Fused heteroaryl compounds, and methods thereof for treating diseases, disorders, and conditions relating to aberrant function of a sodium channel

The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. For example, such compounds include those having the structure:or pharmaceutically acceptable salts thereof. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel, including Dravet syndrome or epilepsy, using such compounds are also provided herein.

BACKGROUND

Sodium ion (Na+) channels primarily open in a transient manner and are quickly inactivated, thereby generating a fast Na+ current to initiate the action potential. The late or persistent sodium current (INaL) is a sustained component of the fast Na+ current of cardiac myocytes and neurons. Many common neurological and cardiac conditions are associated with abnormal INaL enhancement, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals (see, e.g.,Pharmacol Ther(2008) 119:326-339). Accordingly, pharmaceutical compounds that selectively modulate sodium channel activity, e.g., abnormal INaL, are useful in treating such disease states.

SUMMARY OF THE INVENTION

Described herein are fused heteroaryl compounds and compositions useful for preventing and/or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late or persistent sodium current (INaL). In one aspect, the present disclosure features compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR6;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), optionally substituted by one or more R3;

each Rcis independently hydrogen, alkyl, aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl is optionally substituted by one or more R7;

each Rdis independently hydrogen or alkyl; and

Described herein are fused heteroaryl compounds and compositions useful for preventing and/or treating a disease, disorder, or condition, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, e.g., abnormal late or persistent sodium current (INaL). In one aspect, the present disclosure features compounds of Formula (I-2):

In another aspect, the present disclosure provides a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure features a compound of Formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present invention features a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present invention provides a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (IVb):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present invention features a compound of Formula (V):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of formula (Va):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present invention features a compound of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (VIa):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (VIIa):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (VIIb):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In another aspect, the present disclosure provides a compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein.

In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a disclosed compound (e.g., a compound of Formulae (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIIa), (VIIb), (VIII)).

Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing Detailed Description, Examples, and Claims.

DETAILED DESCRIPTION OF THE INVENTION

As generally described herein, the present invention provides compounds and compositions useful for preventing and/or treating a disease, disorder, or condition described herein, e.g., a disease, disorder, or condition relating to aberrant function of a sodium ion channel, such as abnormal late sodium current (INaL). Exemplary diseases, disorders, or conditions include epilepsy or an epilepsy syndrome.

Definitions

Chemical Definitions

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

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

Compound described herein may also comprise one or more isotopic substitutions. For example, H may be in any isotopic form, including1H,2H (D or deuterium), and3H (T or tritium); C may be in any isotopic form, including12C,13C, and14C; O may be in any isotopic form, including16O and18O; and the like.

The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

“Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group, e.g., having 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1-6alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like.

“Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 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) (“C2-20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” or “alkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene,” groups may be substituted or unsubstituted with one or more substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate 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, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

“Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

Examples of representative heteroaryls include the following:

The term “cycloalkyl,” as used herein, refers to a monocyclic saturated or partially unsaturated hydrocarbon ring system, for example, having 3-8 or 3-6 carbon atoms in its ring system, referred to herein as C3-8cycloalkyl or C3-6cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl.

“Heterocyclyl” or “heterocyclic” 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 (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

“Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, carbocyclyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

“Haloalkyl” refers to an alkyl group substituted with one or more halogen atoms.

“Nitro” refers to the radical —NO2.

In general, the term “substituted”, whether preceded by the term “optionally” or not, 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 which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g, infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal 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,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors 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 therapeutic and prophylactic treatment.

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

Compounds

In one aspect, the present invention features a compound of Formula (II):

In some embodiments, X is CR6. In some embodiments, Y is CR6. In some embodiments, Z is CR6. In some embodiments, each of X, Y, and Z is independently CR6.

In some embodiments, one of X, Y, and Z is N. In some embodiments, Y is N. In some embodiments, Y is N and X is CR6. In some embodiments, Y is N and Z is CR6. In some embodiments, Y is N and each of X and Z is independently CR6. In some embodiments, R6is hydrogen.

In some embodiments, Z is N. In some embodiments, Z is N and X is CR6. In some embodiments, Z is N and Y is CR6. In some embodiments, Z is N and each of X and Y is independently CR6. In some embodiments, R6is hydrogen.

In some embodiments, A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl).

In some embodiments, A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the para position. In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the meta position. In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the ortho position.

In some embodiments, A is substituted with at least one R3, and each R3is cyano, nitro, carbocyclyl, heterocyclyl, —SRc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein carbocyclyl, and heterocyclyl are optionally substituted with one or more R5.

In some embodiments, each of R1and R2is independently alkyl. In some embodiments, R1is hydrogen and R2is alkyl. In some embodiments, R1is alkyl and R2is hydrogen.

In some embodiments, the compound of Formula (II) is not:

In another aspect, a compound of Formula (Ha):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR6, wherein at least one of X, Y, and Z is N;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), optionally substituted by one or more R3;

each Rdis independently hydrogen or alkyl; and

each R7is independently alkyl, haloalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein the compound is not one of the following:

In some embodiments, X is N, Y is CR6(e.g., CH), and Z is CR6(e.g., CH). In some embodiments, Y is N, X is CR6(e.g., CH), and Z is CR6(e.g., CH). In some embodiments, Z is N, X is CR6(e.g., CH), and Y is CR6(e.g., CH).

In some embodiments, A is aryl. In some embodiments, A is 6-membered aryl (e.g., phenyl).

In some embodiments, A is heteroaryl. In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

In some embodiments, A is

In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the para position. In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the meta position. In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the ortho position.

In some embodiments, A is substituted with at least one R3, and each R3is cyano, nitro, carbocyclyl, heterocyclyl, —SRc, —N(Rd)2, —C(O)Rc, —C(O)ORc, or —C(O)N(Rd)2, wherein carbocyclyl, and heterocyclyl are optionally substituted with one or more R5.

In some embodiments, each of R1and R2is independently alkyl. In some embodiments, R1is hydrogen and R2is alkyl. In some embodiments, R1is alkyl and R2is hydrogen.

In another aspect, the present invention features a compound of Formula (III):

In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is 6-membered heteroaryl. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the para position. In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the meta position. In some embodiments, A is a 6-membered aryl or 6-membered heteroaryl and is substituted by R3in the ortho position.

In some embodiments, each of R1and R2is independently alkyl. In some embodiments, R1is hydrogen and R2is alkyl. In some embodiments, R1is alkyl and R2is hydrogen.

In some embodiments, the compound of Formula (III) is not:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided is a compound of Formula (III-a):

In some embodiments, A is aryl (e.g., phenyl). In some embodiments, A is heteroaryl. In some embodiments, A is a 6-membered heteroaryl. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

In some embodiments, A is substituted by one or more R3. In some embodiments, A is a 6-membered aryl or heteroaryl and is substituted by R3in the para position. In some embodiments, A is a 6-membered aryl or heteroaryl and is substituted by R3in the meta position. In some embodiments, A is a 6-membered aryl or heteroaryl and is substituted by R3in the ortho position.

In some embodiments, the compound of Formula (II-a) is not:

or a pharmaceutically acceptable salt thereof.

In one aspect, the present disclosure provides a compound of Formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein:

R1is cyano, C1-6haloalkyl, or C3-8carbocyclyl optionally substituted with one or more halogen,

m is 0, 1, or 2;

each Rdis independently hydrogen or C1-6alkyl; and

or a pharmaceutically acceptable salt thereof.

In some embodiments, R1is C1-6haloalkyl or C3-8carbocyclyl optionally substituted with one or more halogen.

In certain embodiments, R1is selected from the group consisting of: —CF3, CHF2, CH2CF, —CCl3, cyclopropyl optionally substituted with one or two Fs.

In some embodiments, R2is hydrogen or cyano.

In other embodiments, R3is selected from the group consisting of C1-6alkyl optionally substituted with one or more halogen; C3-8carbocyclyl; and —ORc.

In certain embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In some embodiments, m is 0.

In certain embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

In other embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention features a compound of Formula (IV):

In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is a 6-membered aryl substituted by R3in the para position.

In some embodiments, each of R1and R2is independently alkyl. In some embodiments, R1is alkyl and R2is hydrogen.

In another aspect, the present disclosure provides a compound of Formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl optionally substituted by one or more R3;

and each Rdis independently hydrogen or alkyl.

In some embodiments, A is aryl.

In other embodiments, A is phenyl.

In certain embodiments, A is phenyl substituted by 1 R3.

In some embodiments, A is phenyl substituted by 1 R3in the para position.

In other embodiments, R3is selected from the group consisting of C1-6alkyl optionally substituted with one or more halogen; C3-8carbocyclyl; and —ORc.

In certain embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In some embodiments, m is 0.

In other embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

In other embodiments, R1is alkyl substituted with 1-4 R4.

In other embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a compound of formula (IVb):

or a pharmaceutically acceptable salt thereof, wherein:

R4is C1-6alkyl, halo, or ORc, wherein C1-6alkyl is optionally substituted with one or more R5;

m is 0, 1, or 2;

and each Rdis independently hydrogen or C1-6alkyl.

In some embodiments, R1is C1-6alkyl or C3-8carbocyclyl, wherein C1-6alkyl or C3-8carbocyclyl is optionally substituted with one or more halogen.

In other embodiments, R1is selected from the group consisting of: —CF3, CHF2, CH2F, or cyclopropyl optionally substituted with one or two Fs.

In some embodiments, R2is hydrogen or cyano.

In other embodiments, R3is selected from the group consisting of C1-6alkyl optionally substituted with one or more halogen; C3-8carbocyclyl; and —ORc.

In certain embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In some embodiments, m is 0.

In other embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

In certain embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention features a compound of Formula (V):

In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is a 6-membered aryl substituted by R3in the para position.

In some embodiments, each of R1and R2is independently alkyl. In some embodiments, R1is alkyl and R2is hydrogen.

In another aspect, the present invention provides a compound of formula (Va):

or a pharmaceutically acceptable salt thereof, wherein:

R4is C1-6alkyl, halo, or ORc, wherein C1-6alkyl is optionally substituted with one or more R5;

m is 0, 1, or 2;

and each Rdis independently hydrogen or C1-6alkyl.

In some embodiments, R1is C1-6alkyl or C3-8carbocyclyl, wherein C1-6alkyl or C3-8carbocyclyl is optionally substituted with one or more halogen.

In other embodiments, R1is selected from the group consisting of: —CF3, CHF2, CH2CF, or cyclopropyl or cyclopentyl substituted with one or two Fs.

In other embodiments, R3is selected from the group consisting of C1-6alkyl optionally substituted with one or more halogen; C3-8carbocyclyl; and —ORc.

In other embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In some embodiments, m is 0.

In other embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

In certain embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention features a compound of Formula (VI):

In some embodiments, A is 6-membered aryl (e.g., phenyl). In some embodiments, A is a 6-membered aryl substituted by R3in the para position.

In some embodiments, each of R1and R2is independently alkyl. In some embodiments, R1is alkyl and R2is hydrogen.

In another aspect, the present disclosure provides a compound of Formula (VIa):

or a pharmaceutically acceptable salt thereof, wherein:

R4is C1-6alkyl, halo, or ORc, wherein C1-6alkyl is optionally substituted with one or more R5;

m is 0, 1, or 2;

and each Rdis independently hydrogen or C1-6alkyl.

In some embodiments, R1is C1-6alkyl or C3-8carbocyclyl, wherein C1-6alkyl or C3-8carbocyclyl is optionally substituted with one or more halogen.

In certain embodiments, R1is selected from the group consisting of: —CF3, CHF2, CH2CF, or cyclopropyl or cyclopentyl substituted with one or two Fs.

In some embodiments, R2is hydrogen or cyano.

In certain embodiments, R3is selected from the group consisting of C1-6alkyl optionally substituted with one or more halogen; C3-8carbocyclyl; and —ORc.

In other embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In some embodiments, m is 0.

In certain embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

In other embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure provides a compound of formula VIIa:

or a pharmaceutically acceptable salt thereof, wherein:

R1is C1-6alkyl, cyano, C1-6haloalkyl, or C3-8carbocyclyl optionally substituted with one or more halogen,

R3is selected from the group consisting of: C1-6alkyl, cyano, C3-10carbocyclyl, —ORc, —C(O)Rc, —C(O)ORc, and —C(O)N(Rd)2, wherein C1-6alkyl or C3-10carbocyclyl is optionally substituted with one or more R5;

R4is C1-6alkyl, halo, or ORc, wherein C1-6alkyl is optionally substituted with one or more R5;

m is 0, 1, or 2;

each Rdis independently hydrogen or C1-6alkyl;

wherein the compound is not:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R1is selected from the group consisting of: —CH3, CF3, CHF2, and cyclopropyl.

In certain embodiments, R2is cyano or C1-6haloalkyl.

In other embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In certain embodiments, R3is —ORc, wherein Rcis selected from the group consisting of C1-6alkyl substituted with 1, 2, or 3 halogens or C3-8carbocyclyl optionally substituted with cyano or CF3.

In some embodiments, Rcis selected from the group consisting of: —CF3, —CH2CF3,

In other embodiments, m is 0.

In some embodiments, m is 1 or 2, and R2is cyano or C1-6haloalkyl.

In certain embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

and a pharmaceutically acceptable salt thereof.

In other embodiments, the present disclosure provides a compound represented by:

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and X are independently N or CH, wherein at least one of X, Y, and Z is N;

R1is C1-6alkyl, cyano, C1-6haloalkyl, or C3-8carbocyclyl optionally substituted with one or more halogen,

R3is selected from the group consisting of: C1-6alkyl, cyano, C3-10carbocyclyl, —ORc, —C(O)Rc, —C(O)ORc, and —C(O)N(Rd)2, wherein C1-6alkyl or C3-10carbocyclyl is optionally substituted with one or more R5;

R4is C1-6alkyl, halo, or ORc, wherein C1-6alkyl is optionally substituted with one or more R5;

m is 0, 1, or 2;

each Rdis independently hydrogen or C1-6alkyl; and

In some embodiments, R1is selected from the group consisting of: —CH3, CF3, CHF2, and cyclopropyl.

In some embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In other embodiments, R3is —ORc, wherein Rcis selected from the group consisting of C1-6alkyl substituted with 1, 2, or 3 halogens or C3-8carbocyclyl optionally substituted with cyano or CF3.

In certain embodiments, Rcis selected from the group consisting of: —CF3, —CH2CF3,

In some embodiments, m is 0.

In other embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

and a pharmaceutically acceptable salt thereof.

A compound represented by:

or a pharmaceutically acceptable salt thereof, wherein:

X, Y, and X are independently N or CH,

R1is C1-6alkyl, cyano, C1-6haloalkyl, or C3-8carbocyclyl optionally substituted with one or more halogen,

R3is selected from the group consisting of: C1-6alkyl, cyano, C3-10carbocyclyl, —ORc, —C(O)Rc, —C(O)ORc, and —C(O)N(Rd)2, wherein C1-6alkyl or C3-10carbocyclyl is optionally substituted with one or more R5;

R4is C1-6alkyl, halo, or ORc, wherein C1-6alkyl is optionally substituted with one or more R5;

m is 0, 1, or 2;

each Rdis independently hydrogen or C1-6alkyl; and

In some embodiments, R1is selected from the group consisting of: —CH3, CF3, CHF2, and cyclopropyl.

In some embodiments, R3is selected from the group consisting of CF3, —OCF3, —OCH2CF3, —CH2—CH2-cyclopropyl optionally substituted with —CN or CF3, and cyclopropyl optionally substituted with —CN or CF3.

In other embodiments, R3is —ORc, wherein Rcis selected from the group consisting of C1-6alkyl substituted with 1, 2, or 3 halogens or C3-8carbocyclyl optionally substituted with cyano or CF3.

In some embodiments, Rcis selected from the group consisting of: —CF3, —CH2CF3,

In certain embodiments, m is 0.

In other embodiments, R4is selected from the group consisting of methyl, F, —OMe, and —CH2—OMe.

or a pharmaceutically acceptable salt thereof.
Methods of Treatment

Described herein are compounds and compositions thereof and their use to treat a disease, disorder, or condition relating to aberrant function of a sodium channel ion channel, e.g., abnormal late sodium (INaL) current. In some embodiments, a compound provided by the present invention is effective in the treatment of epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder. Compounds of the invention may also modulate all sodium ion channels, or may be specific to only one or a plurality of sodium ion channels, e.g., Nay 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, and 1.9.

In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes a pharmaceutically acceptable addition salt, a pharmaceutically acceptable ester, a hydrate of an addition salt, a tautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, a stereoisomer or mixture of stereoisomers (pure or as a racemic or non-racemic mixture) of a compound described herein, e.g. a compound of Formulae (I), (I-2), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIIa), (VIIb), (VIII); such as a compound of Formulae (I), (I-2), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIIa), (VIIb), (VIII) named herein.

In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR6;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), optionally substituted by one or more R3;

each Rcis independently hydrogen, alkyl, aryl, or heteroaryl, wherein alkyl, aryl, and heteroaryl is optionally substituted by one or more R7;

each Rdis independently hydrogen or alkyl; and

In one aspect, the present disclosure provides a method of treating a neurological disorder or a psychiatric disorder, wherein the method comprises administering to a subject in need thereof a compound of Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein:

each of X, Y, and Z is independently N or CR6;

A is aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), optionally substituted by one or more R3;

each Rdis independently hydrogen or alkyl; and

In some embodiments, the neurological disorder is epilepsy.

In other embodiments, the neurological disorder is an epileptic encephalopathy.

In some embodiments, A is aryl (e.g., phenyl).

In other embodiments, A is phenyl substituted by 1-3 R3(e.g., wherein at least 1 R3is in the para position).

In certain embodiments, A is heteroaryl (e.g., pyridyl).

In some embodiments, A is pyridyl substituted by 1-3 R3(e.g., wherein at least 1 R3is in the para position).

In other embodiments, at least one R3is alkyl or —ORc(e.g., —OCF3)

In some embodiments, each of R1and R2is independently alkyl (e.g., substituted with 1-4 R4).

In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from:

or a pharmaceutically acceptable salt thereof.
Epilepsy and Epilepsy Syndromes

The compounds described herein are useful in the treatment of epilepsy and epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cell activity in the brain becomes disrupted, causing seizures or periods of unusual behavior, sensations and sometimes loss of consciousness. Seizure symptoms will vary widely, from a simple blank stare for a few seconds to repeated twitching of their arms or legs during a seizure.

Epilepsy may involve a generalized seizure or a partial or focal seizure. All areas of the brain are involved in a generalized seizure. A person experiencing a generalized seizure may cry out or make some sound, stiffen for several seconds to a minute a then have rhythmic movements of the arms and legs. The eyes are generally open, the person may appear not to be breathing and actually turn blue. The return to consciousness is gradual and the person maybe confused from minutes to hours. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures. In a partial or focal seizure, only part of the brain is involved, so only part of the body is affected. Depending on the part of the brain having abnormal electrical activity, symptoms may vary.

The compounds described herein may also be useful in the treatment of epilepsy syndromes. Severe syndromes with diffuse brain dysfunction caused, at least partly, by some aspect of epilepsy, are also referred to as epileptic encephalopathies. These are associated with frequent seizures that are resistant to treatment and severe cognitive dysfunction, for instance West syndrome.

In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsy or an epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

In one aspect, the present invention features a method of treating epilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy with febrile seizures, intractable childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migrating partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy) comprising administering to a subject in need thereof a compound of Formula (I-2):

Neurodevelopmental Disorders

In one aspect, the present invention features a method of treating a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder with epilepsy) comprising administering to a subject in need thereof a compound of Formula (I):

The compounds described herein may be useful in the treatment of pain. In some embodiments, the pain comprises neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder. In some embodiments, the methods described herein further comprise identifying a subject having pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) prior to administration of a compound described herein (e.g., a compound of Formulae (I), (1-2), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIIa), (VIIb), (VIII)).

In one aspect, the present invention features a method of treating pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or a related headache disorder) comprising administering to a subject in need thereof a compound of Formula (I):

In one aspect, the present invention features a method of treating a neuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiple sclerosism, myotonia, paramyotonia congenita, potassium-aggravated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation) comprising administering to a subject in need thereof a compound of Formula (I-2):

In some embodiments, a compound of the present invention (e.g., a compound of Formulae (I), (I-2), (II), (IIa), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (VI), (VIa), (VIIa), (VIIb), (VIII)) may have appropriate pharmacokinetic properties such that they may active with regard to the central and/or peripheral nervous system. In some embodiments, the compounds provided herein are used to treat a cardiovascular disease such as atrial and ventricular arrhythmias, including atrial fibrillation, Prinzmetal's (variant) angina, stable angina, unstable angina, ischemia and reperfusion injury in cardiac, kidney, liver and the brain, exercise induced angina, pulmonary hypertension, congestive heart disease including diastolic and systolic heart failure, and myocardial infarction. In some embodiments, the compounds provided herein may be used in the treatment of diseases affecting the neuromuscular system resulting in itching, seizures, or paralysis, or in the treatment of diabetes or reduced insulin sensitivity, and disease states related to diabetes, such as diabetic peripheral neuropathy.

In any and all aspects, in some embodiments, the compound of Formula (I) or (I-2) is selected from:

or a pharmaceutically acceptable salt thereof.

In any and all aspects, in some embodiments, the compound of Formula (I) or (I-2) is selected from:

or a pharmaceutically acceptable salt thereof.
Pharmaceutical Compositions and Routes of Administration

Compounds provided in accordance with the present invention are usually administered in the form of pharmaceutical compositions. This invention therefore provides pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.)

In one aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

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

One mode for administration is parenteral, particularly by injection. The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally used for injection, but less preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Oral administration is another route for administration of compounds in accordance with the invention. Administration may be via capsule or enteric coated tablets, or the like. In making the pharmaceutical compositions that include at least one compound described herein, the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

The compositions of the invention can be Formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art Controlled release drag delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present invention employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

The compositions are preferably Formulated in a unit dosage form. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The compounds are generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains from 1 mg to 2 g of a compound described herein, and for parenteral administration, preferably from 0.1 to 700 mg of a compound a compound described herein. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen 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, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

Combination Therapy

A compound or composition described herein (e.g., for use in modulating a sodium ion channel, e.g., the late sodium (INaL) current) may be administered in combination with another agent or therapy. A subject to be administered a compound disclosed herein may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. These diseases or conditions can relate to epilepsy or an epilepsy syndrome, a neurodevelopmental disorder, pain, or a neuromuscular disorder.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from a combination treatment of the sodium channel blockers of the invention with other therapeutic agents include, without limitation, angina including stable angina, unstable angina (UA), exercised-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, heart failure including congestive (or chronic) heart failure and diastolic heart failure and heart failure with preserved ejection fraction (diastolic dysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseases or conditions include anti-anginals, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid lowering agents.

The co-administration of the sodium channel blockers of the invention with therapeutic agents suitable for treating cardiovascular related conditions allows enhancement in the standard of care therapy the patient is currently receiving.

Nitrates dilate the arteries and veins thereby increasing coronary blood flow and decreasing blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into the cells of the heart and blood vessels causing the blood vessels to relax thereby increasing the supply of blood and oxygen to the heart Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil), nifedipine (Adalat Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics eliminate excess fluids in the tissues and circulation thereby relieving many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload on the heart by expanding the blood vessels and decreasing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

Vasodilators reduce pressure on the blood vessels by making them relax and expand. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

Cardiac glycosides are compounds that increase the force of the heart's contractions. These compounds strengthen the pumping capacity of the heart and improve irregular heartbeat activity. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There are three main types of antithrombotics—platelet inhibitors, anticoagulants, and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, thereby reducing clotting in the arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (plavix), dipyridamole, cilostazol, persantine sulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, such as abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockers and calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent the formation of new clots. Examples of anticoagulants include bivalirudin (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examples of thrombolytic agents include streptokinase, urokinase, and tenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate and rhythm. Examples of antiarrhythmic agents include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta blockers are also used as antiarrhythmic agents.

Combinations with amiodarone and dronedarone are of particular interest given the recently discovered synergistic effects of the sodium channel blocker ranolazine and amioarone and dronedarone.

Antihypertensive Agents

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol or fatty sugars present in the blood. Examples of lipid lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, such as atorvastatin (Lipitor), fluvastatin (Lescot), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient presenting with an acute coronary disease event often suffers from secondary medical conditions such as one or more of a metabolic disorder, a pulmonary disorder, a peripheral vascular disorder, or a gastrointestinal disorder. Such patients can benefit from treatment of a combination therapy comprising administering to the patient ranolazine in combination with at least one therapeutic agent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to the lungs. Examples of pulmonary disorders include, without limitation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

Examples of therapeutics agents used to treat pulmonary disorders include bronchodilators including beta2 agonists and anticholinergics, corticosteroids, and electrolyte supplements. Specific examples of therapeutic agents used to treat pulmonary disorders include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Rroventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes, including type I and type II diabetes, metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid lowering agents, as described in the section “Cardiovascular Agent Combination Therapy” above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretin mimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels (arteries and veins) located outside the heart and brain, including, for example peripheral arterial disease (PAD), a condition that develops when the arteries that supply blood to the internal organs, arms, and legs become completely or partially blocked as a result of atherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associated with the gastrointestinal tract. Examples of gastrointestinal disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcer disease, and pancreatitis.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety Agents Combination Therapy

Patients presenting with an acute coronary disease event may exhibit conditions that benefit from administration of therapeutic agent or agents that are antibiotics, analgesics, antidepressant and anti-anxiety agents in combination with ranolazine.

Antibiotics

Analgesics are therapeutic agents that are used to relieve pain. Examples of analgesics include opiates and morphinomimetics, such as fentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Given the ability of the sodium channel blockers of the invention to treat neuropathic pain via inhibition of the Nay 1.7 and 1.8 sodium channels, combination with analgesics are particularly envisioned. See U.S. Patent Application Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Accordingly, one aspect of the invention provides for a composition comprising the sodium channel blockers of the invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises the sodium channel blockers of the invention and at least two therapeutic agents. In further alternative embodiments, the composition comprises the sodium channel blockers of the invention and at least three therapeutic agents, the sodium channel blockers of the invention and at least four therapeutic agents, or the sodium channel blockers of the invention and at least five therapeutic agents.

The methods of combination therapy include co-administration of a single formulation containing the sodium channel blockers of the invention and therapeutic agent or agents, essentially contemporaneous administration of more than one formulation comprising the sodium channel blocker of the invention and therapeutic agent or agents, and consecutive administration of a sodium channel blocker of the invention and therapeutic agent or agents, in any order, wherein preferably there is a time period where the sodium channel blocker of the invention and therapeutic agent or agents simultaneously exert their therapeutic effect.

EXAMPLES

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts,Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, trituration, high pressure liquid chromatography (HPLC), or supercritical fluid chromatography (SFC). Note that flash chromatography may either be performed manually or via an automated system. The compounds provided herein may be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS). NMR chemical shifts are reported in part per million (ppm) and are generated using methods well known to those of skill in the art.

LIST OF ABBREVIATION

THE tetrahydrofuran

EtOH ethanol

TEA triethylamine

DCM dichloro me thane

MeI methyl iodide

Pd(dppf)Cl2[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane

Example 1: Synthesis of Compound 1

Synthesis of A-2

Synthesis of A-3

A mixture of A-2 (2.50 g, 10.48 mmol) and TFAA (6.60 g, 31.43 mmol) in THF (20 mL) was stirred at 65° C. for 8 hours. The mixture was concentrated and the resulting residue was diluted with H2O (30 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with sat Na2CO3(30 mL), water (40 mL×2) and brine (50 mL), dried over Na2SO4, filtered and concentrated to give the erode product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) to give A-3 (1.40 g, 6.35 mmol) as a solid.1H NMR (400 MHz, CDCl3) δH=8.20 (s, 1H), 7.59-7.53 (m, 2H), 6.94 (dd, 1H). LCMS Rt=0.77 min using Method B, MS ESI calcd. for C8H5ClF3N2[M+H]+ 221.0, found 220.9.

Synthesis of Compound 1

Example 2: Synthesis of Compound 2

Example 3: Synthesis of Compound 3

Example 4: Synthesis of Compound 4

Example 5: Synthesis of Compound 5

Example 6: Synthesis of Compound 6

Synthesis of A-4

Synthesis of Compound 6

Example 7: Synthesis of Compound 7

Synthesis of A-6

Synthesis of A-7

Synthesis of A-8

Synthesis of Compound 7

Example 8: Synthesis of Compound 8

Synthesis of A-10

Synthesis of A-11

Synthesis of A-12

To a mixture of A-11 (300 mg, 911.11 μmol) in THE (10 mL) was added TFAA (702 mg, 3.34 mmol), and the mixture was stirred at 20° C. for 1 hour and 65° C. for 2 hours. The mixture was concentrated to give a residue that was diluted with H2O (30 mL) and sat. Na2CO3(30 mL), and extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE=10% to 20% to 30%) to afford A-12 (270.00 mg, 739.26 μmol) as a solid.1H NMR (400 MHz, CDCl3) δH=8.94 (s, 2H), 7.79 (brs, 1H), 7.62 (d, 2H), 7.40 (d, 2H), 4.85 (d, 2H).

Synthesis of Compound 8

Example 9: Synthesis of Compound 9

Synthesis of A-14

To a suspension of A-13 (2.00 g, 11.01 mmol) in EtOH (10 mL) was added N2H4.H2O (661.51 mg, 13.21 mmol), and the mixture was stirred at 80° C. for 16 hours. TEA (3 mL) was then added, followed by the addition of water (5 mL), ACN (10 mL), and toluene (2×10 mL). After each addition, the mixture was concentrated to dryness. The residue was dissolved in ACN (20 mL), and TFAA (3.47 g, 16.52 mmol) and TEA (2.23 g, 22.02 mmol) were added. The mixture was stirred at 15° C. for 2 days. The mixture was diluted with H2O (80 mL) and extracted with EtOAc (80 mL×2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give the erode product, which was purified by flash chromatography on silica gel (PE:EtOAc=1:1 to EtOAc) to give A-14 (1.50 g, 5.86 mmol) as a solid.1H NMR (400 MHz, DMSO-d6) δH=10.65 (s, 1H), 9.72 (t, 1H), 4.01 (d, 2H), 2.45-2.39 (m, 2H), 2.33-2.27 (m, 2H).

Synthesis of A-15

To a mixture of A-14 (1.50 g, 6.72 mmol) in AcOH (10 mL) was added Br2(1.18 g, 7.39 mmol, 381.18 μL) and the mixture was stirred at 50° C. for 16 hours. The mixture was concentrated, diluted with sat. NaHCO3(10 mL), and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to afford A-15 (1.20 g, 5.02 mmol) as a solid. LCMS Rt=0.18 min using Method B, MS ESI calcd. for C7H7F3N3O2[M+H]+222.0, found 221.9.

Synthesis of A-16

To a solution of A-15 (1.20 g, 5.43 mmol) in SULFOLANE (20) was added POCl3(6.66 g, 43.44 mmol), and the mixture was stirred at 100° C. for 16 hours. The mixture was poured into water (200 mL) with stirring, neutralized with solid Na2CO3until pH=10, and extracted with EtOAc (200 mL×2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (PE:EtOAc=10:1 to 5:1) to afford A-16 (350.00 mg, 1.58 mmol) as a solid.1H NMR (400 MHz, DMSO-d6) δ=7.91 (d, 1H), 7.63 (s, 1H), 6.85 (d, 1H).

Synthesis of Compound 9

Example 10: Synthesis of Compound 10

Synthesis of A-17

To a mixture of A-11 (400 mg, 1.21 mmol) in THF (10 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (634.31 mg, 3.64 mmol), and the mixture was stirred at 20° C. for 16 hours. The mixture was concentrated, H2O (20 mL) and sat. Na2CO3(20 mL) were added, and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=10% to 30% to 55%) to afford A-17 (400 mg, 1.14 mmol) as a solid. LCMS Rt=0.79 min using Method B, MS ESI calcd. for C14H11F5N3O2[M+H]+348.1, found 347.9.

Synthesis of Compound 10

Example 11: Synthesis of Compound 11

Synthesis of A-18

To a mixture of Compound 8 (400 mg, 1.15 mmol) in DCM (10 mL) was added NBS (307.59 mg, 1.73 mmol), then the mixture was stirred at 20° C. for 1 hour. The mixture was diluted with DCM (50 mL), and the organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=5% to 10% to 15%) to afford A-18 (400 mg, 0.94 mmol) as a solid.1H NMR (400 MHz, CDCl3) δH=8.64 (d, 1H), 8.44 (d, 1H), 7.63 (d, 2H), 7.43 (d, 2H).

Synthesis of Compound 11

Example 12: Synthesis of Compound 12

Synthesis of 12-b

Synthesis of 12-c

Synthesis of 12-d

Synthesis of 12-e

Synthesis of A-19

A mixture of A-9 (1 g, 5.44 mmol) and 10% Pd/C (500 mg) in TEA (10 mL) and TFAA (10 mL) was stirred at 20° C. under H2(15 psi) for 1.5 hours. The mixture was then concentrated and purified by flash chromatography on silica gel (EtOAc in PE=0 to 40%) to afford A-19 (1000 mg, 3.47 mmol) as an oil. LCMS Rt=0.61 min using Method B, MS ESI calcd. for C7H6BrF3N3O [M+2+H]+286.0, found 285.8.

Synthesis of A-20

A mixture of A-19 (1 g, 3.52 mmol) in POCl3(10 mL) was stirred at 145° C. for 32 hours. The mixture was concentrated, and the residue was poured into ice-water (30 mL), basified with Na2CO3(solid) to pH˜9, and extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0% to 30%) to afford A-20 (160 mg, 0.59 mmol) as a solid.1H NMR 400 MHz, CDCl3) δH=8.54 (s, 1H), 8.33 (d, 1H), 7.79 (s, 1H). LCMS Rt=0.70 min using Method B, MS ESI calcd. for C7H4BrF3N3[M+2+H]+267.9, found 267.6.

Synthesis of Compound 12

Example 13: Synthesis of Compound 13

Example 14: Synthesis of Compound 14

Example 15: Synthesis of Compound 15

Synthesis of A-21

Synthesis of A-22

A mixture of A-22 (1 g, 4.15 mmol) in POCl3(10.33 mL, 110.87 mmol) was stirred at 135° C. for 24 hours. The mixture was concentrated, and the residue was poured into ice-water (30 mL), basified with Na2CO3(solid) to pH˜8, and extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the crude product, which was purified by flash chromatography silica gel (EtOAc in PE=5% to 10% to 17%) to afford A-22 (710 mg, 3.08 mmol) as a solid.1H NMR (400 MHz, CDCl3) δH=8.99 (d, 1H), 8.12 (s, 1H), 7.96 (s, 1H). LCMS Rt=0.69 min using Method B, MS ESI calcd. for C7H4ClF3N3[M+H]+222.0, found 221.8.

Synthesis of Compound 15

Example 16: Synthesis of Compound 16

Synthesis of A-24

Synthesis of A-25

To a solution of A-24 (2.2 g, 5.85 mmol) in DCM (30 mL) was added 10% HCl (30 mL). The reaction mixture was stirred at 15° C. for 16 hours. The aqueous phase was separated and washed with DCM (10 mL), then concentrated afford A-25 (1200 mg, 4.83 mmol), which was used directly in next step. LCMS Rt=0.19 min using Method B, MS ESI calcd. for C7H7BrN3[M+H+2]+214.0, found 213.8.

Synthesis of A-26

To a mixture of A-25 (1.2 g, 4.83 mmol) and Et3N (3.33 mL, 24.14 mmol) in DCM (30 mL) was added TFAA (2.04 mL, 14.49 mmol). The reaction mixture was stirred at 15° C. for 1 hour. The reaction was quenched with sat. NaHCO3(50 mL), extracted with DCM (50 mL×3), and the combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford A-26 (1500 mg, 4.87 mmol) as an oil, which was used directly in next step. LCMS Rt=0.73 min using Method B, MS ESI calcd. for C9H6BrF3N3O [M+H+2]+310.0, found 309.9.

Synthesis of A-27

A mixture of A-26 (1.5 g, 4.87 mmol) and TFA (3 mL, 40.26 mmol) in DCM (30 mL) was heated to 30° C. and stirred for 16 hours. The reaction mixture was concentrated, and the residue was treated with sat. NaHCO3(100 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give a residue that was purified by flash chromatography on silica gel (EtOAc in PE, 0% to 5% to 10%) to afford A-27 (170 mg, 0.59 mmol) as a solid.1H NMR (400 MHz, DMSO-d6) δH=8.94 (s, 1H), 8.05 (d, 1H), 7.69 (d, 1H). LCMS Rt=0.78 min using Method B, MS ESI calcd. for C9H4BrF3N3[M+H]+290.0, found 289.8.

Synthesis of Compound 16

Example 17: Synthesis of Compound 17

Synthesis of 17-2

Synthesis of 17-3

Synthesis of 17-4

Synthesis of 17-5

Synthesis of 17-6

Example 18: Synthesis of Compound 18

Example 19: Synthesis of Compound 19

Example 20: Synthesis of Compound 20

Example 21: Synthesis of Compound 21

Synthesis of A-28

To a mixture of A-25 (300 mg, 1.21 mmol) and TEA (0.84 mL, 6.04 mmol) in DCM (30 mL) was added (2,2-difluoroacetyl) 2,2-difluoroacetate (630.34 mg, 3.62 mmol). The reaction mixture was stirred at 15° C. for 1 hour. The reaction was quenched with sat. NaHCO3(50 mL) and extracted with DCM (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated, and the residue was purified by flash chromatography on silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-28 (110 mg, 0.40 mmol) as a solid.

Synthesis of Compound 21

Example 22: Synthesis of Compound 22

Example 23: Synthesis of Compound 23

Synthesis of 23-2

To a suspension of NaH (453.66 mg, 11.34 mmol) in THF (50 mL) was added 2,2,2-trifluoroethanol (1.13 g, 11.34 mmol) at 0° C., and the mixture was stirred at 20° C. for 1 hour. Then to the mixture was added 5-bromo-2,3-difluoro-pyridine (2 g, 10.31 mmol), and the mixture was stirred at 20° C. for another 4 hours. The mixture was quenched with sat. NH4Cl (50 mL), and the mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to afford compound 23-2 (1500 mg, 5.4743 mmol, 53% yield) as an oil.1H NMR (400 MHz, CDCl3) δH=8.00 (d, 1H), 7.58 (dd, 1H), 4.81 (q, 2H).

Synthesis of 23-3

Example 24: Synthesis of Compound 24

Synthesis of A-29

Synthesis of A-30

A mixture of A-29 (330 mg, 1.08 mmol), 3,3-difluorocyclobutanecarboxylic acid (220.39 mg, 1.62 mmol), HATU (615.72 mg, 1.62 mmol) and DIPEA (418.57 mg, 3.24 mmol) in DMF (5 mL) was stirred at 20° C. for 12 hours. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic phase was washed with water (10 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the erode product, which was purified by flash chromatography on silica gel (EtOAc in PE=20% to 50% to 80%) to afford A-30 (300 mg, 0.62 mmol) as a solid. LCMS Rt=0.81 min using Method B, MS ESI calcd. for C17H15F5N3O2[M+H]+388.1, found 388.0.

Synthesis of Compound 24

Example 25: Synthesis of Compound 25

Synthesis of A-31

Synthesis of A-32

To a solution of A-32 (200 mg, 0.58 mmol) in DMF (4 mL) was added NBS (102.52 mg, 0.58 mmol). The resulting mixture was stirred at 15° C. for 16 hours, at which point the desired product was observed by LCMS. Saturated NH4Cl aqueous (20 mL) and EtOAc (20 mL) were added to the reaction mixture, and the organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give the erode product, which was purified by silica gel (EtOAc in PE=0% to 10% to 20%) to afford A-32 (230 mg, 0.54 mmol) as a solid.1H NMR (CDCl3400 MHz) δH=8.07 (d, 2H), 7.97 (d, 1H), 7.41 (d, 2H), 7.32 (d, 1H).

Synthesis of Compound 25

Example 26: Synthesis of Compound 26

Synthesis of A-33

Synthesis of A-34

Synthesis of Compound 26

Example 27: Synthesis of Compound 27

Synthesis of A-35

To a mixture of Compound 7 (300 mg, 0.50 mmol) in carbon tetrachloride (10 mL) and 1,4-dioxane (5 mL) was added Br2.dioxane (625.95 mg, 2.52 mmol), then the mixture was stirred at 20° C. for 24 hours. Another batch of Br2.dioxane (625.95 mg, 2.52 mmol) was then added, and the mixture was stirred at 20° C. for another 24 hours. The mixture was poured into water (50 mL), then solid NaHSO3was added until the mixture turned yellow. The mixture was extracted with EtOAc (50 mL×2), and the combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the erode product, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 30%) to afford A-35 (300 mg, 0.67 mmol) as a solid.1H NMR (400 MHz, CDCl3) δH=9.13 (d, 1H), 8.29 (s, 1H), 7.99 (d, 2H), 7.38 (d, 2H). LCMS Rt=0.96 min using Method B, MS ESI calcd. for C14H7BrF6N3O [M+H]+426.0, found 425.9.

Synthesis of Compound 27

Example 28: Synthesis of Compound 28

Synthesis of A-36

To a mixture Compound 15 (290 mg, 0.66 mmol) in carbon tetrachloride (10 mL) and 1,4-dioxane (5 mL) was added Br2.dioxane (820.88 mg, 3.31 mmol). The mixture was stirred at 20° C. for 16 hours. The mixture was poured into water (50 mL), then to the mixture was added solid NaHSO3until the mixture turned to yellow. The mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the erode product, which was purified by flash chromatography by silica gel (EtOAc in PE=0 to 30%) to afford A-36 (150 mg, 0.32 mmol) as a solid. LCMS Rt=0.95 min using Method B, MS ESI calcd. for C16H11BrF6N3O2[M+H]+470.0, found 470.0.

Synthesis of Compound 28

Example 29: Synthesis of Compound 29

Synthesis of A-37

A mixture of A-22 (500 mg, 2.26 mmol), [4-(trifluoromethyl)phenyl]boronic acid (557.18 mg, 2.93 mmol), Cs2CO3(1470.4 mg, 4.51 mmol) and Pd(dppf)Cl2.CH2Cl2(368.57 mg, 0.45 mmol) in 1,4-dioxane (30 mL) and water (5 mL) was stirred at 85° C. for 16 hours. The mixture was filtered through Celite and eluted with EtOAc (20 mL×2). The filtrate was concentrated and diluted with EtOAc (30 mL), washed with water (10 mL×2) and brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=0 to 10% to 40%) to afford A-37 (600 mg, 1.52 mmol) as a solid. LCMS Rt=0.88 min using Method B, MS ESI calcd. for C14H8F6N3[M+H]+332.1, found 331.9.

Synthesis of A-38

A mixture of A-37 (550 mg, 1.39 mmol) and Br2.dioxane (1724.88 mg, 6.96 mmol) in carbon tetrachloride (10 mL) and 1,4-dioxane (5 mL) was stirred at 20° C. for 16 hours. The mixture was poured into water (100 mL), then NaHSO3(solid) was added and the mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with water (20 mL×2) and brine (20 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography by silica gel (EtOAc in PE=0 to 50%) to afford A-38 (550 mg, 1.32 mmol) as a solid.1H NMR (400 MHz, CDCl3) δH=9.16 (d, 1H), 8.35 (s, 1H), 8.09 (d, 2H), 7.79 (d, 2H). LCMS Rt=0.95 min using Method B, MS ESI calcd. for C14H7BrF6N3[M+H]+410.0, found 410.0.

Synthesis of Compound 29

Example 30: Synthesis of Compound 30

Synthesis of A-39

To a mixture of Compound 26 (160 mg, 0.45 mmol) in DMF (3 mL) was added NBS (96.46 mg, 0.54 mmol) and the mixture was stirred at 20° C. for 16 hours, at which point the desired product was observed. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by flash chromatography on silica gel (EtOAc in PE=10% to 30%) to afford A-39 (70 mg, 0.12 mmol) as an oil. LCMS Rt=0.96 min using Method B, MS ESI calcd. for C17H11BrF5N2O [M+H]+433.0, found 432.9.

Synthesis of Compound 30

Example 31: Synthesis of Compound 31

Example 32: Synthesis of Compound 32

Example 33 Synthesis of Compound 33

Example 34: Efficacy of Exemplary Compounds in the Modulation of Late Sodium Current (INaL)

Functional characterization of exemplary compounds to modulate INaL expressed by the NaV1.6 voltage-gated sodium channel was accomplished using the PatchXpress™ high throughput electrophysiology platform (Molecular Devices, Sunnyvale, Calif.). HEK-293 cells expressing recombinant human NaV1.6 (hNaV1.6) were grown in DMEM/high-glucose Dulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400 μg/mL G418. Cells were grown to 50%-80% confluency prior to harvesting. Trypsinized cells were washed, allowed to recover for 1 hour and then resuspended in extracellular recording solution at a concentration of 1×106cells/ml. The onboard liquid handling facility of the PatchXpress was used for dispensing cells and applying test compounds. Nay late currents were evoked by the application of 300 nM ATX-II. INaL was evoked by depolarizing pulses to 0 mV for 200 ms from a non-inactivating holding potential (e.g., −120 mV) at a frequency of 0.1 Hz. INaL amplitude and stability were determined by analyzing the mean current amplitude over the final 20 ms of the test pulse. Following steady state block with exemplary compounds (e.g., as described herein), a Na+free solution containing an impermeant cation (e.g., Choline or NDMG) was added to confirm the identify of the sodium current. Percent steady-state inhibition of INaL was calculated as: [(INaL_compound)/(INaL_control)]*100, where INaL_compound and INaL_control represent INaL recorded in the presence or absence of compound, respectively.

Results from this assay relating to percent inhibition of NaV1.6 at 1 μM are summarized in Table 1 below. In this table, “A” indicates inhibition of less than 30%; “B” indicates inhibition of between about 30% to about 70%; and “C” indicates inhibition of greater than 70%.

EQUIVALENTS AND SCOPE