbonyl;

[0371] S 1 ′ and S 2 ' are each independently hydrogen or alkyl, or S 1 ′ and S 2 ' together to form a carbonyl group;

[0372] X 2'Does not exist, is -CH 2 -、-CHCH 3 -or-CONH-;

[0373] X 3 ' is selected from the group consisting of: carbocyclyl, heterocyclyl, aryl and heteroaryl;

[0374] X 1 'yes

[0375]

[0376] in:

[0377] R 1 ' is selected from the group consisting of: hydrogen, alkyl, carbocyclyl and heterocyclyl;

[0378] R 2 ' and R 3 ' are each independently selected from the group consisting of: hydrogen, deuterium, alkyl, hydroxy, alkoxy, halo, carbocyclyl and heterocyclyl; or R 2 ' and R 3 'Together they form a ring-like ring;

[0379] R 11 ' is hydrogen or methyl;

[0380] 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 comprising at least one methyl substituent;

[0381] R 13 Selected from the group consisting of hydrogen, deuterium and alkyl; and pharmaceutically acceptable salts thereof.

[0382] In some embodiments, the compound of formula (Va) is also represented by formula (Vb):

[0383]

[0384] And among them W 1 ', W 2 '、S 1 ′、S 2 ′、X 1 ', X 2 ' and X 3 'As defined in formula (Va).

[0385] In some embodiments of Formula (Va) or Formula (Vb), X 3' is selected from the group consisting of phenyl, benzimidazole and adamantane ring, wherein phenyl and benzimidazole are each optionally substituted with one or two substituents selected from chlorine and fluorine.

[0386] In some embodiments, the compound of formula (Va) is:

[0387]

[0388] In some aspects, the present disclosure also provides a compound represented by formula (VIa):

[0389]

[0390] in

[0391] R 1 ′ and R 2 ' are each hydrogen, or R 1 ′ and R 2 ' together to form a carbonyl group; and

[0392] R 3 ' is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, amino, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy; and pharmaceutically acceptable salts thereof.

[0393] In some embodiments, R 3 ' is isoquinoline. In some embodiments, R 3 ' is naphthyridine.

[0394] In some embodiments, the compound of formula (VIa) is:

[0395] as well as

[0396]

[0397] In one aspect, the present disclosure also provides a compound having the following structure:

[0398]

[0399] 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 a compound 1,4-diazepane core of formula (III), including compounds of formula (IV). In certain embodiments disclosed herein, there is a compound selected from formula (I), formula (II), or formula (III):

[0400]

[0401]

[0402] The 1,4-diazepane nucleus of formula (III) optionally comprises 2,7-CH 2 -bridge, 2,7-CH 2 CH 3 Bridge or 3,7-CH 2 CH 3 bridge;

[0403] n is selected from 0, 1 or 2;

[0404] W 1 and W 2 are independently selected from H, -CH 3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 、-CH 2 CF 3 、-CH 2 OCF 3 , cyclopropyl or -CH 2 Ocyclopropyl, or

[0405] W 1 and W 2 Together they form a cyclic ring including cyclopropyl, cyclobutyl, oxetane, or W 1 and W 2 Together is = O;

[0406] S 1 and S 2 Independently selected from -H, -CH 3 、-CH 2 CH 3 or -CF 3 ;

[0407] X 2 Does not exist, is -CH 2 or -CONH-;

[0408] X 3 is a right-handed substitution of a piperazine nucleus or a 1,4-diazepane nucleus selected from formula (i):

[0409]

[0410] Among them A 1 Selected from -CH, -CF 2 , -COH, -N, -O or -CR 6 ,and

[0411] Where R 6 is absent, is 1 or 2, and is independently selected from -H, -Cl, -F, -CF 2 、-CH 3 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-OCF 3 、-OCHF 2 , -CN, cyclopropyl or aryl;

[0412] Formula (ii)

[0413]

[0414] Where R 10 is absent, is 1 or 2, and is independently selected from -Cl, -F, -CH 3 , -CF 3 , -CHF 2 、-CH 2 CH 3 、-OCH 3 、-OCH 2 CH 3 、-OCF 3 、-OCHF 2 , -CN, cyclopropyl or aryl; or

[0415] adamantane ring; phenyl, the phenyl optionally comprising 1 or 2 substituents independently selected from fluorine or chlorine; pyrazole, the pyrazole optionally comprising at least one substituent selected from methyl (such as two methyl substituents), cyclopropyl or tert-butyl; indazole, the indazole optionally comprising at least one methyl substituent; phenylpyrazole, wherein the pyrazole optionally comprises at least one substituent selected from -CH 2 CH 2 (CH 3 ) 2 phenyltriazole, wherein the phenyl group optionally comprises at least one substituent selected from chlorine or fluorine, such as a chlorine substituent and a fluorine substituent; phenylimidazole, wherein the phenyl group optionally comprises at least one substituent selected from chlorine or fluorine, such as a chlorine substituent and a fluorine substituent, and wherein the imidazole optionally comprises at least one substituent selected from methyl or -CH 2 CH 2 (CH 3 ) 2 benzofuran; quinazoline; or benzisoxazole; and

[0416] X 1 is a levorotatory substitution of a piperazine nucleus selected from:

[0417]

[0418]

[0419] Where R 1 Selected from -H, deuterium, -CH 3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 、-CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0420] R 2 Selected from -H, deuterium, -CH 3 、-CH 2 CH 3 , -CF 3 or cyclopropyl;

[0421] R 3 Selected from -H or deuterium, or R 2 and R 3 together form a cyclic ring selected from cyclopropyl, cyclobutyl or oxetane;

[0422] R 4 Selected from -CH 3 、-CH 2 CH 3 , -CF 3 , -F or CH 2 O alkyl;

[0423] R 8 Selected from -H, -CH 3 、-CH 2 CH 3 , -CF 3 、-F、-CH 2 OCH 3 , cyclopropyl, -CH 2 CF 3 、-CH 2 OCF 3 or -CH 2 Ocyclopropyl;

[0424] R 9 Selected from -H, -CH 3 , -CF 3 , -F or CH 2 CH 3, or R 8 and R 9 together form a cyclic ring selected from cyclopropyl, cyclobutyl or oxetane;

[0425] R 11 Selected from -H or -CH 3 ;

[0426] R 12 Selected from -H, deuterium, -CH 3 、-CH 2 OH, -COOH, -CH 2 OCH 3 、-COOCH 3 , or R 11 and R 12 together form an azetidine ring optionally comprising at least one methyl substituent;

[0427] R 13 Selected from -H, deuterium or -CH 3 ;

[0428] R 14 Selected from tetrahydropyran, phenyl, optionally containing -OCH 3 or -OH-substituted cyclopentane, -C(CH 3 ) 3 , methoxycyclohexane, containing at least one selected from -CH 3 , -F or =O substituted cyclohexane;

[0429] R 15 Selected from -OCH 3 or -Cl;

[0430] R 16 is selected from indole or tetrahydropyran optionally comprising at least one methyl substituent; and

[0431] A 2 Selected from -CH 2 , -CF 2 , -CHOH or -O-,

[0432] or a pharmaceutically acceptable salt thereof.

[0433] In certain embodiments, X 1 is formula (a), and R 1 , R 2 , R 3 , R 11 , R 12 and R 13 In certain embodiments, S 1 and S 2 is -H. In certain embodiments, X2 does not exist, and in some embodiments, X 2 is -CONH. In certain embodiments, X 3 is formula (i), and in certain embodiments of formula (i), R 6 It is 2, including one each of fluorine and chlorine.

[0434] In certain embodiments, the compounds disclosed herein include compounds of formula (I), wherein the compound has the structure shown below:

[0435]

[0436]

[0437]

[0438]

[0439]

[0440] or a pharmaceutically acceptable salt thereof.

[0441] In certain embodiments, the compounds disclosed herein include compounds of formula (II), wherein the compound has the structure shown below:

[0442]

[0443] or a pharmaceutically acceptable salt thereof.

[0444] In certain embodiments, the compounds disclosed herein include compounds of formula (III), wherein the compound has the structure shown below:

[0445]

[0446] or a pharmaceutically acceptable salt thereof.

[0447] In certain embodiments, the compounds disclosed herein are compounds of formula (III), wherein the compound is a compound of formula (IV):

[0448]

[0449] Where W 1 , W 2 , S 1 , S 2 , X 1 , X 2 and X 3As defined above in formula (III), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds disclosed herein include compounds of formula (IV), wherein the compound has the structure shown below:

[0450]

[0451] or a pharmaceutically acceptable salt thereof.

[0452] Composition

[0453] In one aspect, a compound of Formula (I), (II), (III) or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, can be in the form of a pharmaceutical composition, such as in a dosage form. As used herein, the terms pharmaceutical composition and dosage form can be used interchangeably.

[0454] In some embodiments, the composition useful in the methods described herein can be a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, and an excipient for modifying the release rate of a compound of formula (I), (II), (III), or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition can be a swellable core technology formulation.

[0455] In certain embodiments, dosage forms that can be used in the methods described herein can be dosage forms, such as oral dosage forms, comprising a compound of Formula (I), (II), (III) or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, and a release-modifying polymer (e.g., a controlled release polymer, a hydrophilic matrix polymer (e.g., an HPMC polymer), a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel) or a polyacrylate polymer (e.g., RL100, RS100)).

[0456] In some embodiments, the dosage form may comprise from about 0.9% to about 40% by weight (e.g., from about 0.9% to about 30%, from about 1% to about 25%, from about 2% to about 25%, from about 3% to about 20%, from about 4% to about 20%, from about 5% to about 20%, from about 5% to about 15%, from about 5% to about 10%, or about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% by weight). %, about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19 wt %, about 20 wt %, about 21 wt %, about 22 wt %, about 23 wt %, about 24 wt %, about 25 wt %, about 26 wt %, about 27 wt %, about 28 wt %, about 29 wt %, about 30 wt %, about 40 wt %) of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the dosage form comprises about 30 wt % to about 40 wt % of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, the dosage form may contain about 4 weight % to about 25 weight %, such as about 19 weight % to about 20 weight %, about 21 weight % to about 22 weight %, about 4 weight % to about 15 weight %, about 4 weight % to about 10 weight %, about 4 weight % to about 5 weight %, about 5 weight % to about 6 weight % or about 9 weight % to about 10 weight % of a compound of Formula (I), Formula (II), Formula (III) or Formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0458] In some embodiments, dosage forms that can be used in the methods described herein can be dosage forms or compositions containing about 0 mg to about 60 mg (e.g., about 1 mg to about 20 mg, about 5 mg to about 25 mg, about 10 mg to about 30 mg, about 15 mg to about 35 mg, about 20 mg to about 40 mg, about 25 mg to about 55 mg, or about 30 mg to about 60 mg) of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0459] In other embodiments, dosage forms that can be used in the methods described herein can be dosage forms or compositions comprising 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), (II), (III), or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, and a modified release polymer (e.g., a controlled release polymer, a hydrophilic matrix polymer (e.g., an HPMC polymer), a hydrophobic matrix polymer (e.g., ethyl cellulose, ethocel), or a polyacrylate polymer (e.g., RL100, RS100)).

[0460] In other embodiments, the dosage form comprises about 4 mg to about 6 mg (e.g., about 5 mg) of a compound of Formula (I), (II), (III), or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the dosage form comprises 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), (II), (III), or (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the dosage form comprises about 55 mg to 65 mg of a modified release polymer (e.g., HPMC polymer). In some embodiments, the dosage form comprises about 10 wt % to about 70 wt % of a modified release polymer (e.g., HPMC polymer). In some embodiments, the dosage form comprises about 50 wt % to about 60 wt % of a modified release polymer (e.g., HPMC polymer).

[0462] 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 15mg to 40mg (e.g., about 15mg to about 25mg, about 20mg to about 25mg, about 25mg to about 30mg, about 30mg to about 40mg) of microcrystalline cellulose. In some embodiments, the dosage form comprises about 15mg to about 25mg of microcrystalline cellulose. In some embodiments, the dosage form comprises about 30mg to about 40mg 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) of microcrystalline cellulose.

[0463] In some embodiments, the dosage form further comprises a glidant. In some embodiments, the glidant 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.

[0464] In some embodiments, about 80% of the compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, is released within 7 hours after administration to a subject. In certain embodiments, about 80% of the compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, is released within 7 hours using a USPI type apparatus, a medium containing 900 mL of 0.1 M HCl, and a paddle speed of 100 rpm.

[0465] In some embodiments, after administration to a subject, the dosage form has a C max The value is less than a reference oral dosage form (e.g., a dosage form without any expected release rate profile (e.g., a dosage form without a modified release rate profile or without a modified release polymer, such as an HPMC polymer)). In some embodiments, after administration to a subject, the dosage form has a t max The value is greater than a reference oral dosage form (eg, a dosage form without any intended release rate profile (eg, a dosage form without a modified release rate profile or without a modified release polymer, such as an HPMC polymer)).

[0466] In other embodiments, the dosage form is administered to the patient once a day. In certain embodiments, the dosage form is administered to the 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.

[0467] In some embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) comprising about 15 mg to 25 mg of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof; and about 55 mg to 65 mg of an HPMC polymer.

[0468] In other embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) comprising about 14% to about 25% by weight of a compound of Formula (I), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof; and about 53% to about 64% by weight of an HPMC polymer.

[0469] In certain embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) comprising about 3 mg to 8 mg of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof; and about 55 mg to 65 mg of an HPMC polymer.

[0470] In some embodiments, the dosage form that can be used in the methods described herein can be an oral dosage form (e.g., granules) comprising about 3 wt % to about 8 wt % of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof; and about 53 wt % to about 64 wt % of an HPMC polymer.

[0471] In other embodiments, the dosage form that can be used in the methods described herein can be an oral (e.g., granular) composition comprising a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof; and a modified release polymer (e.g., a controlled release polymer, such as an HPMC polymer as a hydrophilic matrix polymer).

[0472] 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 pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 14% to about 25% by weight, 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 a pharmaceutically acceptable salt thereof.

[0473] 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), (II), (III), or (IV), or a pharmaceutically 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), (II), (III), or (IV), or a pharmaceutically 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), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof.

[0474] In some embodiments, the composition comprises a diluent. In some embodiments, the diluent comprises microcrystalline cellulose. In other embodiments, the composition comprises about 15 mg to 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 comprises about 15 wt % to about 35 wt % (e.g., about 15 wt % to about 20 wt %, about 20 wt % to about 25 wt %, 25 wt % to about 30 wt %, or 30 wt % to about 35 wt %) of microcrystalline cellulose.

[0475] 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 glidant. In some embodiments, the glidant 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. In some embodiments, the compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutically acceptable salt thereof, is stable in the formulation at about 25°C at 60% relative humidity for at least 24 months. In some embodiments, the compound is stable at about 25°C at 60% relative humidity for at least 36 months. In some embodiments, the compound is stable at about 25°C at 60% relative humidity for at least 48 months. In other embodiments, the compound is stable at about 25°C at 60% relative humidity for at least 60 months. In some embodiments, the compound is stable at about 40°C at 75% relative humidity for at least 6 months.

[0476] Immediate release formulations

[0477] In some embodiments, the dosage form or composition that can be used in the methods described herein can be a dosage form or composition comprising a compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), Formula (II), Formula (III), or Formula (IV) or a pharmaceutically acceptable salt thereof is released immediately after administration to a subject.

[0478] In other embodiments, the dosage form that can be used in the methods described herein can be an oral capsule for immediate release, comprising about 15 mg to about 20 mg of a compound of Formula (I), (II), (III) or (IV) or a pharmaceutically acceptable salt thereof; and about 75 mg to 85 mg of a diluent; about 2 mg to 10 mg of a binder; about 1% to about 5% of a disintegrant; and about 0.1 mg to 5 mg of a lubricant.

[0479] Application

[0480] In one aspect, the compounds, compositions, dosage forms, etc. described herein can be administered to a subject. In some embodiments, the dosage form is administered to the subject more than once a day (eg, twice a day, three times a day, or four times a day).

[0481] In some embodiments, the dosage form is administered to the subject once a day (e.g., one 20 mg tablet once a day, two 20 mg tablets once a day, or three 20 mg tablets once a day). In some embodiments, the dosage form is administered to the subject twice a day (e.g., one 10 mg tablet twice a day, one 20 mg tablet twice a day, two 20 mg tablets twice a day, or three 20 mg tablets twice a day). In some embodiments, the dosage form is administered to the subject every other day. In certain embodiments, about 1 mg to 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 pharmaceutically acceptable salt thereof, is administered to the subject every day. In other embodiments, about 15 mg to 25 mg of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, is administered to the subject every day. In certain embodiments, about 30 mg to 40 mg of a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, is administered to the subject every day.

[0482] Compounds provided according to the present disclosure are usually administered in the form of pharmaceutical compositions. Therefore, the present invention provides pharmaceutical compositions containing the following as active ingredients: one or more of the compounds described or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants. Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. The general technology for preparing pharmaceutical compositions is disclosed in the field of medicine (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (GS Banker and CT Rhodes, ed.).

[0483] The pharmaceutical compositions can be administered by any of the acceptable modes of pharmaceutical administration having similar utility, e.g., as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal, and transdermal routes, by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topically, as an inhalant, or, e.g., by impregnated or coated devices such as stents, or arterial inserted cylindrical polymers, in single or multiple doses.

[0484] In some embodiments, the compounds and compositions described herein are administered orally. The compound or its composition can be formulated in liquid or oral dosage form. Administration can be carried out by capsules or tablets (e.g., enteric coated tablets) and the like. In the process of preparing a pharmaceutical composition including at least one compound described herein, the active ingredient is usually diluted by an excipient and / or encapsulated in such carriers that can be in the form of capsules, sachets, paper or other containers. When an excipient is used as a diluent, the excipient can be in the form of a solid, semisolid or liquid material (as described above), and the excipient serves as a medium, carrier or medium for the active ingredient. Therefore, the composition can be in the form of tablets, pills, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or liquid media) or ointments or capsules (e.g., soft or hard gelatin capsules) containing, for example, up to 10% by weight of an active compound.

[0485] In some embodiments, the compounds and compositions described herein are administered parenterally, for example, by injection or intravenously.The compounds or compositions thereof can be formulated in liquid dosage forms and can include one or more excipients.

[0486] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, 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; emulsifiers and suspending agents; preservatives such as methyl benzoate and hydroxypropyl benzoate; sweeteners; and flavoring agents.

[0487] The compositions disclosed herein can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems, which include reservoirs coated with polymers or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents No. 3,845,770; No. 4,326,525; No. 4,902,514; and No. 5,616,345. Another formulation for the method disclosed herein uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or intermittent infusion of the compounds disclosed herein in controlled amounts. The general structure and use of transdermal patches for delivering medicaments are described in the art. See, for example, U.S. Patents No. 5,023,252, No. 4,992,445 and No. 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0488] The composition is preferably formulated in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dosage for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect and a suitable pharmaceutical excipient (e.g., tablets, capsules, ampoules). The compound is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it should be understood that the actual amount of the compound administered will generally be determined by the doctor in view of the relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered and its relative activity; the age, weight and response of the individual patient; the severity of the patient's symptoms, etc.

[0489] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogenous mixture of a compound as disclosed herein. When referring to these preformulated compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0490] Tablets or pills disclosed herein can be coated or otherwise combined to provide a dosage form with an extended effect advantage, or to avoid the acidic conditions of the stomach. For example, tablets or pills can comprise an inner dosage component and an outer dosage component, the latter adopting the form of a film to be positioned above the former. Two components can be separated by an enteric layer, which is used to resist the disintegration in the stomach and allows the inner component to be transmitted intactly into the duodenum or to be delayed release. Various materials can be used for such enteric layers or coatings, and such materials include many polymeric acids and polymeric acids and mixtures of such materials as shellac, hexadecanol and cellulose acetate.

[0491] Methods for treating diseases or conditions associated with abnormal function or activity of T-type calcium channels

[0492] On the one hand, the present disclosure provides a method for treating a disease or condition related to abnormal function or activity of a T-type calcium channel in a subject in need, the method comprising administering to the subject daily (e.g., once, twice, three times) a therapeutically effective amount of a compound of formula (I), formula (II), formula (III) or formula (IV) as disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The present disclosure similarly provides a therapeutically effective amount of a compound of formula (I) as disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating a disease or condition related to abnormal function or activity of a subject in need of a T-type calcium channel.

[0493] In typical embodiments, the disclosure is intended to encompass the compounds disclosed herein and pharmaceutically acceptable salts, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes pharmaceutically acceptable addition salts, hydrates of addition salts, tautomeric forms, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or as a racemic or non-racemic mixture) of the compounds described herein. In all embodiments of the methods disclosed herein, the compounds may be in the form of a composition including a pharmaceutical composition or dosage form.

[0494] Epilepsy and epileptic syndromes

[0495] The compositions described herein can be used to treat epilepsy and epileptic syndromes. Epilepsy is a central nervous system disorder in which the activity of nerve cells in the brain is disrupted, resulting in recurring seizures that can manifest as abnormal movements, periods of abnormal behavior, sensations, and sometimes loss of consciousness. Seizure symptoms vary widely, from a simple blank stare for a few seconds to repeated twitching of an arm or leg during a seizure.

[0496] Epilepsy may involve generalized seizures, involving multiple areas of the brain, or partial or focal seizures. Generalized seizures involve all areas of the brain. People experiencing generalized seizures may cry or make some sounds, stiffen for several seconds to a minute, and then have rhythmic movements of arms and legs. Eyes may be open, and / or the person may not seem to be breathing and become blue. The recovery of consciousness may be gradual, and the person may feel confused in a few minutes to a few hours. The following are the main types of generalized seizures: tonic-clonic, tonic, clonus, myoclonus, myoclonus-tonic-clonic, myoclonus-atonia, atonia and absence (typical, atypical, myoclonus, eyelid myoclonus) seizures and epileptic spasms. In partial or focal seizures, only a part of the brain is involved, therefore only a part of the body is affected. Depending on the part of the brain with abnormal electrical activity, symptoms may be different.

[0497] As used herein, epilepsy includes generalized, partial, complex partial (e.g., a seizure involving only part of the brain but in which consciousness is impaired), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0498] The compositions described herein can also be used to treat epileptic syndromes. Severe syndromes with diffuse brain dysfunction caused at least in part by some aspects of epilepsy are also called epileptic encephalopathy. These are associated with frequent epileptic seizures and severe cognitive dysfunction (e.g., West syndrome) that are resistant to treatment.

[0499] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, severe myoclonic epilepsy in infancy (Dravet syndrome), Angelman syndrome, CDKL5 deficiency, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy or Glut1 deficiency syndrome. 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 Rege syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for hereditary 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: AWhole-Exome Sequencing Study of 17,606 Individuals," Am. J Human Gen. 2019; 105(2): 267-282. In some embodiments, the epilepsy syndrome is epilepsy with myoclonic-atonic seizures (Doose syndrome) or myoclonic unstable epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spikes and waves (CSWS) during sleep. In some embodiments, the epilepsy syndrome is Landau-Krivinger syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0500] Absence seizures

[0501] Absence seizures are one of the most common types of seizures in patients with idiopathic generalized epilepsy (IGE) (Berg et al., Epilepsy 2000). Absence seizures are relatively short, non-convulsive seizures characterized by the sudden onset of loss of consciousness and responsiveness, usually lasting 10-30 seconds, with rapid recovery of normal consciousness without post-ictal confusion. On accompanying EEG recordings, seizures are characterized by the sudden onset and offset of systemic 1-6Hz (e.g., 3Hz) peak and wave discharges. Absence seizures often occur multiple times a day, interrupting learning and psychosocial function, and there is a risk of injury due to frequent episodes of loss of consciousness. Typically, absence seizures begin in early childhood and are relieved during adolescence. However, in a small number of patients, they persist into adulthood, and often develop drug resistance, and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures are often highly disabling, particularly by disqualifying the patient from obtaining a motor vehicle license or engaging in occupations and hobbies in which the seizure-related phase of loss of consciousness constitutes a safety risk, and are associated with severe psychosocial disability (Wirrell et al., 1997).

[0502] Although absence seizures are generally considered to be relatively "easy" to treat, randomized controlled trials in patients with childhood absence epilepsy have shown that even the most effective antiepileptic drugs, ethosuximide and valproate, only completely control seizures in 53% and 58% of patients, respectively, at 16 weeks (as assessed by video-EEG recordings) (Glauser et al., 2010), and in 45% and 44% of patients, respectively, at 12 months (Glauser et al., 2013). Lamotrigine, another antiepileptic drug commonly used to treat absence seizures, only controls seizures in 29% of patients at 16 weeks and in 21% of patients at 12 months. In addition, both ethosuximide and valproate are often 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 potential. Other treatment options for absence seizures are limited, with only benzodiazepines having established efficacy, and these drugs are often poorly tolerated due to sedation and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, with patients often treated with multiple medications that result in severe side effects and fail to achieve seizure control.

[0503] There is a lot of evidence that low threshold (T-type) calcium channels play a role in the development and maintenance of absence seizures and are a key component of the oscillatory burst discharges that occur in thalamocortical neurons during absence seizures (Pinault and O'Brien, 1997). In some embodiments, the present disclosure relates to a method for treating absence seizures with a composition comprising a compound of formula (I), formula (II), formula (III) as described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the absence seizure is a refractory absence seizure. In some embodiments, the absence seizure is refractory to an anti-epileptic drug (e.g., ethosuximide, valproic acid, or lamotrigine).

[0504] In some embodiments, the subject suffers from epilepsy. In some embodiments, the absence seizure is an atypical absence seizure. In some embodiments, the absence seizure comprises an adult absence seizure, a juvenile absence seizure, or a childhood absence seizure.

[0505] In some embodiments, the methods described herein further comprise identifying a subject suffering from absence seizures.

[0506] Genetic epilepsy

[0507] In certain embodiments, the epilepsy or epilepsy syndrome is hereditary epilepsy or hereditary epilepsy syndrome. In certain embodiments, the epilepsy or epilepsy syndrome is hereditary systemic epilepsy. In certain embodiments, epilepsy or epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early childhood epileptic encephalopathy, severe myoclonic epilepsy in infants, severe myoclonic epilepsy in infants with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptic pediatric focal epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen encephalitis, malignant migratory partial epileptic seizures in infancy, autosomal dominant nocturnal frontal lobe epilepsy, KCNQ2 epileptic encephalopathy and KCNT1 epileptic encephalopathy.

[0508] In some embodiments, the methods described herein further comprise identifying a subject having epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, severe myoclonic epilepsy of infancy, severe myoclonic epilepsy of infancy with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic pediatric focal 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 administering a composition described herein.

[0509] In one aspect, disclosed herein is a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, severe myoclonic epilepsy of infancy, severe myoclonic epilepsy of infancy with SCN1A mutations, generalized epilepsy with febrile seizures, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infant seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptic pediatric focal 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), the method comprising administering to a subject in need thereof a composition described herein.

[0510] The compositions of the invention can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more 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, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, S IAT9, SIKl, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0511] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of the following prior to administering a composition described herein: 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, KC NQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC 13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H and CACNA1I.

[0512] The compositions of the invention may also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more of the following: 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, DN AJC5, 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, KCN Q3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PI GN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A , SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, S PTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT,ARHGEF15, 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.

[0513] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more 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, D NAJC5, 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, KC NQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, P IGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A , SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, S PTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT,ARHGEF15, 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.

[0514] The compositions as disclosed herein may also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more 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, CTNNB 1. CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, G ABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KC NC1, KCNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LG11, MAGI2, MBD5, MECP2, MEF2C, MFSD8(CLN7) , NALCN, NGLY1, NHLRC1(EPM2B), NPRL3, NR2F1, NRXN1, PACS1, PCDH19, PIGAPIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN 1), 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.

[0515] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of: 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, FRRS1L, GABBR2, GA BRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCN C1, 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, PIGAPIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1 ), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, S MC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX and ZEB2.

[0516] The compositions as disclosed herein can also be used to treat epileptic encephalopathy, wherein the subject has a mutation in one or more 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, K CNC1, KCNJ1O, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PC DH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SC N8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0517] In some embodiments, the methods described herein further comprise identifying a subject having a mutation in one or more of: 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, KC NC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCD H19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN 8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0518] Mood disorders

[0519] Also provided herein are methods of treating psychiatric disorders using the compounds disclosed herein, such as mood disorders, e.g., clinical depression, postpartum depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent transient depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect for a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or condition described herein (e.g., neuroendocrine diseases and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's Disease), women's health disorders or conditions).

[0520] Clinical depression is also known as major depressive disorder, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder and recurrent depression, and refers to a mental disorder characterized by a general and persistent low mood, with low self-esteem and loss of interest or pleasure in normally pleasurable activities. Some people with clinical depression have difficulty sleeping, lose weight, and generally feel anxious and irritable. Clinical depression affects how individuals feel, think and act, and may cause a variety of emotional and physical problems. Individuals with clinical depression may have difficulty carrying out daily activities, and feel as if life is not worth living.

[0521] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying spells, feeling restless, difficulty sleeping, extreme exhaustion (emotional and / or physical), changes in appetite, difficulty focusing, increased anxiety and / or worry, feelings of separation from the baby and / or fetus, and loss of interest in activities that were previously pleasurable.

[0522] Postpartum depression (PND) is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, loss of libido, crying attacks, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., refractory depression as described herein).

[0523] In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy. Such depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression experience an increased risk of PND.

[0524] Atypical depression (AD) is characterized by increased emotional reactivity (e.g., abnormal anhedonia) and motivation, significant weight gain or increased appetite. Patients with AD may also have excessive sleep or sleepiness (hypersomnia), a sense of heaviness in the limbs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0525] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood that is more pronounced than sadness or loss, excessive weight loss, or excessive guilt.

[0526] Psychotic major depressive disorder (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0527] Catatonic depression refers to major depressive disorder that involves disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, and be immobile or display meaningless or strange movements.

[0528] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes in the fall or winter.

[0529] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. These problems are less severe and tend to be more persistent (e.g., at least 2 years).

[0530] Double depression is defined as a period of severe depressed mood (dysthymia) lasting at least 2 years and marked by a phase of major depressive disorder.

[0531] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0532] Recurrent brief depressive disorder (RBD) refers to a condition in which an individual has depressive episodes about once a month, with each episode lasting 2 weeks or less, and usually less than 2-3 days.

[0533] Minor depressive disorder or minor depression means depression in which at least 2 symptoms are present for 2 weeks.

[0534] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During mania, the individual may feel or appear unusually happy, energetic, or irritable. The individual often makes poorly thought-out decisions with little regard for the consequences. The need for sleep is often reduced. During depression, there may be tearfulness, poor eye contact with others, and a negative outlook on life. People with this condition have a high risk of suicide within 20 years, greater than 6%, while the incidence of self-harm is 30-40%. Other mental health issues, such as anxiety disorders and substance use disorders are often associated with bipolar disorder.

[0535] Depression due to a chronic medical condition is depression caused by a chronic medical condition, such as cancer or chronic pain, chemotherapy, or chronic stress.

[0536] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) do not relieve the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve symptoms but relapse. Refractory depression occurs in patients with depression who are resistant to at least one standard pharmacological treatment (including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple uptake inhibitors and / or antianxiety drugs) and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0537] Postoperative depression refers to depressed feelings after surgery (e.g., because of having to deal with someone's death). For example, a person may have persistent feelings of sadness or emptiness, a loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0538] A mood disorder associated with a condition or disorder of a woman's health refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a condition or disorder of a woman's health (eg, as described herein).

[0539] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts or unusual preoccupations with suicide. The range of suicidal ideation varies widely, from fleeting thoughts, for example, to extensive thoughts, detailed plans, role-playing, and / or incomplete attempts. Symptoms include talking about suicide, obtaining means to commit suicide, withdrawing from social situations, preoccupying oneself with death, feeling confused or hopeless about a situation, increasing use of alcohol or drugs, doing dangerous or self-destructive things, and saying goodbye to people as if they were never to be seen again.

[0540] Symptoms of depression include persistent anxiety or sadness, helplessness, despair, pessimism, feelings of worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty moving, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of vitality, poor self-esteem, lack of positive ideas or plans, lethargy, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts and suicide attempts. The presence, severity, frequency and duration of symptoms can vary from case to case. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., by mental status examination).

[0541] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, mood disorders, anxiety disorders, stress, post-traumatic stress disorder, bipolar disorder and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0542] In some embodiments, the method comprises monitoring subjects with known depression scales, e.g., Hamilton depression (HAM-D) scale, Clinical Global Impression-Improvement Scale (CGI) and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a decrease in the total score of Hamilton depression (HAM-D) performed by the subject. The therapeutic effect can be evaluated during a specified treatment period. For example, the therapeutic effect can be determined by a decrease in the total score of HAM-D relative to baseline after administering the composition described herein (e.g., 12, 24 or 48 hours after administration; or 24, 48, 72 or 96 hours or more; 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).

[0543] In some embodiments, the subject suffers from mild depressive disorder, for example, mild severe depressive disorder. In some embodiments, the subject has moderate depressive disorder, for example, moderate severe depressive disorder. In some embodiments, the subject has severe depressive disorder, for example, severe severe depressive disorder. In some embodiments, the subject has extremely severe depressive disorder, for example, extremely severe severe depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (i.e., before treatment with the composition described herein) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between 14 and 18 and includes the end value. In some embodiments, the baseline HAM-D total score of the subject is between 19 and 22 and includes the end value. In some embodiments, the HAM-D total score of the subject before treatment with the composition described herein is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15 or 20. In some embodiments, the subject has a total HAM-D score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound or composition disclosed herein. In some embodiments, the total HAM-D score after treatment with a compound or composition disclosed herein is less than 10, 7, 5, or 3. In some embodiments, the decrease in the total HAM-D score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM-D score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a compound or composition disclosed herein. In some embodiments, the decrease from baseline HAM-D total score to the 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 decrease from baseline HAM-D total score to the 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 decrease in the HAM-D total score after treatment with a compound or composition disclosed herein relative to the baseline HAM-D total score.

[0544] 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 a HAM-D score) within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 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 a HAM-D total score) within the first or second day of treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in a HAM-D total score) within less than or equal to 14 days after 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 a HAM-D total score) within less than or equal to 21 days after initiating treatment with a composition described herein. In some embodiments, the method for treating depressive disorders (e.g., major depressive disorder) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in a HAM-D total score) within 28 days after starting treatment with a compound or composition disclosed herein. In some embodiments, the therapeutic effect is a decline in the HAM-D total score relative to baseline after treatment with a compound or composition disclosed herein. In some embodiments, the HAM-D total score of the subject before treatment with a compound or composition disclosed herein is at least 24. In some embodiments, the HAM-D total score of the subject before treatment with a compound or composition disclosed herein is at least 18. In some embodiments, the HAM-D total score of the subject before treatment with a compound or composition disclosed herein is between 14 and 18 and includes end values. In some embodiments, the decline in the HAM-D total score relative to the baseline HAM-D total score after treating the subject with a compound or composition disclosed herein is at least 10. In some embodiments, the decline in the HAM-D total score relative to the baseline HAM-D total score after treating the subject with a compound or composition disclosed herein is at least 15. In some embodiments, the total HAM-D score associated with treating the subject with a compound or composition disclosed herein is no greater than a number ranging from 6 to 8. In some embodiments, the total HAM-D score associated with treating the subject with a compound or composition disclosed herein is no greater than 7.

[0545] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression-Improvement Scale (CGI)) within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less. In some embodiments, the CNS disorder is a depressive disorder, e.g., a major depressive disorder. In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score at the end of the treatment period (e.g., 14 days after administration) relative to baseline.

[0546] The therapeutic effect of major depressive disorder can be determined by the reduction of Montgomery-Asberg Depression Rating Scale (MADRS) scoring shown by the experimenter.For example, MADRS scoring can be in 4 days, 3 days, 2 days or 1 day; Or 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours or reduce in less time.MADRS is a diagnostic questionnaire with ten items (about obvious sadness, sadness reported, inner tension, sleep reduction, decreased appetite, concentration difficulties, fatigue, sensitivity deterioration, pessimistic thoughts and suicidal thoughts), and psychiatrists use the questionnaire to measure the severity of the depressive episode of the patient with mood disorder.In certain embodiments, the therapeutic effect is the decline of MADRS scoring relative to baseline at the end of the treatment period (for example, after applying 14 days).

[0547] pain

[0548] The compounds and compositions described herein can be used to treat 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.

[0549] In some embodiments, the methods described herein further comprise identifying a subject suffering from pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine) prior to administering a dosage form or composition described herein (e.g., a dosage form or composition comprising a compound of Formula (A), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof).

[0550] Tremor

[0551] The methods described herein can be used to treat tremor, for example, the compounds or compositions disclosed herein can be used to treat cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease tremor, physiological tremor, or rubrosomal 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 (with Charcot-Marie-Tooth, Roussy-Levy, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, carbon monoxide, manganese, arsenic, toluene); drug-induced (neuroleptics tricyclics, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor may be neurological and may be classified as physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor), primary orthostatic tremor, task- and position-specific tremor, dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes' tremor (i.e., red nucleus tremor), palatal tremor, toxic or drug-induced tremor, and psychogenic tremor. Tremor may be familial.

[0552] In some embodiments, the subject treated with the compounds of the present disclosure has a clinical diagnosis of essential tremor. In some embodiments, the subject treated with the compounds of the present disclosure has essential tremor but does not have intention tremor.

[0553] A tremor is an involuntary, rhythmic oscillation of one or more body parts (eg, hands, arms, eyes, face, head, vocal cords, trunk, and / or legs).

[0554] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after a purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum or pathways, such as from tumors, stroke or other focal lesion diseases (e.g., multiple sclerosis) or neurodegenerative diseases.

[0555] Dystonic tremors occur in individuals affected by dystonia (a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful and abnormal postures or positions). Dystonic tremors may affect any muscle in the body. Dystonic tremors occur irregularly and can often be relieved by complete rest or certain sensory manipulations.

[0556] Essential tremor or benign essential tremor is the most common type of tremor. Essential tremor can be mild, and some are non-progressive, and can be slowly progressive, starting on one side of the body but usually affecting both sides. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved. The frequency of tremors may decrease as a person ages, but the severity may increase. Aggravated emotions, stress, fever, physical fatigue, or low blood sugar may trigger tremors and / or increase their severity. Symptoms usually progress over time and can be noticeable and persistent after they occur.

[0557] 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. Cramps are felt in the thighs and legs, and patients may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occur in patients with essential tremor.

[0558] Parkinson's disease tremor is caused by damage to structures in the brain that control movement. Parkinson's disease tremor is often seen as a "ball rolling" movement of the hands, which may also affect the jaw, lips, legs, and trunk. The onset of Parkinson's disease tremor usually begins after age 60. The movement begins in one limb or side of the body and can progress to include the other side.

[0559] Rubrostral tremor is characterized by a coarse, slow tremor that can be present at rest, in posture, and with intent. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0560] In some embodiments, the tremor is selected from essential tremor, Parkinson's disease tremor, or cerebellar tremor.

[0561] 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 Jul;34(7):950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor," Mov. Disord. 2013 Nov;28(13):1793-800; Deuschl G. et al., "Treatment of patients with essential tremor," Lancet Neurol. 2011;10:148-61; and Reich et al., "Treatment of patients with essential tremor," Lancet Neurol. 2011;10:148-61; and SG et al., "Essential Tremor", Med. Clin. N. Am. 2019; 103: 351-356. The disclosure of the reference is incorporated herein in its entirety.

[0562] In some embodiments, the methods described herein reduce upper extremity tremor scores by at least 25%, where the tremor scores can be converted to amplitudes compared to a baseline. For example, in certain embodiments, the methods described herein reduce tremor amplitude by an average of about 40%, as measured by the Essential Tremor Rating Assessment Scale (TETRAS) upper extremity score, such as described in Elble, RJ, "The Essential Tremor Rating Assessment Scale", Journal of Neurology Neuromed. 2016; 1(4): 34-38. In some embodiments, the methods described herein reduce TETRAS performance scores by at least 25%, compared to a baseline. In some embodiments, the methods described herein reduce symptom severity by an average of at least 35%, compared to a baseline, as measured by the TETRAS performance score.

[0563] Ataxia

[0564] Ataxia, including cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally related to the loss or failure of coordination. The patient showing ataxia may be difficult to adjust the power, range, direction, speed and rhythm involved in posture, balance and limb movement. For example, the ataxia of the trunk can cause the posture to sway and increase, and the center of gravity cannot be kept on the support bottom. The primary or secondary symptoms of ataxia and ataxic gait and tremor of the limbs may be accompanied by speech disorders, dysphagia, ventilation and speech abnormalities and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, thus seriously interfering with the activities of daily life.

[0565] As noted above, ataxia may be caused by a variety of underlying diseases and conditions in the patient, including cerebellar disorders and neurodegenerative diseases and diseases caused by chronic or long-term exposure to toxins. Symptoms of ataxia may be due to a 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 long-term or chronic exposure to toxins (including drugs and alcohol), etc.; 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 caused by long-term or chronic exposure to toxins. Diseases, disorders, syndromes and conditions that may result in ataxia symptoms that may be treated with the methods described herein include, but are not limited to, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar hypoplasia, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (retinal tapetum lucidum), ... degeneration of the cerebellum parenchyma, autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar hypoplasia (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal conditions, autonomic dysfunction, balance disorders, tardive symptom syndrome, endocrine disorders, disorders caused by chronic exposure to toxins (e.g., alcohol, drugs, anticonvulsants, relaxants), fragile X / tremor ataxia syndrome, Friedreich's ataxia ataxia), frontal lobe dysfunction, hereditary disorders, granulomatous vasculitis of the central nervous system, Hallervorden-Spatz disease, hereditary motor and sensory neuropathies, hydrocephalus (e.g., low or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem responses, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller Fisher Syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonus-ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, Parkinson's disease (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe damage to the brain (e.g.,Caused by head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infections or brain tumors), spastic hemiparesis, spastic paraplegia 23, spastic paraplegia glaucoma precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular dystrophy-deafness), spinocerebellar ataxia (malformation), 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 disease type II), spinocerebellar ataxia (X-linked, 2), spinocerebellar ataxia (v-linked, 3), spinocerebellar ataxia (X-linked, 4), spinocerebellar degeneration (book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebral base artery insufficiency and diseases caused by vitamin deficiency, etc. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia and fragile X chromosome / tremor ataxia syndrome. In another specific embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X / ataxia tremor syndrome.

[0566] tinnitus

[0567] Provided herein are methods of treating tinnitus in a subject in need thereof, and the methods comprise administering a compound or composition as disclosed herein. Tinnitus is a condition in which the affected person perceives sounds in one or both ears or the head when no external sounds are present. Often referred to as "ringing" in the ears, tinnitus can occur intermittently or constantly, with the perceived volume ranging from low to painfully high. However, the perceived volume of tinnitus may vary from patient to patient, where an objective measure of the volume of tinnitus in one patient may be considered painful, but in another patient, the same volume may be considered subtle.

[0568] Sleep disorders

[0569] Provided herein are methods for treating or preventing sleep disorders (e.g., narcolepsy), comprising administering a compound or composition disclosed herein. For example, the sleep disorder can be a central disorder of narcolepsy, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia caused by a medical disorder, hypersomnia caused by 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).

[0570] Combination therapy

[0571] On the other hand, the compounds or compositions described herein (for example, for regulating T-type calcium ion channels) can be administered in combination with at least one other agent or therapy. The subject to be administered the compounds or compositions disclosed herein may suffer from a disease, disorder or condition or at least one symptom thereof that will benefit from treatment with another agent or therapy. In certain embodiments, these diseases or conditions may be related to epilepsy or epilepsy syndrome (for example, absence epilepsy, juvenile myoclonic epilepsy or hereditary epilepsy) or tremor (for example, essential tremor).

[0572] Antiepileptic drugs

[0573] Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, trigine, levetiracetam, lorazepam, midazolam, oxcarbazepine, permpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0574] Analgesics

[0575] Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opioids and morphine mimetics, 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), combinations with analgesics are particularly contemplated.

[0576] Morning tremor medication

[0577] Medications for tremor included propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, topamax, midazolam, atenolol, clonazepam, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide.

[0578] The present disclosure will be more fully understood by reference to the following examples.

[0579] Examples

[0580] The present invention is now described with reference to the following examples. These examples are provided for illustrative purposes only, and the present invention is not limited to these examples, but encompasses all variations that are obvious as a result of the teaching provided herein.

[0581] Materials and methods

[0582] General Experimental Details

[0583] Purification by chromatography refers to the use of IsoleraTM One purification system. When used in SEPAFLASH™ irregular silica purification, “Santai SEPAFLASH™ irregular silica” refers to pre-packed polypropylene columns containing unbound activated silica with an average size of 40-63 μm and a nominal Irregular particles of porosity. The fractions containing the desired product (identified by TLC and / or LCMS analysis) are merged and the organic fraction is recovered by evaporation to obtain the final product. In the case of using thin layer chromatography (TLC), it refers to a silica gel TLC plate, typically a 3×6 cm silica gel (e.g., UV-III) on a glass plate with a fluorescent indicator (254 nm). Microwave experiments are performed using a Biotage starter + using a single-mode resonator and dynamic field tuning. A temperature of 40-300° C. can be achieved, and a pressure of up to 30 bar can be reached.

[0584] NMR spectra were obtained on a Bruker AscendTM 400 MHz, 5 mm BBFO probe H, C, F, P, single Z gradient dual channel instrument running TopSpin 4.1.

[0585] Compound names are generated standardly using the Structure to Name function in ChemDraw Professional 20.

[0586] abbreviation

[0587] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0588] DCM Dichloromethane

[0589] DIPEA N,N-Diisopropylethylamine

[0590] DMF N,N-Dimethylformamide

[0591] DPPA Diphenylphosphorylazide

[0592] FA Formic acid

[0593] HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoroborate

[0594] K 2 CO 3 Potassium carbonate

[0595] MeCN Acetonitrile

[0596] PE Petroleum Ether

[0597] TFA Trifluoroacetic acid

[0598] THF Tetrahydrofuran

[0599] Analytical LC-MS conditions

[0600] Method 1:

[0601] Column: HALO C18 2.7 μm, 3.0 mm × 30 mm;

[0602] Mobile phase: MeCN (0.05% HCOOH)-water (0.05% HCOOH);

[0603] Gradient: 5% to 95% MeCN in 1.4 min, hold 0.6 min, total run time 2.5 min;

[0604] Flow rate: 1.8 ml / min;

[0605] Column temperature: 50 °C;

[0606] Wavelength: 214 and 254nm PDA;

[0607] Shimadzu LCMS2020 mass spectrometer.

[0608] Method 2: Column: XBridge C18 3.5 μm, 2.1 mm×50 mm; Mobile phase: MeCN-water (0.1% NH 4 OH); Gradient: 5% to 95% MeCN in 1.8 min, hold 0.7 min, total run time 3.0 min; Flow rate: 1.0 ml / min; Column temperature: 50 °C; Wavelength: 214 and 254 nm PDA. Shimadzu LCMS2020 mass spectrometer.

[0609] Analytical HPLC conditions

[0610] Method A:

[0611] Column: ZORBAX ECLIPES PLUS C18, 1.8 μm, 4.6 mm x 50 mm;

[0612] Mobile phase: water (0.05% TFA)-MeCN (0.05% TFA);

[0613] Gradient: 5% to 95% MeCN in 4.5 min, hold 1 min, total run time 7.0 min;

[0614] Column temperature: 55 °C;

[0615] Flow rate: 2.0 ml / min;

[0616] Wavelength range: 190nm to 800nm;

[0617] Instrument: Shimadzu LC-2030C 3D Plus.

[0618] Method B:

[0619] Column: XBridge BEH C18 2.5 μm 3.0 mm x 30 mm;

[0620] Mobile phase: water (0.1% NH 3 / H 2 O)-MeCN (100%);

[0621] Gradient: 5% to 95% MeCN in 5.5 min, hold 1 min, total run time 8 min;

[0622] Column temperature: 45 °C;

[0623] Flow rate: 1.5 ml / min;

[0624] Wavelength range: 190nm to 800nm;

[0625] Instrument: Shimadzu LC-2030C 3D Plus.

[0626] Analytical HNMR conditions

[0627] HNMR: Bruker 400, temperature: 25°C

[0628] 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)

[0629] Solution 1 :

[0630]

[0631] General method 1 :

[0632] Step 1: Preparation of tert-butyl 4-[2-(tert-butylamino)-2-oxo-ethyl]piperazine-1-carboxylate (Intermediate 3)

[0633]

[0634] To a solution of N-tert-butyl-2-chloro-acetamide (120 mg, 0.80 mmol) (Intermediate 2) in MeCN (10 mL) was added K 2 CO 3 The product was stirred for 12 hours at room temperature. The resulting mixture was filtered and the filtrate was concentrated to dryness. The residue was added to DCM (10 mL) and washed with water (2x10 mL) and then with saturated brine (10 mL). The organic layer was separated and dried (Na 2 O). 2 SO 4 ), followed by concentration 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.

[0635] MS observed value (ESI+): [(M+H) + ]:300.1.R t : 1.63 minutes (method 2)

[0636] Step 2: Preparation of N-tert-butyl 2-piperazin-1-yl-acetamide hydrochloride (Intermediate 4)

[0637]

[0638] 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 hours 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.

[0639] MS observed value (ESI+): [(M+H) + ]:200.2.R t :0.33 minutes (method 1)

[0640] Step 3: Preparation of 2-chloro-4-(3-chloro-5-fluoro-phenyl)oxazole (Intermediate 6)

[0641]

[0642] 5-isobutyl-1-phenyl-pyrazole-3-carboxylic acid (800mg, 3.20mmol) (intermediate 5) is dissolved in dry THF (10mL) and cooled to 0°C. Lithium aluminum hydride (186mg, 4.90mmol) is added in portions. The reaction mixture is refluxed for 4 hours, then cooled to 0°C, and the reaction mixture is quenched by adding water (3mL), then adding 15% NaOH aqueous solution (1.5mL) and water (3mL). After stirring at room temperature for 15 minutes, solid is removed by filtration. The filtrate is concentrated to dryness to obtain a crude product, which is used in the next step without further purification.

[0643] Step 4: Preparation of (5-isobutyl-1-phenyl-pyrazol-3-yl)methanamine (Intermediate 7)

[0644]

[0645] 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 hours. The reaction mixture was cooled to room temperature and then washed with water (10 mL) and PPh 3 The product was stirred for 16 hours at room temperature under reduced pressure. The obtained mixture was concentrated to dryness, and the residue was added to DCM (10 mL), and the organic matter was washed with water (2x10 mL), then washed with saturated saline solution (10 mL). The organic matter was then separated and dried (Na 2 SO 4 ) before concentrating in vacuo. The crude product was purified by silica gel column chromatography eluting with 1% MeOH / DCM to give the title compound (5-isobutyl-1-phenyl-pyrazol-3-yl)methanamine (650 mg, 73% yield) as a yellow solid.

[0646] MS observed value (ESI+): [(M+H) + ]:230.0.R t : 1.27 minutes (method 2)

[0647] Step 5: Preparation of 2-chloro-N-[(5-isobutyl-1-phenyl-pyrazol-yl)methyl]acetamide (Intermediate 8)

[0648]

[0649] To (5-isobutyl-1-phenyl-pyrazole-3-yl) methylamine (150mg, 0.65mmol) (intermediate 7) and DIPEA (0.10mL, 0.78mmol) in DCM (9mL) in the cooling 0 DEG C of solution was added dropwise acetyl chloride (57 μL, 0.71mmol) in DCM (1mL). The resulting mixture was stirred at 0 DEG C for 30 minutes, and then returned to room temperature and stirred for another 2 hours. The resulting mixture was concentrated to dryness, and the residue was added to DCM (10mL), and the organic matter was washed with water (2x10mL), then washed with saturated brine solution (10mL). The organic layer was separated and dried (Na 2 SO 4 ) and then concentrated in vacuo. The crude product was then purified by silica gel column chromatography eluting with 1% MeOH / 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.

[0650] MS observed value (ESI+): [(M+H) + ]:306.0.R t : 1.66 minutes (method 2)

[0651] Step 6: Preparation of 2-[4-[2-(tert-butylamino)-2-oxo-ethyl]piperazin-1-yl]-N-[(5-isobutyl-1-phenylpyrazol-3-yl)methyl]acetamide (Compound 1)

[0652]

[0653] 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 K 2 CO 3 To 4-[(5-isobutyl-1-phenyl-pyrazole-3-yl)methyl]acetamide (136mg, 0.98mmol) and 22-chloro-N-[(5-isobutyl-1-phenyl-pyrazole-3-yl)methyl]acetamide (100mg, 0.32mmol) (intermediate 8). The reaction solution was stirred at 50°C for 12 hours. The resulting mixture was filtered, and the filtrate was concentrated in a vacuum. The resulting oil was purified by silica gel column chromatography eluted with 1-2% MeOH / DCM to give the title compound 2-[4-[2-(tert-butylamino)-2-oxo-ethyl]piperazine-1-yl]-N-[(5-isobutyl-1-phenyl-pyrazole-3-yl)methyl]acetamide (40mg, 24% yield, 95% purity) as a yellow oil.

[0654] MS observed value (ESI+): [(M+H) + ]:469.3.R t : 1.71 minutes (method 2)

[0655] HPLC: R t : 3.17 minutes (Method B)

[0656] 1 H NMR (400MHz, DMSO) δ8.10 (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).

[0657] The following compounds listed in Table 1 below were prepared in a similar manner:

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665] 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)

[0666] Solution 2 :

[0667]

[0668] General Method 2 :

[0669] Step 1: Preparation of 2-[(2-bromoimidazol-1-yl)methoxy]ethyltrimethyl-silane (Intermediate 10)

[0670]

[0671] NaH (490mg, 20.4mmol) was added to a solution of 2-bromo-1H-imidazole (1g, 6.80mmol) (intermediate 9) in THF (20mL). The mixture was stirred at 0°C for 30 minutes, then treated with 2-(trimethylsilyl)ethoxymethyl chloride (1.45mL, 8.16mmol), and continued to stir for 2 hours. The reaction solution was quenched by adding EtOH, then concentrated to dryness, and the residue was added to DCM (40mL), and the organic matter was washed with water (25mL), then washed with saturated brine solution (20mL). The organic layer was separated and dried (Na 2 SO 4 ) and then concentrated to dryness. The crude product was then purified by flash column chromatography eluting with 10% EtOAc / 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.

[0672] MS observed value (ESI+): [(M+H) + ]:277.0.R t : 1.17 minutes (method 1)

[0673] Step 2: Preparation of 2-bromo-3-(2-methylsilylethoxymethyl)imidazole-4-carbaldehyde (Intermediate 11)

[0674]

[0675] at -20 °C in N 2 To a solution of n-BuLi (1.17mL, 2.81mmol) in THF (1.5mL) was added dropwise a solution of 2,2,6,6-tetramethylpiperidine (397mg, 2.81mmol) in THF (1mL). The reaction mixture was stirred for 30 minutes at -20°C. 2-[(2-bromoimidazol-1-yl)methoxy]ethyl-trimethyl-silane (600mg, 2.16mmol) (intermediate 10) in THF (2mL) was added dropwise at -78°C. The reaction mixture was stirred for 45 minutes at -78°C. DMF (15g, 21.64mmol) was added, and the reaction was allowed to warm to room temperature. It was then stirred for 16 hours. The reaction mixture was heated to room temperature by adding saturated NH 4 The product was quenched with aqueous Cl solution and then extracted with EtOAc (3x10 mL). The combined organic extracts were washed with water (2x10 mL) and then with saturated brine solution (10 mL), then separated and dried (Na 2 SO4 ) and then concentrated to dryness. The crude product was then purified by flash column chromatography eluting with EtOAc / PE to give 2-bromo-3-(2-trimethylsilylethoxymethyl)imidazole-4-carbaldehyde (300 mg, 41% yield, 90% purity) as a yellow oil.

[0676] MS observed value (ESI+): [(M-14+H) + ]:291.0.R t :1.01 minutes (Method 2)

[0677] Step 3: Preparation of tert-butyl 4-[[2-bromo-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]methyl]piperazine 1-carboxylate (Intermediate 12)

[0678]

[0679] 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 (one drop). The mixture was stirred at 45 °C for 16 h and washed with NaBH(OAc). 3 The reaction mixture was stirred at 45 ° C for 4 hours. The reaction solution was concentrated to dryness, and the residue was added to DCM (20 mL), and the organic matter was washed with water (2x10 mL), and then washed with saturated brine (15 mL). The organic layer was separated and dried (Na 2 SO 4 ), then concentrated to dryness. The crude product was then purified by C18 positive 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 light yellow oil.

[0680] MS observed value (ESI+): [(M+H) + ]:475.2.R t : 2.07 minutes (method 2)

[0681] 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)

[0682]

[0683] 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 mixture of 20% 1,4-dioxane in water (3.0 mL) were added (3-chloro-5-fluoro-phenyl)boronic acid (44 mg, 0.25 mmol) (Intermediate 13), Pd(PPh 3 ) 4 (24 mg, 0.02 mmol) and Na 2 CO 3 (45 mg, 0.42 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction solution was concentrated to dryness, and the residue was added to DCM (15 mL), and the organic matter was washed with water (2x8 mL), then with saturated brine (10 mL). The organic matter was then separated and dried (Na 2 SO 4 ), then concentrated to dryness. The crude product was then purified by flash column chromatography eluting with 10% EtOAc / 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.

[0684] MS observed value (ESI+): [(M+Na) + ]:557.2.R t : 1.48 minutes (method 2)

[0685] Step 5: Preparation of 1-[[2-(3-fluoro-5-fluoro-phenyl)-1H-imidazol-5-yl]methyl]piperazine hydrochloride (Intermediate 15)

[0686]

[0687] 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 4M HCl-dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours 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.

[0688] MS observed value (ESI+): [(M+H) + ]:295.1.Rt :0.65 minutes (method 1)

[0689] 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)

[0690]

[0691] To a solution of 1-[[2-(3-chloro-5-fluoro-phenyl)-1H-imidazole-5-yl]methyl]piperazine hydrochloride (93mg, 0.28mmol) (intermediate 15) in MeCN (1.5mL) was added N-tert-butyl-2-chloro-acetamide (42mg, 0.28mmol) (intermediate 2) and DIPEA (0.24mL, 1.40mmol). The reaction mixture was stirred at 40°C for 16 hours, then concentrated to dryness, and the residue was added to DCM (20mL), and the organic matter was washed with water (2x10mL), then washed with saturated brine solution (15mL). The organic matter was then separated and dried (Na 2 SO 4 ), and then concentrated to dryness. The crude product was then purified by C18 positive pressure chromatography (MeCN / 0.05% NH 3 / H 2 0, MeCN 1-95% in 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.

[0692] MS observed value (ESI+): [(M+H) + ]:408.1.Rt:1.36 minutes (method 2)

[0693] 1 H NMR (400MHz, DMSO) δ12.20 (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).

[0694] The following compounds listed in Table 2 below were prepared in a similar manner:

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702] 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)

[0703] Solution 3 :

[0704]

[0705] General Method 3 :

[0706] Step 1: Preparation of tert-butyl 4-(2-hydrazino-2-oxo-ethyl)piperazine-1-carboxylate (Intermediate 17)

[0707]

[0708] 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 hours at 80° C. The mixture was concentrated in vacuo to give the crude product tert-butyl 4-(2-hydrazinyl-2-oxo-ethyl)piperazine-1-carboxylate (190 mg) as a white solid, which was used in the next step without further purification.

[0709] MS observed value (ESI+): [(M+H) + ]:259.0.R t :0.89 minutes (Method 2)

[0710] 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)

[0711]

[0712] At 150°C, 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), K 2 CO 3 A solution of (20 mg, 0.14 mmol) in 1-butanol (15 mL) was stirred for 5 hours. The reaction solution was concentrated to dryness, and the residue was added to DCM (5 mL), and the organic matter was washed with water (2x5 mL), then washed with saturated brine (5 mL). The organic matter was dried (Na 2 SO 4 ), concentrated, and purified by flash column chromatography eluting with 2% MeOH / 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.

[0713] MS observed value (ESI+): [(M+H) + ]:396.1.R t :1.00 min (method 1)

[0714] Step 3: Preparation of 1-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine hydrochloride (Intermediate 20)

[0715]

[0716] 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 hours 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, quantitative) as a yellow solid, which was used in the next step without further purification.

[0717] MS observed value (ESI+): [(M+H) + ]:296.0.R t : 0.74 minutes (method 1)

[0718] Step 4: Preparation of N-tert-butyl-2-[4-[[μ-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazin-1-yl]acetamide (Compound 61)

[0719]

[0720] To 1-[[5-(3-chloro-5-fluoro-phenyl)-4H-1,2,4-triazol-3-yl]methyl]piperazine hydrochloride (125mg, 0.38mmol) (intermediate 20), N-tert-butyl-2-chloro-acetamide (61.93mg, 0.41mmol) (intermediate 2) and TEA (0.26mL, 1.88mmol) in MeCN (3mL) was stirred for 5 hours at 50°C. The reaction solution was concentrated to dryness, and the residue was added to DCM (5mL), and the organic matter was washed with water (2x5mL), then washed with saturated brine solution (15mL). The organic matter was dried (Na 2 SO 4 ) 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.

[0721] MS observed value (ESI+): [(M+H) + ]:409.2.R t :0.85 minutes (method 1)

[0722] HPLC: R t : 2.33 minutes (Method A)

[0723] 1 H NMR (400MHz, DMSO) δ14.19 (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).

[0724] 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]heptyl6-yl)acetamide (Compound 62)

[0725] Solution 4 :

[0726]

[0727] General Method 4 :

[0728] Step 1: Preparation of 4-chloro-2-(chloromethyl)-6-fluoro-1H-benzo[d]imidazole (Intermediate 22)

[0729]

[0730] To 3-chloro-5-fluoro-benzene-1,2-diamine (2.0g, 12.45mmol) (intermediate 21) in DCM (21mL) solution, add 2-chloro-1,1,1-trimethoxy-ethane (2.50g, 16.19mmol) and p-toluenesulfonic acid (2.38g, 1.25mmol). Reaction solution was stirred at room temperature for 12 hours. Reaction solution was concentrated to dryness, and residue was added in DCM (80mL), and organic matter was washed with water (2x13mL), then washed with saturated brine solution (13mL). Then organic matter was separated and dried (Na 2 SO 4 ) followed by concentration in vacuo. The crude product was purified by silica gel chromatography eluting with 1-2% MeOH / DCM to afford 4-chloro-2-(chloromethyl)-6-fluoro-1H-benzimidazole (2.5 g, 84% yield, 92% purity) as an off-white solid.

[0731] MS observed value (ESI+): [(M+H) + ]:218.9.R t : 0.83 minutes (method 1)

[0732] 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)

[0733]

[0734] 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 K 2 CO 3The product was stirred for 4 hours at 50 ° C. After cooling to room temperature, the reaction mixture was washed with water (5 mL) and extracted with DCM (3x5 mL). The combined organic extracts were washed with saturated brine (2x3 mL) and the organic phase was dried (Na 2 O). 2 SO 4 ) and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with 30% EtOAc / 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).

[0735] MS observed value (ESI+): [(M+H) + ]:381.1.Rt:1.66min(Method 2)

[0736] 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)

[0737]

[0738] To 4M aqueous HCl (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 hours. The pH of the reaction mixture was adjusted with saturated Na 2 CO 3 The aqueous solution was adjusted to 8 and the resulting mixture was extracted with DCM (3 x 10 mL). The combined organics were dried (Na 2 SO 4 ) and concentrated in vacuo to give the crude product 4-chloro-2-(3,6-diazabicyclo[3.1.1]hept-3-ylmethyl)-6-fluoro-1H-benzimidazole (66 mg, 60% yield, 95% purity) as a yellow oil.

[0739] MS observed value (ESI+): [(M+H) + ]:281.2.Rt:0.45min (Method 1)

[0740] 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]heptyl6-yl)acetamide (Compound 62)

[0741]

[0742] To a solution of 4-chloro-2-(3,6-diazabicyclo[3.1.1]hept-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 / DCM to give the title compound N-tert-butyl-2-[3-[(4-chloro-6-fluoro-1H-benzoimidazol-2-yl)methyl]-3,6-diazabicyclo[3.1.1]hept-6-yl]acetamide (28 mg, 30% yield, 97.7% purity) as an off-white solid.

[0743] MS observed value (ESI+): [(M+H) + ]:394.2.Rt:0.71min (Method 1)

[0744] 1 H NMR (400MHz, DMSO) δ7.28 (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).

[0745] The following compounds listed in Table 3 below were prepared in a similar manner:

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777] 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)

[0778] Solution 5 :

[0779]

[0780] General Method 5 :

[0781] Step 1: Preparation of tert-butyl 8-[2-(tert-butylamino)-2-oxo-ethyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (Intermediate 27)

[0782]

[0783] 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 K 2 CO 3 (3.91 g, 28.26 mmol). The reaction mixture was stirred at 40 ° C for 16 hours. The reaction solution was concentrated to dryness, and the residue was added to EtOAc (200 mL), and the organic matter was washed with water (150 mL), and then washed with saturated brine (120 mL). The organic matter was then separated and dried (Na 2 SO 4 ) and then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with 35% EtOAc / 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.

[0784] MS observed value (ESI+): [(M+H) + ]:326.2.R t : 0.78 minutes (method 1)

[0785] Step 2: Preparation of N-tert-butyl-2-(3,8-diazabicyclo[3.2.1]octan-8-yl)acetamide; hydrochloride (Intermediate 28)

[0786]

[0787] 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 4M HCl in dioxane (60 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under vacuum 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.

[0788] MS observed value (ESI+): [(M+H) + ]:226.0.R t :0.38 minutes (method 1)

[0789] 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)

[0790]

[0791] 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 K 2 CO 3 The product was concentrated to dryness and the residue was added to DCM (10 mL). The organic matter was washed with water (2x8 mL) and then with saturated saline solution (10 mL). The organic matter was then separated and dried (Na 2 O 4 3 O 4 4 4 0 4 0 0 4 4 7 0 4 6 ... 2 SO 4 ), followed by concentration in vacuo. The crude product was then purified by preparative HPLC (MeCN / 0.05% NH 3 Yu H 2 O, MeCN 15% to 95% for 15 min) to give the desired product as an off-white solid, N-tert-butyl-2-[3-[(4-chloro-7-fluoro-1H-benzoimidazol-2-yl)methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]acetamide (42 mg, 26% yield, 95.1% purity).

[0792] MS observed value (ESI+): [(M+H) + ]:408.3.Rt :1.58 minutes (Method 2)

[0793] 1 H NMR (400MHz, DMSO) δ7.41 (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).

[0794] The following compounds listed in Table 4 below were prepared in a similar manner:

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838] Example 7: In vitro Cav3.1 single point and IC50 (VDB) data

[0839] Certain compounds (as indicated) were tested for human Cav3.1 calcium channel activity by patch clamp assay as disclosed herein.

[0840] The inhibition of T-type voltage-gated calcium channels (Cav3.1) was evaluated using the HEK-293natClytin / TASK1+Cav3.1 cell line. Currents were recorded using the SyncroPatch 384PE automated patch clamp system. Pulse generation and data acquisition were performed using PatchController384V1.3.0 and DataController384V1.2.1 (Nanion Technologies). Offline analysis was performed using Excel and Graphpad Prism (V 8.4.2), with complete data files uploaded to Dotmatics. Access resistance and apparent membrane capacitance were estimated using built-in protocols. Currents were recorded from cell populations in a whole-cell configuration. The cells were lifted, ground and resuspended at 800,000 cells / ml. Prior to the experiment, cells were allowed to recover in a cell bank. Currents were recorded at room temperature. The external solution contained the following (in mM): NaCl 80, NMDG 60, KCl 4, MgCl 2 1. CaCl 2 6, glucose 5 and HEPES 10 (pH = 7.4, osmotic pressure about 300 mOsm). The extracellular solution was used as a washing solution, reference and compound delivery solution. The internal solution contained the following (in mM): CsF 110, CsCl 10, NaCl 10, EGTA 10, HEPES 10 (pH = 7.2, osmotic pressure about 295 mOsm).

[0841] Compound plates were produced at 2-fold concentration in the extracellular solution. When added to the recording wells, the compounds were diluted to 1:2. The amount of DMSO in the extracellular solution was kept constant at the level used for the highest tested concentration. For voltage clamp experiments on Cav3.1, data were sampled at 10 KHz. After seals and channels were established in the entire cell configuration, the cells were kept at -120 mV. Cav3.1 currents were excited to -20 mV using a 100 ms step size (to measure the resting state block), followed by a 1600 ms step size to -65 mV, and a second 100 ms step size to -20 mV (to measure the voltage-dependent block). A voltage protocol was applied every 15 seconds in the absence and presence of the compound being studied. 2.5 mM nickel was used to completely inhibit Cav3.1 currents to allow non-Cav3.1 currents to be subtracted offline. Current amplitudes (pA) were measured in peaks 1 and 2. The average of the last 3 scans for each liquid period (vehicle, compound under study, full block) was calculated. Nickel-sensitive currents were used to calculate the % inhibition in the presence of the compound under study. In Table 6 below, human Cav3.1 inhibition data for the compounds are shown at a given single point concentration, and for some examples, their IC μ0 .

[0842] Table 6

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

Claims

1. A compound represented by formula (Ia): in: B is absent or selected from the group consisting of –CH2, –CH2-CH2, –CH2-CH2-CH2, –O-, –CH2-O-, –O-CH2-, and –CH2O-CH2; 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, a heterocyclyl or a 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 group; X2' does not exist and is -CH2-, -CHCH3- or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl and heteroaryl; X1' is selected from the group consisting of: (i) in: R2' and R3' are each independently selected from the group consisting of: H, deuterium, alkyl, hydroxy, 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 group; 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, carbocyclic and heterocyclic groups; Z2' and Z3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, -COZ'5 and SO2Z6'; or wherein Z2' and Z3' together with the nitrogen to which they are bonded form a heterocyclyl; Z5' is C 36 Carbocyclic group; Z6' is C 16 Alkyl; or Z7' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups; or (ii) in R6′ is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein B is absent.

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

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

5. The compound according to any one of claims 1 to 4, wherein W1' and W2' are both hydrogen.

6. The compound according to any one of claims 1 to 5, wherein both S1' and S2' are hydrogen.

7. The compound according to any one of claims 1 to 6, wherein R2' and R3' are both hydrogen. The compound according to claim 7 , wherein R4′ and R5′ together form a carbonyl group.

9. The compound according to claim 8, wherein R1' is -NZ2'Z3'.

10. The compound according to claim 9, wherein Z2' is hydrogen or methyl; and Z3' is C 16 Alkyl, C 36 A carbocyclic or heterocyclic group, wherein C 16 Alkyl, C 36 Each of the carbocyclyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxy, halo, methoxy, trifluoromethyl, and -COOCH3.

11. The compound according to claim 10, wherein Z2' is hydrogen, and Z3' is C 16 alkyl.

12. The compound according to claim 11, wherein Z3' is tert-butyl.

13. The compound of claim 10, wherein Z2' is hydrogen, and Z3' is cyclopropyl, cyclobutyl or oxetane.

14. The compound according to claim 7, wherein R4' and R5' are each independently hydrogen, hydroxy or halo.

15. The compound of claim 14, wherein R1' is -NZ2'Z3', Z2' is hydrogen, and Z3' is -COZ5'.

16. The compound according to claim 14, wherein R1' is alkyl, carbocyclyl or heterocyclyl.

17. The compound according to any one of claims 1 to 16, wherein X2' is -CONH-.

18. according to the compound described in any one of claims 1 to 17, wherein X3 'is aryl or heteroaryl, wherein each of aryl and heteroaryl is optionally substituted by one or more substituents selected from the group consisting of: halo, hydroxyl, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl and tert-butyl.

19. The compound of claim 18, wherein X3' is selected from the group consisting of phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran; quinazoline phenylimidazole, phenyltriazole, phenylpyrazole and adamantane ring.

20. The compound of claim 19, wherein X3' is phenyl optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro, cyano, methyl, methoxy, difluoromethoxy and trifluoromethoxy.

21. The compound according to claim 19, wherein X3' is benzimidazole optionally substituted with two substituents selected from the group consisting of chlorine and fluorine.

22. The compound according to claim 1, wherein the compound is:

23. A compound represented by formula (Ib): in: The stereocenters indicated by * are all in S configuration or all in R configuration; B is selected from the group consisting of –CH2, CH2CH2, CH2-CH2CH2, –O, CH2-O, –O-CH2 and CH2OCH2; S1' and S2' are each independently selected from the group consisting of -H and -CH3, or S1' and S2' together form a carbonyl group; X2' does not exist, it is -CH 2- 、-CHCH 3- or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl and heteroaryl; X1' is selected from the group consisting of: (i) in: R2' and R3' are each independently selected from the group consisting of: -H, deuterium, alkyl, hydroxy, 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 group; 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, carbocyclic and heterocyclic groups; Z2' and Z3' are each independently selected from the group consisting of hydrogen, deuterium, alkyl, carbocyclyl, heterocyclyl, COZ'5 and SO2Z6'; or wherein Z2' and Z3' together with the nitrogen to which they are bonded form a heterocyclyl; Z5' is C 36 Carbocyclic group; Z6' is C 16 Alkyl; or Z7' is selected from the group consisting of alkyl, carbocyclic and heterocyclic groups; or (ii) in R6′ is selected from the group consisting of alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; and pharmaceutically acceptable salts thereof.

24. The compound of claim 23, wherein B is -CH2.

25. The compound according to claim 23, wherein B is -CH 2- CH 2- .

26. A compound according to any one of claims 23 to 25, wherein both S1' and S2' are hydrogen.

27. A compound according to any one of claims 23 to 26, wherein R2' and R3' are both hydrogen.

28. The compound of claim 26, wherein R4' and R5' together form a carbonyl group.

29. The compound according to claim 28, wherein R1' is NZ2'Z3'.

30. The compound of claim 29, wherein Z2' is hydrogen or methyl; and Z3' is C 16 Alkyl, C 36 A carbocyclic or heterocyclic group, wherein C 16 Alkyl, C 36 Each of the carbocyclyl and heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of methyl, trifluoromethyl, hydroxy, halo, methoxy, trifluoromethoxy, and -COOCH3.

31. The compound of claim 30, wherein Z2' is hydrogen, and Z3' is C 16 alkyl.

32. The compound of claim 31, wherein Z3' is tert-butyl.

33. The compound of claim 30, wherein Z2' is hydrogen and Z3' is cyclopropyl, cyclobutyl or oxetane.

34. The compound of claim 26, wherein R4' and R5' are each independently hydrogen, hydroxy or halo.

35. The compound of claim 34, wherein R1' is NZ2'Z3', Z2' is hydrogen, and Z3' is -COZ5'.

36. The compound of claim 34, wherein R1' is alkyl, carbocyclyl or heterocyclyl.

37. A compound according to any one of claims 23 to 36, wherein X2' is -CONH-.

38. according to the compound described in any one of claims 23 to 37, wherein X3 'is aryl or heteroaryl, wherein each of aryl and heteroaryl is optionally substituted by one or more substituents selected from the group consisting of: halo, hydroxyl, cyano, amino, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyclopropyl and tert-butyl.

39. The compound of claim 38, wherein X3' is selected from the group consisting of phenyl, pyrazole, indazole, imidazole, benzimidazole, benzisoxazole, benzofuran; quinazoline phenylimidazole, phenyltriazole, phenylpyrazole, bicycloheptane, bicyclooctane and adamantane ring.

40. The compound of claim 39, wherein X3' is phenyl optionally substituted with two substituents selected from the group consisting of chloro, fluoro, methyl, methoxy, difluoromethoxy and trifluoromethoxy.

41. The compound of claim 23, wherein the compound is:

42. A compound represented by formula (Ic): in: One stereocenter indicated by * is in the S configuration, and the other stereocenter indicated by * is in the R configuration; B is –CH2-, –CH2-CH2, –CH2-CH2-CH2, –O-, –CH2-O-, –O-CH2-, and CH2OCH2; D is carbon or nitrogen; X1' is an alkyl group, X2' is -NHCO- or -CONH-; and X3' is aryl or heteroaryl; and pharmaceutically acceptable salts thereof.

43. The compound of claim 42, wherein C is -CH2-O-CH2-.

44. A compound according to claim 42 or 43, wherein X1' is tert-butyl.

45. The compound according to any one of claims 42 to 44, wherein X3' is phenyl or benzimidazole, wherein phenyl and benzimidazole are each optionally substituted with one or two substituents selected from the group consisting of chloro, fluoro and difluoromethoxy.

46. ​​The compound of claim 42, wherein the compound is:

47. A compound represented by formula (IVa): in: Stereocenters indicated by * are in R or S configuration; X1' is an alkyl group; X2' is -O- or NR1R2, wherein R1 and R2 are each independently H or alkyl; and X3' is aryl or heteroaryl; and pharmaceutically acceptable salts thereof.

48. The compound according to claim 47, wherein the compound is:

49. A compound represented by formula (Va): in: The 1,4-diazepane nucleus in the compound of formula (Va) optionally comprises a 2,7-CH2 bridge, a 2,7CH2CH2 bridge, a 3,7CH2 bridge or a 3,7CH2CH2 bridge; W1' and W2' are each independently hydrogen, deuterium, alkyl and alkoxy; or W1' and W2' together form a carbocyclic group, a heterocyclic group or a carbonyl group (=O); W3 is hydrogen or carbonyl; S1' and S2' are each independently hydrogen or alkyl, or S1' and S2' together form a carbonyl group; X2' does not exist and is -CH2-, -CHCH3- or -CONH-; X3' is selected from the group consisting of carbocyclyl, heterocyclyl, aryl and heteroaryl; X1' is in: 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, hydroxy, 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 comprising at least one methyl substituent; R 13 Selected from the group consisting of hydrogen, deuterium and alkyl; and pharmaceutically acceptable salts thereof.

50. The compound of claim 48, wherein the compound is represented by formula (Vb): And wherein W1′, W2′, S1′, S2′, X1′, X2′ and X3′ are as defined in claim 48.

51. The compound according to claim 48 or 49, wherein X3' is selected from the group consisting of phenyl, benzimidazole and adamantane ring, wherein phenyl and benzimidazole are each optionally substituted with one or two substituents selected from chlorine and fluorine.

52. The compound of claim 48, wherein the compound is:

53. A compound represented by formula (VIa): in R1' and R2' are each hydrogen, or R1' and R2' together form a carbonyl group; and R3' is aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, amino, methyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy; and pharmaceutically acceptable salts thereof.

54. The compound of claim 52, wherein R3' is isoquinoline or naphthyridine.

55. The compound of claim 52, wherein the compound is:

56. A compound having the following structure:

57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55 and a pharmaceutically acceptable carrier.

58. The pharmaceutical composition of claim 56, further comprising a modified release polymer.

59. The pharmaceutical composition of claim 57, wherein the modified release polymer is hydroxypropyl methylcellulose, ethyl cellulose, or a polyacrylate polymer.

60. 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, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 55 or a pharmaceutical composition according to any one of claims 56 to 58.

61. The method of claim 59, wherein the disease or condition associated with abnormal function or activity of a T-type calcium channel is selected from the group consisting of psychiatric disorders, pain, tremor, seizures, epilepsy, and epilepsy syndromes.

62. The method of claim 60, wherein the disease or condition associated with abnormal function or activity of a T-type calcium channel is tremor.

63. The method of claim 61, wherein the disease or condition associated with abnormal function or activity of a T-type calcium channel is essential tremor.

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