Fast skeletal muscle myosin inhibitors

Abstract

Provided are compounds of Formula (I): Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Description

FAST SKELETAL MUSCLE MYOSIN INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit of United States Provisional Patent Application No. 63 / 554,657 filed February 16, 2024, which is hereby incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are heterocyclic compounds, pharmaceutical compositions comprising such compounds, and methods of treating various neuromuscular diseases and conditions with such compounds.BACKGROUND

[0003] Aberrant contraction of skeletal muscle is a contributor to numerous debilitating conditions such as tremor, spasticity, muscular dystrophy, cerebral palsy, and multiple sclerosis. Currently, the treatment options for these and other neuromuscular diseases are severely limited or non-existent. Available therapeutics carry a wide range of neurological and cardiovascular side effects due to significant off-target effects. Thus, there is a need for the development of compounds that selectively modulate skeletal muscle contractility through new mechanisms of action. Such compounds may have better outcomes in terms of relief of symptoms, safety, long- and short-term patient mortality, and improved therapeutic index.SUMMARY

[0004] In one aspect, provided is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X is -CH2- or -O-;R1is 5- to 6-membered heteroaryl or -C(0)NRN-(C3-CS cycloalkyl), wherein the 5- to 6- membered heteroaryl is optionally substituted with 1-4 independently selected R1Asubstituents;RNis hydrogen or Ci-Ce alkyl; each R1Ais independently Ci-Ce alkyl optionally substituted with 1-3 independently selected Ci-C6alkoxy substituents;R2is hydrogen or Ci-Ce alkyl;R3is Ci-C6alkyl, Ca-Cs cycloalkyl, Ce-Cio aryl, 4- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein each Ci-Ce alkyl, Ca-Cs cycloalkyl, Ce-Cio aryl, 4- to 10- membered heterocyclyl, 5-membered heteroaryl, and 7- to 10-membered heteroaryl of R3is optionally substituted with 1-5 independently selected R3Asubstituents, and wherein each 6- membered heteroaryl of R3is substituted with 1-4 independently selected R3Asubstituents; or R2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents; each R3Ais independently halogen, Ci-Ce alkyl, Ca-Cs cycloalkyl, Ci-Ce alkoxy, or 4- to 10- membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Aare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents; each R3Bis independently Ci-Ce alkyl, Ca-Cx cycloalkyl, Ci-Ce alkoxy, or 4- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Bare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents; andR4is hydrogen or halogen.

[0005] Provided in some embodiments are compounds selected from the group consisting of compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0006] Provided in another aspect is a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] Provided in some aspects are methods of treating a neuromuscular disease in a subject in need thereof, the method including administering to the subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb). In some embodiments, the neuromuscular disease is tremor. In some embodiments, the neuromuscular disease is spasticity. In some embodiments, the neuromuscular disease is distal arthrogryposis. In some embodiments, the neuromuscular disease is muscular dystrophy. In some embodiments, the neuromuscular disease is associated with movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, or carpal tunnel syndrome. In some embodiments, the neuromuscular disease is multiple sclerosis. In some embodiments, the neuromuscular disease is associated with stroke. In some embodiments, the neuromuscular disease is cerebral palsy. In some embodiments, the neuromuscular disease is associated with physical trauma.

[0008] Also provided are methods of inhibiting fast skeletal muscle myosin, wherein the method involves contacting the fast skeletal muscle myosin with a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb) or any variation thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb) or any variation thereof.DETAILED DESCRIPTIONDefinitions

[0009] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0010] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I) includes all subgroups of Formula (I) defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and / or described herein. References to a compound of Formula (I) include ionicforms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and / or protected forms thereof. In some embodiments, references to a compound of Formula (I) include polymorphs, solvates, co-crystals, isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula (I) include polymorphs, solvates, and / or co-crystals thereof. In some embodiments, references to a compound of Formula (I) include isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula (I) include solvates thereof. Similarly, the term “salts” includes solvates of salts of compounds.

[0011] "Alkyl" encompasses straight and branched carbon chains having the indicated number of carbon atoms, for example, from 1 to 20 carbon atoms, or 1 to 8 carbon atoms, or 1 to 6 carbon atoms. For example, Ci-6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, "propyl" includes n-propyl and isopropyl; and "butyl" includes n-butyl, sec-butyl, isobutyl and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec -butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 -methylpentyl.

[0012] "Aryl" indicates an aromatic carbocyclic ring having the indicated number of carbon atoms, for example, 6 to 12 or 6 to 10 carbon atoms. Aryl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, a l,2,3,4-tetrahydronaphthalen-5- yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-l-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a l,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via anaromatic carbon atom) is considered an aryl group, while 1 ,2,3,4- tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non- aromatic nitrogen atom) is not considered an aryl group. However, the term “aryl” does not encompass or overlap with “heteroaryl”, as defined herein, regardless of the point ofattachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl. Additional examples of aryl groups comprising an aromatic carbon ring fused to a non-aromatic ring are described below.

[0013] When a range of values is given (e.g., Ci-6 alkyl), each value within the range as well as all intervening ranges are included. For example, “Ci-6 alkyl” includes Ci, C2, C3, C4, C5, C6, C1-6, C2-6, C3-6, C4-6, C5-6, Ci-5, C2-5, C3-5, C4-5, C , C2-4, C3-4, C1-3, C2-3, and C1-2 alkyl.

[0014] "Cycloalkyl" indicates a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, for example, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Cycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as fused, bridged, spirocyclic, and caged ring groups (e.g., norbomane, bicyclo[l.l.l]pentane, bicyclo[2.2.2]octane). In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while l,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.

[0015] "Heteroaryl" indicates an aromatic ring containing the indicated number of atoms (e.g., 5 to 12, or 5 to 10 membered heteroaryl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 1. Unless otherwise indicated, heteroaryl groups may be bound to the parent structure by a carbon or nitrogen atom, as valency permits. For example, “pyridyl” includes 2-pyridyl, 3- pyridyl and 4-pyridyl groups, and “pyrrolyl” includes 1 -pyrrolyl, 2-pyrrolyl and 3-pyrrolyl groups.

[0016] In some instances, a heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2, 3 -thiadiazole, 1,2,4- thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine. In other instances, a heteroaryl group is polycyclic. Polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.

[0017] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-lH-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[l,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[l,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-lH-indazolyl, 2,3-dihydro-lH-benzo[d]imidazolyl, 2,3- dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, l,3-dihydrobenzo[c]isoxazolyl, 2,3- dihydrobenzo [d] isoxazolyl, 2,3-dihydrobenzo [d] oxazolyl, 2,3-dihydrobenzo [b] thiophenyl, l,3-dihydrobenzo[c]thiophenyl, l,3-dihydrobenzo[c]isothiazolyl, 2,3- dihydrobenzo [d] isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H- cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4Hpyrrolo[3,4- d]thiazolyl , 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-l-one, l,2-dihydroindazol-3-one, lH-benzo[d]imidazol-2(3H)-one, benzofuran- 2(3H)-one, benzofuran-3(2H)-one, isobenzofuran- l(3H)-one, benzo[c]isoxazol-3(lH)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo [b] thiophen-3(2H)-one, benzo [c] thiophen- 1 (3H)-one, benzo [c] isothiazol-3( 1 H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol- 6-one, l,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazoline-2,4(lH,3H)-dione, quinoxalin-2(lH)-one, quinoxaline-2,3(lH,4H)-dione, cinnolin-4(3H)-one, pyridin-2(lH)-one, pyrimidin-2(lH)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, lH-pyrrolo[3,2-b]pyridin-2(3H)-one, lH-pyrrolo[3,2-c]pyridin-2(3H)- one, lH-pyrrolo[2,3-c]pyridin-2(3H)-one, lH-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2- dihydropyrazolo[3,4-d]thiazol-3-one and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. Asdiscussed herein, whether each ring is considered an aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl group is determined by the atom through which the moiety is bound to the parent structure.

[0018] “Heterocyclyl" or “heterocycloalkyl” indicates a non-aromatic, fully saturated ring having the indicated number of atoms (e.g., 3 to 10, or 3 to 7, membered heterocycloalkyl) made up of one or more heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) selected from N, O and S and with the remaining ring atoms being carbon. Heterocycloalkyl groups may be monocyclic or polycyclic (e.g., bicyclic, tricyclic), fused bridged, or spiro. Examples of heterocyclo alkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. In addition, one ring of a fused polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl), provided the fused polycyclic heterocycloalkyl group is bound to the parent structure via a non-aromatic carbon or nitrogen atom. For example, a 1,2,3,4-tetrahydroquinolin-l-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclyl or heterocycloalkyl group, while l,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a heterocyclyl or heterocycloalkyl group.

[0019] Non-aromatic, monocyclic rings that contain one or more heteroatoms such asare “heterocycloalkenyl”. Such rings are not “heteroaryl”, nor are they “heterocyclyl”, nor are they “heterocycloalkyl”.

[0020] "Halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0021] Furthermore, some compounds may sometimes exist in tautomeric forms. It will be understood that although structures are shown, or named, in a particular form, the invention also includes the tautomer thereof. Also, some compounds may sometimes exist in atropoisomeric forms. It will be understood that although structures are shown in a particular form, the invention also includes the corresponding atropoisomeric forms thereof.

[0022] The compounds of the invention and disclosure may contain one or more chiral centers and therefore, such compounds (and intermediates thereof) can exist as racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like. Chiral compounds shown or named herein without a defined stereochemistry at a chiral center are intended to include any or all possible stereoisomer variations at the undefined stereocenter unless otherwise indicated. The depiction or naming of a particular stereoisomer means the indicated stereocenter has the designated stereochemistry with the understanding that minor amounts of other stereoisomers may also be present unless otherwise indicated, provided that the utility of the depicted or named compound is not eliminated by the presence of another stereoisomer.

[0023] “Protecting group” has the meaning conventionally associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site, and such that the group can readily be removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a “hydroxy protected form” contains at least one hydroxy group protected with a hydroxy protecting group. Likewise, amines and other reactive groups may similarly be protected.

[0024] The term "pharmaceutically acceptable salt" refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0025] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.

[0026] A “solvate” is formed by the interaction of a solvent and a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of compound to water, such as monohydrates, dihydrates and hemi-hydrates.

[0027] The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocyclyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from oneanother. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0028] By "optional" or "optionally" is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0029] The compounds disclosed and / or described herein can be enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be made, for example, by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds may improve the efficacy and increase the duration of action of compounds disclosed and / or described herein. Deuterium substituted compounds can be synthesized using various methods, such as those described in: Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10); Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0030] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such mediaand agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0031] The terms “patient,” “individual,” and “subject” refer to an animal, such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows and humans. In some embodiments, the patient or subject is a human, for example a human that has been or will be the object of treatment, observation or experiment. The compounds, compositions and methods described herein can be useful in both human therapy and veterinary applications.

[0032] As used herein, the term "therapeutic" refers to the ability to modulate the fast skeletal muscle myosin. As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the chemical entity with the a target or due to the interaction of the chemical entity with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.

[0033] The term "therapeutically effective amount" or "effective amount" refers to that amount of a compound disclosed and / or described herein that is sufficient to affect treatment, as defined herein, when administered to a patient in need of such treatment. A therapeutically effective amount of a compound may be an amount sufficient to treat a disease responsive to modulation of fast skeletal muscle myosin. The therapeutically effective amount will vary depending upon, for example, the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound, the dosing regimen to be followed, timing of administration, the manner of administration, all of which can readily be determined by one of ordinary skill in the art. The therapeutically effective amount may be ascertained experimentally, for exampleby assaying blood concentration of the chemical entity, or theoretically, by calculating bioavailability.

[0034] Treatment" (and related terms, such as “treat”, “treated”, "treating") includes one or more of: inhibiting a disease or disorder; slowing or arresting the development of clinical symptoms of a disease or disorder; and / or relieving a disease or disorder (i.e., causing relief from or regression of clinical symptoms). The term encompasses situations where the disease or disorder is already being experienced by a patient. The term covers both complete and partial reduction of the condition or disorder, and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, compounds described and / or disclosed herein may prevent an existing disease or disorder from worsening, assist in the management of the disease or disorder, or reduce or eliminate the disease or disorder.

[0035] "ATPase" refers to an enzyme that hydrolyzes ATP. ATPases include proteins comprising molecular motors such as the myosins.

[0036] As used herein, “selective binding” or “selectively binding” refers to preferential binding to a target protein in one type of muscle or muscle fiber as opposed to other types. For example, a compound selectively binds to fast skeletal muscle myosin if the compound preferentially binds fast skeletal muscle myosin in comparison with cardiac myosin.Compounds

[0037] Compounds and salts thereof (such as pharmaceutically acceptable salts) are detailed herein, including in the Brief Summary and in the appended claims. Also provided are the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and mixtures thereof in any ratio including racemic mixtures, salts and solvates of the compounds described herein, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.

[0038] In one aspect, provided are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:X is -CH2- or -O-;R1is 5- to 6-membered heteroaryl or -C(0)NRN-(C3-CS cycloalkyl), wherein the 5- to 6- membered heteroaryl is optionally substituted with 1-4 independently selected R1Asubstituents;RNis hydrogen or Ci-Ce alkyl; each R1Ais independently Ci-Ce alkyl optionally substituted with 1-3 independently selected Ci-C6alkoxy substituents;R2is hydrogen or Ci-Ce alkyl;R3is Ci-C6alkyl, Ca-Cs cycloalkyl, Ce-Cio aryl, 4- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein each Ci-Ce alkyl, Ca-Cs cycloalkyl, Ce-Cio aryl, 4- to 10- membered heterocyclyl, 5-membered heteroaryl, and 7- to 10-membered heteroaryl of R3is optionally substituted with 1-5 independently selected R3Asubstituents, and wherein each 6- membered heteroaryl of R3is substituted with 1-4 independently selected R3Asubstituents; or R2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents; each R3Ais independently halogen, Ci-Ce alkyl, Ca-Cs cycloalkyl, Ci-Ce alkoxy, or 4- to 10- membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Aare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents; each R3Bis independently Ci-Ce alkyl, Ca-Cx cycloalkyl, Ci-Ce alkoxy, or 4- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Bare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents; andR4is hydrogen or halogen.

[0039] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (I) is a compound of Formula (la):or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (I) is a compound of Formula (lb):or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (I) is a compound of Formula (II):or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, the compound of Formula (II) is a compound of Formula (Ila):or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments of Formula (II), or a pharmaceutically acceptable salt thereof, the compound of Formula (II) is a compound of Formula (lib):(lib), or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments of Formula (I), or a pharmaceutically acceptable salt thereof, the compound of Formula (I) is a compound of Formula (III):or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments of Formula (III), or a pharmaceutically acceptable salt thereof, the compound of Formula (III) is a compound of Formula (Illa):or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments of Formula (III), or a pharmaceutically acceptable salt thereof, the compound of Formula (III) is a compound of Formula (Illb):or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments of Formula (I), (la), or (lb), or a pharmaceutically acceptable salt thereof, X is -CH2- or -O-. In some embodiments, X is -CH2-. In some embodiments, X is -O-.

[0048] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R1is 5- to 6-membered heteroaryl optionally substituted with 1-4 independently selected R1Asubstituents. In some embodiments, R1is 5- to 6-membered heteroaryl optionally substituted with 1-2 independently selected R1Asubstituents. In some embodiments, R1is 5- to 6-membered heteroaryl optionally substituted with 1 R1Asubstituent. In some embodiments, R1is 5- membered heteroaryl optionally substituted with 1-4 independently selected R1Asubstituents. In some embodiments, R1is selected from the group consisting of oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, and pyridinyl, each of which is optionally substituted with 1-3 independently selected R1Asubstituents. In some embodiments, R1is oxadiazolyl optionally substituted with one R1Asubstituent. In some embodiments, R1is a 1,2,4-oxadiazolyl optionally substituted with one R1Asubstituent. In some embodiments, R1is a 1,2,4-oxadiazolyl substituted with one R1Asubstituent. In some embodiments, R1is selected from the group consisting of:optionally substituted with 1-4 independently selected R1Asubstituents. In some r1 iments, R1is RAZ embodN. In some embodiments,

[0049] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R1is -C(O)NRN-(C3-CS cycloalkyl). In some embodiments, R1is -C(O)NRN-cyclopropyl. In some embodiments, R1is -C(O)NRN- cyclobutyl. In some embodiments, R1is -C(O)NRN-cyclopentyl. In some embodiments, R1is -C(O)NRN-cyclohexyl. In some embodiments, R1is -C(O)NRN-cycloheptyl. In some embodiments, R1is -C(O)NRN-cyclooctyl. In some embodiments,

[0050] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, RNis hydrogen or Ci-Ce alkyl. In some embodiments, RNis hydrogen. In some embodiments, RNis Ci-Ce alkyl. In some embodiments, RNis methyl or ethyl. In some embodiments, RNis methyl. In some embodiments, RNis ethyl. In some embodiments, RNis propyl. In some embodiments, RNis butyl. In some embodiments, RNis pentyl. In some embodiments, RNis hexyl.

[0051] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, each R1Ais independently Ci-Ce alkyl optionally substituted with 1-3 independently selected Ci-Ce alkoxy substituents. In some embodiments, each R1Ais independently Ci-Ce alkyl substituted with 1-3 independently selected Ci-Ce alkoxy substituents. In some embodiments, each R1Ais methyl optionally substituted with 1-3 independently selected Ci-Ce alkoxy substituents. In some embodiments, each R1Ais ethyl optionally substituted with 1-3 independently selected Ci-Ce alkoxy substituents. In some embodiments, each R1Ais propyl optionally substituted with 1-3 independently selected Ci-Ce alkoxy substituents. In some embodiments, each R1Ais methyl substituted with one Ci-Ce alkoxy substituent. In some embodiments, each R1Ais ethylsubstituted with one Ci-Ce alkoxy substituent. In some embodiments, each R1Ais methyl substituted with one methoxy substituent. In some embodiments, each R1Ais methyl substituted with one ethoxy substituent. In some embodiments, each R1Ais ethyl substituted with one methoxy substituent. In some embodiments, each R1Ais ethyl substituted with one ethoxy substituent. In some embodiments, R1Ais-CH2OCH3. In some embodiments, each R1Ais unsubstituted Ci-Ce alkyl. In some embodiments, each R1Ais unsubstituted methyl or ethyl. In some embodiments, each R1Ais unsubstituted methyl. In some embodiments, each R1Ais unsubstituted ethyl.

[0052] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R2is hydrogen or Ci-Ce alkyl. In some embodiments, R2is hydrogen. In some embodiments, R2is Ci-Ce alkyl. In some embodiments, R2is methyl or ethyl. In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is propyl. In some embodiments, R2is butyl. In some embodiments, R2is pentyl. In some embodiments, R2is hexyl.

[0053] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is Ci-Ce alkyl, C3-C8 cycloalkyl, Ce- C10 aryl, 4- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each Ci- Ce alkyl, C3-C8 cycloalkyl, Ce-Cio aryl, 4- to 10-membered heterocyclyl, 5-membered heteroaryl, and 7- to 10-membered heteroaryl of R3is optionally substituted with 1-5 independently selected R3Asubstituents, and wherein each 6-membered heteroaryl of R3is substituted with 1-4 independently selected R3Asubstituents. In some embodiments, each Ci- Ce alkyl, C3-C8 cycloalkyl, Ce-Cio aryl, 4- to 10-membered heterocyclyl, 5-membered heteroaryl, and 7- to 10-membered heteroaryl of R3is unsubstituted. In some embodiments, each Ci-Ce alkyl, C3-C8 cycloalkyl, Ce-Cio aryl, 4- to 10-membered heterocyclyl, 5- membered heteroaryl, and 7- to 10-membered heteroaryl of R3is substituted with 1-5 independently selected R3Asubstituents.

[0054] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is Ci-Ce alkyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is Ci-Ce alkyl substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is methyl optionally substituted with 1-3 independently selected R3Asubstituents. In someembodiments, R3is ethyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is propyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is unsubstituted Ci-Ce alkyl. In some embodiments, R3is unsubstituted methyl, ethyl, or propyl. In some embodiments, R3is unsubstituted methyl. In some embodiments, R3is unsubstituted ethyl. In some embodiments, R3is unsubstituted propyl. In some embodiments, R3isor / CH3 / CH3' . In some embodiments, R3is. In some embodiments, R3is ' <~

[0055] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is Ca-Cs cycloalkyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is C3- Cs cycloalkyl substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is C3-C8 cycloalkyl substituted with 1-2 independently selected R3Asubstituents. In some embodiments, R3is C3-C8 cycloalkyl substituted with one R3Asubstituent. In some embodiments, R3is C3-C8 cycloalkyl substituted with 2 independently selected R3Asubstituents. In some embodiments, R3is cyclopropyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is cyclobutyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is cyclopentyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is cyclohexyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is cycloheptyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is cyclooctyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is unsubstituted C3-C8 cycloalkyl. In some embodiments, R3is unsubstituted cyclopropyl. In some embodiments, R3is unsubstituted cyclobutyl. In some embodiments, R3is bicyclo[l.l.l]pentanyl, which is optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is unsubstituted bicyclo [l.l.l]pentanyl. In some embodiments, R3is bicyclo [l.l.l]pentanyl substituted with 1-5 independently selected R3Asubstituents.

[0056] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is Ce-Cio aryl optionally substitutedwith 1-5 independently selected R3Asubstituents. In some embodiments, R3is Ce-Cio aryl substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is phenyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is naphthalenyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is unsubstituted Ce-Cio aryl. In some embodiments, R3is unsubstituted phenyl or naphthyl. In some embodiments, R3is unsubstituted phenyl. In some embodiments, R3is unsubstituted naphthalenyl.

[0057] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 4- to 10-membered heterocyclyl substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is unsubstituted 4- to 10-membered heterocyclyl. In some embodiments, R3is 4-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 5-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 6-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 7-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 8- membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 9-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments,optionally substituted with 1-4 R3A. In some embodiments,R3is unsubstitutedsome embodiments, R3is oxetanyl optionally substituted with 1-4 R3A. In some embodiments, R3is unsubstituted oxetanyl.

[0058] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is 5- or 7- to 10-membered heteroaryl optionally substituted with 1-5 independently selected R3Asubstituents. In someembodiments, R3is 5- or 7- to 10-membered heteroaryl substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is 5- or 7- to 10-membered heteroaryl optionally substituted with 1-4 independently selected R3Asubstituents. In some embodiments, R3is 5-membered heteroaryl optionally substituted with 1-4 independently selected R3Asubstituents. In some embodiments, R3is 7- to 10-membered heteroaryl optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3is unsubstituted 5- or 7- to 10-membered heteroaryl. In some embodiments, R3is 5- or 7- to 10-membered heteroaryl optionally substituted with 1-2 independently selected R3Asubstituents. In some embodiments, R3is 5- or 7- to 10-heteroaryl optionally substituted with one R3Asubstituent In some embodiments, R3is selected from the group consisting of oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazopyridyl, each of which is optionally substituted with 1-3 independently selected R3Asubstituents. In some embodiments, R3is isoxazolyl optionally substituted with one R3Asubstituent. In some embodiments, R3is selected from the group consisting of:substituents.

[0059] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is 6-membered heteroaryl substituted with 1-4 independently selected R3Asubstituents. In some embodiments, R3is 6-membered heteroaryl substituted with 1-3 independently selected R3Asubstituents. In some embodiments, R3is 6-membered heteroaryl substituted with 1-2 independently selected R3Asubstituents. In some embodiments, R3is 6-membered heteroaryl substituted with one R3Asubstituent. In some embodiments, R3is pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, or triazinyl, each of which is substituted with 1-4 independently selected R3Asubstituents. Insome embodiments, R3is selected from the group consisting ofindependently selected R3Asubstituents.

[0060] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3is selected from the group consistingis optionally substituted with 1-5 independently selected R3Asubstituents, and wherein eachis substituted with 1-4 independently selected R3Asubstituents. In some embodiments, R3is4 independently selected R3Asubstituents. In some embodiments, R3isoptionally substituted with 1-4 independently selected R3Asubstituents. In some embodiments, R3issubstituted with 1-4 independently selected R3Asubstituents. In someembodiments, R3issubstituted with 1-4 independently selected R3Asubstituents.In some embodiments, R3issubstituted with 1-3 independently selected R3Asubstituents. In some embodiments,substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3isoptionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3isoptionally substituted with 1-4 independently selected R3Asubstituents. In some embodiments, R3isoptionally substituted with 1-2 independently selected R3Asubstituents. In some embodiments,optionally substituted with 1-5 independently selected R3Asubstituents. In some embodiments, R3isoptionally substituted with 1-5 CH3 independently selected R3Asubstituents. In some embodiments, R3is optionally substituted with 1-3 independently selected R3Asubstituents.

[0061] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3Ais halogen, Ci-Ce alkyl, Ca-Cx cycloalkyl, Ci-Ce alkoxy, or 4- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cs cycloalkyl of R3Aare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents. In some embodiments, R3Ais halogen, Ci-Ce alkyl, or Ci-Ce alkoxy. In some embodiments, R3Ais halogen. In some embodiments, R3Ais chloro. In some embodiments, R3Ais fluoro. In some embodiments, R3Ais bromo. In some embodiments, R3Ais optionally substituted Ci-Ce alkyl. In some embodiments, R3Aisunsubstituted Ci-Ce alkyl. In some embodiments, R3Ais unsubstituted methyl. In some embodiments, R3Ais unsubstituted ethyl. In some embodiments, R3Ais unsubstituted propyl. In some embodiments, R3Ais Ci-Ce alkyl substituted with 1-5 independently selected halogen or Ci-C6alkoxy substituents. In some embodiments, R3Ais Ci-Ce alkyl substituted with 1-5 independently selected halogen substituents. In some embodiments, R3Ais Ci-Ce alkyl substituted with 1-5 independently selected Ci-Ce alkoxy substituents. In some embodiments, R3Ais optionally substituted Ca-Cx cycloalkyl. In some embodiments, R3Ais unsubstituted C3- Cs cycloalkyl. In some embodiments, R3Ais unsubstituted cyclopropyl. In some embodiments, R3Ais unsubstituted cyclobutyl. In some embodiments, R3Ais unsubstituted cyclopentyl. In some embodiments, R3Ais unsubstituted cyclohexyl. In some embodiments, R3Ais unsubstituted cycloheptyl. In some embodiments, R3Ais unsubstituted cyclooctyl. In some embodiments, R3Ais C3-C8 cycloalkyl substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents. In some embodiments, R3Ais C3-C8 cycloalkyl substituted with 1-5 independently selected halogen substituents. In some embodiments, R3Ais C3-C8 cycloalkyl substituted with 1-5 independently selected Ci-Ce alkoxy substituents. In some embodiments, R3Ais Ci-Ce alkoxy. In some embodiments, R3Ais methoxy. In some embodiments, R3Ais ethoxy. In some embodiments, R3Ais 4- to 10-membered heterocyclyl.

[0062] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to form an 8- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to form an unsubstituted 8- to 10- membered heterocyclyl. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to form a moiety selected from the group consisting, each of which is optionally substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to formoptionally substituted with 1-5selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to formoptionally substituted with1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to formoptionally substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2andR3are taken together with the nitrogen atom to which they are attached to formoptionally substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to formoptionally substituted with 1-5 independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to formoptionally substituted with 1-5independently selected R3Bsubstituents. In some embodiments, R2and R3are taken together with the nitrogen atom to which they are attached to form

[0063] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R3Bis Ci-Ce alkyl, Ca-Cx cycloalkyl, Ci- C<> alkoxy, or 4- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Bare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents. In some embodiments, R3Bis Ci-Ce alkyl. In some embodiments, R3Bis methyl. In some embodiments, R3Bis optionally substituted Ci-Ce alkyl. In some embodiments, R3Bis unsubstituted Ci-Ce alkyl. In some embodiments, R3Bis unsubstituted methyl. In some embodiments, R3Bis unsubstituted ethyl. In some embodiments, R3Bis unsubstituted propyl. In some embodiments, R3Bis Ci-Ce alkyl substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents. In some embodiments, R3Bis Ci-C6alkyl substituted with 1-5 independently selected halogen substituents. In some embodiments, R3Bis Ci-Ce alkyl substituted with 1-5 independently selected Ci-Ce alkoxy substituents. In some embodiments, R3Bis optionally substituted Ca-Cs cycloalkyl. In some embodiments, R3Bis unsubstituted Ca-Cx cycloalkyl. In some embodiments, R3Bis unsubstituted cyclopropyl. In some embodiments, R3Bis unsubstituted cyclobutyl. In some embodiments, R3Bis unsubstituted cyclopentyl. In some embodiments, R3Bis unsubstituted cyclohexyl. In some embodiments, R3Bis unsubstituted cycloheptyl. In some embodiments, R3Bis unsubstituted cyclooctyl. In some embodiments, R3Bis Ca-Cs cycloalkyl substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents. In some embodiments, R3Bis Ca-Cs cycloalkyl substituted with 1-5 independently selected halogen substituents. In some embodiments, R3Bis Ca-Cs cycloalkyl substituted with 1-5 independently selected Ci- C<> alkoxy substituents. In some embodiments, R3Bis Ci-Ce alkoxy. In some embodiments, R3Bis methoxy. In some embodiments, R3Bis ethoxy. In some embodiments, R3Bis 4- to 10- membered heterocyclyl.

[0064] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, R4is hydrogen or halogen. In some embodiments, R4is hydrogen. In some embodiments, R4is halogen. In some embodiments,R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is bromo. In some embodiments, R4is iodo.

[0065] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb) or a pharmaceutically acceptable salt thereof, R1and R1Aare taken together to form a

[0066] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb) or a pharmaceutically acceptable salt thereof, R3and R3Aare taken together to form a motif selected from the group consisting of:

[0067] In some embodiments of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or(Illb) or a pharmaceutically acceptable salt thereof, R3and R3Bare taken together to form a

[0068] In some embodiments, provided herein are compounds and pharmaceutically acceptable salts thereof described in Table 1.Table 1

[0069] In some variations, any of the compounds described herein, such as a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a variation of a pharmaceutically acceptable salt thereof, or a compound of Table 1, may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds.Hydrogen atoms may also be replaced with deuterium atoms using other methods known in the art.

[0070] Any formula given herein, such as Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereo meric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Where a compound of Table 1 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio. For example, where a compound of Table 1 has a stereocenter that is in an “S” stereochemical configuration, also provided herein is enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration. Likewise, when a compound of Table 1 has a stereocenter that is in an “R” configuration, also provided herein is enantiomer of the compound in an “S” stereochemical configuration. Also provided are mixtures of the compound with both the “S” and the “R” stereochemical configuration. Additionally, if a compound of Table 1 has two or more stereocenters, also provided are any enantiomer or diastereomer of the compound. For example, if a compound of Table 1 contains a first stereocenter and a second stereocenter with “R” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “S”stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Table 1 contains a first stereocenter and a second stereocenter with “S” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “R” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Table 1 contains a first stereocenter and a second stereocenter with “S” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “S” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Similarly, if a compound of Table 1 contains a first stereocenter and a second stereocenter with “R” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “R” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.

[0071] Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual or subject.

[0072] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0073] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual or subject. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0074] Any variation or embodiment of X, R1, RN, R1A, R2, R3, R3A, R3B, and R4provided herein can be combined with every other variation or embodiment of X, R1, RN, R1A, R2, R3, R3A, R3B, and R4, as if each combination had been individually and specifically described.

[0075] Other embodiments will be apparent to those skilled in the art from the following detailed description.

[0076] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0077] The compound names provided herein, including in Table 1, are provided by ChemDraw Professional 18.2. One of skilled in the art would understand that the compounds may be named or identified using various commonly recognized nomenclature systems and symbols. By way of example, the compounds may be named or identified with common names, systematic or non-systematic names. The nomenclature systems and symbols that are commonly recognized in the art of chemistry include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).Compositions

[0078] Also provided are compositions, such as pharmaceutical compositions, that include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, carriers, excipients, and the like. Suitable medicinal and pharmaceutical agents include those described herein. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient or adjuvant and at least one chemical entity as described herein. Examples of pharmaceuticallyacceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are compositions, such as pharmaceutical compositions that contain one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some aspects, a composition may contain a synthetic intermediate that may be used in the preparation of a compound described herein. The compositions described herein may contain any other suitable active or inactive agents.

[0080] Any of the compositions described herein may be sterile or contain components that are sterile. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure.

[0081] Also provided are packaged pharmaceutical compositions, comprising a pharmaceutical composition as described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.Methods of Use

[0082] The compounds and pharmaceutical compositions herein may be used to treat or prevent a disease or condition in an individual or subject.

[0083] Without being bound by theory, the compounds and pharmaceutical compositions disclosed herein are believed to act by directly inhibiting myosin, a mechanism that no current drug for neuromuscular diseases employs. This inhibition potentially decreases the number of independent myosin heads interacting with actin filaments, thereby reducing the amount and force of contraction. Reducing contraction of skeletal muscle can be important for the treatment of neuromuscular diseases in which over-contraction is an issue.Furthermore, compounds of the invention and disclosure display preferential binding for fast skeletal muscle myosin over cardiac myosin. Selectivity for fast skeletal muscle myosin over cardiac myosin may be important in reducing cardiac -related side-effects.

[0084] In some embodiments, provided are methods of treating or preventing a neuromuscular disease in an individual or subject, comprising administering to the individual or subject in need thereof a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided is a method of treating a neuromuscular disease in a subject in need thereof, comprising administering to the subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, provided are methods of treating or preventing a neuromuscular disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, provided are methods of treating a neuromuscular disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, provided are methods of treating an established or diagnosed neuromuscular disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, provided are methods of preventing neuromuscular disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of at least one chemical entity as described herein.

[0085] Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treatment of a neuromuscular disease in a subject. In some aspects, provided is a compound or composition as described herein for use in a method of treatment of the human or animal body by therapy. In some embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. In some embodiments,provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating or preventing neuromuscular disease. In some embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating neuromuscular disease. In some embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating an established or diagnosed neuromuscular disease. In other embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in preventing neuromuscular disease.

[0086] In some embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with tremor. In some embodiments, In some embodiments, provided herein are compounds of Formula (I),(la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with spasticity. In some embodiments, provided herein are compounds of Formula (I), (la),(lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in ameliorating a symptom associated with neuromuscular disease. In other embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in reducing the risk of a symptom associated with neuromuscular disease. In other embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with stroke, trauma, movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, or carpal tunnel syndrome. In some embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in treating tremor, spasticity, distal arthrogryposis, muscular dystrophy, multiple sclerosis, or cerebral palsy.

[0087] In other embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in modulating the fast skeletal muscle myosin, such as inhibiting the fast skeletal muscle myosin. In yet other embodiments, provided herein are compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, for use in potentiating fast skeletal muscle myosin.

[0088] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human. In some embodiments, the subject has an established or diagnosed neuromuscular disease. In some embodiments, the subject has established or diagnosed tremor. In some embodiments, the subject has established or diagnosed spasticity. In some embodiments, the subject is at risk for developing neuromuscular disease. In some embodiments, the subject has a mutation that increases risk for neuromuscular disease. In some embodiments, the subject has a mutation that increases risk for tremor. In some embodiments, the subject has a mutation that increases risk for spasticity. In some embodiments, the mutation is a sarcomeric mutation.

[0089] In some embodiments, the subject has a high risk of progressive symptoms. In some embodiments, the subject is eligible for surgical intervention or dorsal rhizotomy to treat the neuromuscular disease.

[0090] In some embodiments, the neuromuscular disease is associated with stroke, trauma, movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, or carpal tunnel syndrome. In some embodiments, the neuromuscular disease is associated with a sarcomeric mutation. In some embodiments, the neuromuscular disease is associated with a non- sarcomeric mutation. In some embodiments, the neuromuscular disease is associated with a mutation in myosin binding protein Cl (MYBPC1).

[0091] In some embodiments, provided are methods of treating tremor in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the tremor is resting tremoror action tremor. In some embodiments, the tremor is essential tremor, dystonic tremor, or orthostatic tremor. Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of tremor. In some embodiments, the tremor is resting tremor or action tremor. In some embodiments, the tremor is essential tremor, dystonic tremor, or orthostatic tremor.

[0092] In some embodiments, provided are methods of treating spasticity in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of spasticity.

[0093] In some embodiments, provided are methods of treating distal arthrogryposis in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the distal arthrogryposis is associated with a mutation in myosin binding protein Cl (MYBPC1). Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of distal arthrogryposis. In some embodiments, the distal arthrogryposis is associated with a mutation in myosin binding protein Cl (MYBPC1).

[0094] In some embodiments, provided are methods of treating muscular dystrophy in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the muscular dystrophy is Duchenne Muscular Dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, or limb girdle muscular dystrophy. Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or(Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of muscular dystrophy. In some embodiments, the the muscular dystrophy is Duchenne Muscular Dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, or limb girdle muscular dystrophy.

[0095] In some embodiments, provided are methods of treating multiple sclerosis in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of multiple sclerosis.

[0096] In some embodiments, provided are methods of treating cerebral palsy in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of cerebral palsy.

[0097] In some embodiments, provided are methods of treating a neuromuscular disease in an individual or subject in need thereof, comprising administering to the individual or subject a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some emodiments, the neuromuscular disease is associated with movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, or carpal tunnel syndrome. In some embodiments, the neuromuscular disease is associated with stroke. In some embodiments, the neuromuscular disease is associated with physical trauma. In some embodiments, the physical trauma is a brain injury or a spinal cord injury. Also provided herein is the use of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a neuromuscular disease. In some emodiments,the neuromuscular disease is associated with movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, or carpal tunnel syndrome. In some embodiments, the neuromuscular disease is associated with stroke. In some embodiments, the neuromuscular disease is associated with physical trauma. In some embodiments, the physical trauma is a brain injury or a spinal cord injury.

[0098] Also provided are methods for modulating fast skeletal muscle myosin in an individual or subject which method comprises administering to an individual or subject in need thereof a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, provided are methods of inhibiting fast skeletal muscle myosin, comprising contacting the fast skeletal muscle myosin with at least one chemical entity as described herein, such as a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided are methods of inhibiting fast skeletal muscle myosin, comprising contacting the fast skeletal muscle myosin with at least one chemical entity as described herein, such as a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. Additionally provided herein is the use of at least one chemical entity as described herein, such as a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting the fast skeletal muscle myosin of an individual or subject.

[0099] In some embodiments, the compound reduces the contractility of a muscle fiber. In some embodiments, the compound reduces the contractility of a muscle fiber by greater than 40%, such as greater than 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the compound reduced the contractility of a muscle fiber 40%-90%, such as 40%-80%, 40- 70%, 50%-90%, 50%-80% or 50%-70%. In some embodiments, the compound does not significantly alter calcium transients in the muscle fiber. In some embodiments, the compound decreases the ATPase activity in a muscle fiber. Methods of measuring contractility, ATPase activity, and calcium transients are known in the art, for example, by calcium labeling, electrophysiological recordings, and microscopic imaging. In some embodiments, the compound does not significantly inhibit or induce a cytochrome P450 (CYP) protein.

[0100] One consideration that may limit the use of muscle relaxant drugs in patients is the wide range of neurological and cardiovascular side effects associated with these drugs. Surprisingly, it has been discovered that a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, is capable of selectively modulating fast skeletal myosin relative to cardiac myosin. Accordingly, in some embodiments, provided is a method of modulating fast skeletal myosin while not modulating cardiac myosin in a subject, comprising administering a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof. In some such embodiments, provided is a method of inhibiting fast skeletal myosin while not inhibiting cardiac myosin in a subject, comprising administering a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, provided is a method of treating or preventing a neuromuscular disease in an individual or subject comprising administering a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, wherein the treatment does not result in reduction in either cardiac contractility, ejection fraction, fractional shortening, or cardiac output.

[0102] The pharmacological activity of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof, can be measured using methods known in the art. Such methods include, but are not limited to, cardiac or skeletal myofibril assays, ATPase activity assays, actin-binding assays, in vitro motility assays, tissue-based ex vivo assays, skinned fiber assays, in situ muscle force assays, in situ force measurement assays, and in vivo studies.

[0103] In some embodiments, the selectivity of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof is measured using the ratio of the IC50 of the compound for cardiac myosin, or ICso(CDMF), to the IC50 of the compound for fast skeletal myosin, or ICso(FSKMF). In some embodiments, provided is a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof wherein the ratio of the ICso(CDMF) of the compound to the ICso(FSKMF) of the compound is at least 2. In some such embodiments, the ratio is at least 5. In some suchembodiments, the ratio is at least 10. In some such embodiments, the ratio is at least 20. In some such embodiments, the ratio is at least 50. In some such embodiments, the ratio is at least 100. In some such embodiments, the ratio is at least 150. In some such embodiments, the ratio is at least 200. In some such embodiments, the ratio is at least 250. In some such embodiments, the ratio is at least 275.

[0104] In some embodiments, the selectivity of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof is measured using the ratio of the IC15 of the compound for cardiac myosin, or ICis(CDMF), to the IC15 of the compound for fast skeletal myosin, or ICis(FSKMF). In some embodiments, provided is a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or a compound of Table 1, or a pharmaceutically acceptable salt thereof wherein the ratio of the ICis(CDMF) of the compound to the ICis(FSKMF) of the compound is at least 2. In some such embodiments, the ratio is at least 5. In some such embodiments, the ratio is at least 10. In some such embodiments, the ratio is at least 20. In some such embodiments, the ratio is at least 50. In some such embodiments, the ratio is at least 100. In some such embodiments, the ratio is at least 150. In some such embodiments, the ratio is at least 200. In some such embodiments, the ratio is at least 250. In some such embodiments, the ratio is at least 275.

[0105] In some embodiments, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, may have advantages related to one or more of the following: hERG profile, toxicity profile, safety window, selectivity, off-target profile, favorable drug / drug interaction profile, PK parameters including bioavailability, clearance and half life, mechanism of action, CYP inhibition and time dependent inhibition profile, permeability and / or efflux, solubility, metabolism, unbound fraction, adequate human dose, and ease of synthesis on a large scale.Dosages

[0106] The compounds and compositions disclosed and / or described herein are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease state. While human dosage levels have yet to be optimized for the chemical entities described herein, generally, a daily dose ranges from about 0.01 to 100 mg / kg of body weight; in some embodiments, from about 0.05 to 10.0 mg / kg of body weight,and in some embodiments, from about 0.10 to 1.4 mg / kg of body weight. Thus, for administration to a 70 kg person, in some embodiments, the dosage range would be about from 0.7 to 7000 mg per day; in some embodiments, about from 3.5 to 700.0 mg per day, and in some embodiments, about from 7 to 100.0 mg per day. The amount of the chemical entity administered will be dependent, for example, on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous administration dosage is from about 5 mg to about 500 mg per day, each depending upon the compound pharmacokinetic s .

[0107] A daily dose is the total amount administered in a day. A daily dose may be, but is not limited to be, administered each day, every other day, each week, every 2 weeks, every month, or at a varied interval. In some embodiments, the daily dose is administered for a period ranging from a single day to the life of the subject. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple divided doses, such as in 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.

[0108] Administration of the compounds and compositions disclosed and / or described herein can be via any accepted mode of administration for therapeutic agents including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compound or composition disclosed and / or described herein is administered orally.

[0109] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as tablet, capsule, powder, liquid, suspension, suppository, and aerosol forms. The compounds disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pill, depot injection, osmotic pump, or transdermal (including electrotransport) patch forms) for prolonged timed, and / or pulsed administration at a predetermined rate. In some embodiments,the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

[0110] The compounds disclosed and / or described herein can be administered either alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%, or about 0.5% to 50%, by weight of a compound disclosed and / or described herein. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0111] In some embodiments, the compositions will take the form of a pill or tablet and thus the composition may contain, along with a compounds disclosed and / or described herein, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) encapsulated in a gelatin capsule.

[0112] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing or suspending etc. a compound disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of the compound contained in such parenteral compositions depends, for example, on the physical nature of the compound, the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution areemployable, and may be higher if the composition is a solid which will be subsequently diluted to another concentration. In some embodiments, the composition will comprise from about 0.2 to 2% of a compound disclosed and / or described herein in solution.

[0113] Pharmaceutical compositions of the compounds disclosed and / or described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[0114] In addition, pharmaceutical compositions can include a compound disclosed and / or described herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include those described herein.Kits

[0115] Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container may hold a pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used for preventing, treating or suppressing a condition described herein, and may also indicate directions for either in vivo or in vitro use.

[0116] In one aspect, provided herein are kits containing a compound or composition described herein and instructions for use. The kits may contain instructions for use in the treatment of a neuromuscular disease in an individual or subject in need thereof. A kit may additionally contain any materials or equipment that may be used in the administration of the compound or composition, such as vials, syringes, or IV bags. A kit may also contain sterile packaging.Combinations

[0117] The compounds and compositions described and / or disclosed herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions.

[0118] The compounds and compositions described and / or disclosed herein may be combined with one or more other therapies to treat a neuromuscular disease, such as tremor, spasticity, distal arthrogryposis, muscular dystrophy, multiple sclerosis, or cerebral palsy. In some embodiments, compounds and compositions described and / or disclosed herein may be combined with one or more other therapies to treat a condition associated with stroke, trauma, movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, or carpal tunnel syndrome. In some embodiments, the one or more therapies include therapies that retard the progression of neuromuscular diseases by selectively binding fast skeletal muscle myosin.General Synthetic Methods

[0119] Compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), and (Illb) will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. In addition, one of skill in the art will recognize that protecting groups may be used to protect certain functional groups (amino, carboxy, or side chain groups) from reaction conditions, and that such groups are removed under standard conditions when appropriate. Unless otherwise specified, the variables are as defined above in reference to Formula (I).

[0120] Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g. a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In anotherresolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

[0121] Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

[0122] General methods of preparing compounds described herein are depicted in exemplified methods below. Variable groups in the schemes provided herein are defined as for Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb), or any variation thereof. Other compounds described herein may be prepared by similar methods.

[0123] In some embodiments, compounds provided herein may be synthesized according to Schemes A, B, C, D, or E, wherein R4, R1A, RN,etc are defined as in other embodiments described herein..Scheme A. Synthesis of Intermediates 1.1-1.3Intermediates 1.1 -1.3Scheme B. Synthesis of Intermediates 2.1-2.3(S,S)-N-(p-Toluenesulfonyl)-1 ,2-diphenylethanediamine(chloro) DPPA(p-cymene)ruthenium(ll), formic acid, - ►DBU, Tol, 0 °C~r.tovernightDCM, rtIntermediates 2.1 -2.3Scheme C. Synthesis of Intermediates 3.1 and 3.2Intermediates 3.1 -3.3Scheme D. Synthesis of Intermediates 4.1 and 4.2Intermediates 4.1 -4.3Scheme E. Synthesis of Intermediates 5.1-5.6Intermediates 5.1 -5.6

[0124] Particular non-limiting examples are provided in the Examples section below.EXAMPLESSynthetic Examples

[0125] The following examples are offered to illustrate but not to limit the compositions, uses, and methods provided herein. The compounds are prepared using the general methods described above or below. Starting materials were either purchased from commercial source or prepared according to literature procedures.

[0126] The following abbreviations are used throughout the Examples: TEA (triethylamine), DCM (dichloromethane), (Boc O (di-tert-butyl decarbonate), EA (Ethyl acetate), PE (Petroleum ether, DMF (N,N-dimethylformamide), DIEA (N-ethyl- Nisopropylpropan-2-amine), DMAP [4-(dimethylamino)pyridine], HATU (1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate), HOAt (l-Hydroxy-7-azabenzotriazole), HOBt(Hydroxybenzo triazole), EDCI (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), MeOH (methanol), EtOH (ethanol), iPrOH (propan-2-ol), ACN (acetonitrile), TFA (trifluoroacetic acid), DPPA (Diphenylphosphoryl azide), DBU (l,8-Diazabicyclo(5.4.0)undec-7-ene), THF (tetrahydro furan), PPI13 (triphenylphosphane), SM (starting material), Hex (hexane), NCS (N- chlorosuccinimide), r.t. or rt (room temperature around 21 to 24 °C), DCE (dichloroethane), FA (formic acid), CHCI3 (Chloroform), BnBr (benzyl bromide), HC1 (hydrogen chloride), equiv (equivalent), and DSC (bis(2,5-dioxopyrrolidin-l-yl) carbonate), HBTU (O- (benzotriazol- 1 -yl)-N,N,N’ ,N’ -tetramethyluronium hexafluorophosphate).Example SI: Synthesis (R)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l-amine hydrochloride (Intermediate 1.1)Step 1: Preparation of tert-butyl N-[(lR)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-lH- inden-1 -yl ]carbamate

[0127] To a solution of tert-butyl N-[(17?)-5-cyano-2,3-dihydro-177-inden-l- yl]carbamate (42.2 g, 163.4 mmol, 1 equiv) in ethanol (420 mL) were added hydroxylamine hydrochloride (22.7 g, 326.7 mmol, 2.0 equiv) and triethylamine (33.1 g, 326.7 mmol, 2.0 equiv). The mixture was stirred at 50 °C for 4 h, concentrated under reduced pressure, dissolved in EA (1 L), washed with water, dried over Na2SO4, and concentrated under reduced pressure to give 54.6 g (98%) of tert-butyl A-[(17?)-5-(A-hydroxycarbamimidoyl)- 2,3-dihydro-177-inden-l-yl]carbamate as an off-white solid. LRMS (ES) m / z 292 (M+H).

[0128] Step 2: Preparation of tert-butyl N-[(lR)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3- dihydro- IH-inden- 1 -yl ]carbamate

[0129] To a solution of tert-butyl A-[(17?)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-177- inden-l-yl] carbamate (16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propanoyl propanoate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105 °C for 8 h, cooled to r.t., concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to give (17.5 g, 97%) of tert-butyl A-[(17?)-5-(5-ethyl-l,2,4- oxadiazol-3-yl)-2,3-dihydro-177-inden-l-yl]carbamate as a white solid.Step 3: Preparation of (!R)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l- amine hydrochloride

[0130] To a solution of tert-butyl A-[(lR)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro- 177-inden-l-yl]carbamate (23 g, 70 mmol, 1 equiv) in DCM was added HC1 (4 M in dioxane, 175 mL, 698 mmol, 10 equiv) at r.t. The mixture was stirred at r.t. overnight and diluted with EtOAc (500 mL). The precipitated solids were collected by filtration, washed with PE (2 x 200 mL), and dried under high vacuum to afford (lR)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3- dihydro- l / 7-indcn- 1 -amine hydrochloride (Intermediate 1.1, 16 g, 86%) as a white solid. LRMS (ES) m / z 214.2 (M+H-17).

[0131] Intermediates in the following table were prepared in a similar manner as Intermediate 1.1 using the appropriate starting materialsExample S2: Synthesis of (3S)-6-(5-methyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-l- henzofuran-3-amine hydrochloride (Intermediate 2.1)Step 1: Preparation of 3-oxo-2,3-dihydro-l-benzofuran-6-yl trifluoromethane sulfonate

[0132] To a stirred solution of 6-hydroxy-2,3-dihydro-l-benzofuran-3-one (10 g, 66.6 mmol, 1 equiv) and pyridine (16.2 mL, 199.8 mmol, 3 equiv) in DCM (250 mL) was added (trifluoromethane) sulfonyl trifluoromethanesulfonate (17.9 mL, 106.6 mmol, 1.6 equiv) dropwise at -15 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at -5 °C under nitrogen atmosphere. The reaction was quenched with water (500 ml) at -5 °C. The aqueous layer was extracted with DCM (3 x 300 mL), the combined organic layer was washed with citric acid (2 x 200mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-oxo-2,3-dihydro-l-benzofuran-6- yl trifluoromethanesulfonate (18.6 g, 99%) as a dark brown solid. LRMS (ES) m / z 283 (M+H).Step 2: Preparation of (3R)-3-hydroxy-2,3-dihydro-l-benzofuran-6-yl trifluoromethanesulfonate(S,S)-N-(p-Toluenesulfonyl)- 1 ,2-diphenylethanediamine(chloro)Tfo (p-cymene)ruthenium(ll), formic acid,DCM, rt

[0133] Triethylamine (27.49 mL, 197.739 mmol, 3 equiv) was added to a stirred solution of formic acid (8.70 mL, 230.7 mmol, 3.5 equiv) at 0 °C.The resulting mixture was stirred for 30 min at 0 °C before 3-oxo-2,3-dihydro-l-benzofuran- 6-yl trifluoromethanesulfonate (18.6 g, 65.9 mmol, 1.0 equiv) in DCM (300 mL) was added dropwise, followed by (S,S)-A -(p-tohienesulfonyl)-l-2-diphenylethanediamine(chloro)(p- cymene)ruthenium(II) (0.84 g, 1.32 mmol, 0.02 equiv). The resulting mixture was stirred for 16 h at room temperature before being quenched with water (500 mL), extracted with DCM (2 x 200 mL), the combined organic layer washed with brine (300 mL), dried over sodium sulfate, filtered, and solvent removed under reduced pressure to give (3 / ?)-3-hydroxy-2,3-dihydro- l-benzofuran-6-yl trifluoromethanesulfonate (18.4 g, 98%) as a brown oil. LRMS (ES) m / z: 267 (M+H-18).Step 3: Preparation of (3S)-3-azido-2,3-dihydro-l -benzofuran-6-yl trifluoromethanesulfonate

[0134] DPPA (16.8 mL, 77.7 mmol, 1.2 equiv) was added to a stirred solution of (3R)-3- hydroxy-2,3-dihydro-l-benzofuran-6-yl trifluoromethanesulfonate (18.4 g, 64.7 mmol, 1 equiv) in toluene (300 mL) at -5°C. DBU (14.5 mL, 97.1 mmol, 1.5 equiv) in toluene (30 mL) was added then added dropwise and the reaction allowed to return to rt. After 6 h, the reaction was diluted with EtOAc (100 mL), and water (300 mL). The reaction was then extracted with EtOAc (3 x 200 mL), the organic layers combined, washed with brine (300 mL), dried over sodium sulfate, filtered and solvent removed by rotary evaporation to give (3S)-3-azido-2,3-dihydro-l -benzo furan-6-yl trifluoromethanesulfonate (18.9 g, 94%) as a brown oil which was used in the next step directly.Step 4: Preparation of (3S)-3-amino-2,3-dihydro-l-benzofuran-6-yl trifluoromethanesulfonate

[0135] To a solution of (3S)-3-azido-2,3-dihydro-l-benzofuran-6-yl trifluoromethanesulfonate (18.9 g, 61.1 mmol, 1.0 equiv ) in THF (300 mL) and water (60.00 mL) was added PPI13 (19.2 g, 73.3 mmol, 1.2 equiv ) slowly before being heated to 50 °C for 16 h. The reaction was diluted with EtOAc (500 mL), washed with brine (3 x 200 mL) three times, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (3S)-3-amino-2,3-dihydro-l-benzofuran-6-yl trifluoromethanesulfonate (17.1 g, 99%) as a dark brown solid, which was used for next step without further purification. LRMS (ES) m / z 267 (M+H-17).Step 5: Preparation of tert-butyl N-[(3S)-6-[(trifluoromethane)sulfonyloxy]-2,3-dihydro-l - benzofuran-3 -yl ]carbamate

[0136] To a solution of (35')-3-amino-2,3-dihydro-l-benzofuran-6-yl trifluoromethanesulfonate (20.4 g, 72.0 mmol, 1.0 equiv) in DCM (300 mL) cooled to 0 °C were added TEA (14.6 g, 144.1 mmol, 2 equiv) and a solution of BOC2O (15.7 g, 72.0 mmol, 1 equiv ) in DCM (100 mL) dropwise. The mixture was stirred at r.t. overnight, washed with water (2 x 200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (DCM / PE, 4 / 6) to give tert-butyl 7V-[(35)- 6-[(trifluoromethane)sulfonyloxy]-2,3-dihydro-l-benzofuran-3-yl]carbamate (6.4 g, 23%) as a white solid. LRMS (ES) m / z: 328 (M+H-56).Step 6: Preparation of tert-butyl N-[(3S)-6-cyano-2,3-dihydro-l-benzofuran-3-yl]carbamateoxane2,

[0137] To a solution of tert-butyl A-[(3S)-6-[(trifluoromethane)sulfonyloxy]-2,3- dihydro-l-benzofuran-3-yl]carbamate (3 g, 7.83 mmol, 1 equiv ) in dioxane (50 mL) and water (25 mL) was added K4Ee(CN)6.3H2O (1.8 g, 4.261 mmol, 0.54 equiv), KOAc (1.5 g, 15.284 mmol, 1.95 equiv), X-Phos (72 mg, 0.151 mmol, 0.02 equiv) and 2nd Generation XPhos Precatalyst (60 mg, 0.076 mmol, 0.01 equiv). The mixture was stirred at 100 °C for 2 h, cooled to r.t., filtered to remove the insoluble solids, and the filter cake was washed with ethyl acetate (3 x 20 mL). The filtrate was diluted with water (100 mL), extracted with EtOAc (3 x 100 mL), the combined organic layers dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was resolved by silica gel column chromatography, eluted with CfLC McOH (10:1) to afford tert-butyl A-[(3S)-6-cyano-2,3-dihydro- l-benzofuran-3-yl]carbamate (1.9 g, 87 %) as a white solid. LRMS (ES) m / z 261 [M+H],Step 7: Preparation of tert-butyl N-[(3S)-6-(N-hydroxycarbamimidoyl)-2,3-dihydro-l- benzofuran-3 -yl ]carbamate

[0138] To a solution of tert-butyl 2V-[(3S)-6-cyano-2,3-dihydro-l-benzofuran-3- yl]carbamate (1.87 g, 7.18 mmol, 1 equiv) in EtOH (20 mL) were added NH2OH*HC1 (0.99 g, 14.2 mmol, 1.98 equiv) and triethylamine (1.82 g, 18 mmol, 2.5 equiv).The resulting mixture was stirred for overnight at 60 °C, then cooled to room temperature, diluted with CH2CI2 (100 mL), and then washed with brine(2 x 50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford tert-butyl 7V-[(35)-6-(7V- hydroxycarbamimidoyl)-2,3-dihydro-l-benzofuran-3-yl]carbamate (1.9 g, crude) as a white solid. LRMS (ES) m / z 294 (M+H).Step 8: Preparation of tert-butyl N-[(3S)-6-(5-ethyl-l, 2, 4-oxadiazol-3-yl)-2,3-dihydro-l- benzofuran-3 -yl ]carbamate

[0139] To a solution of tert-butyl (S)-(6-(Af-hydroxycarbamimidoyl)-2,3- dihydrobenzofuran-3-yl)carbamate (1.23 g, 4.193 mmol, 1.00 equiv) in dioxane (15 mL) was added (1,1 -dimethoxy ethyl)dimethylamine (2.36 g, 17.7 mmol, 4.2 equiv). The resulting mixture was stirred for overnight at 60 °C, cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (20:1) to afford tert-butyl (S)-(6-(5-methyl-l,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (1.2 g, 76%) as a brown solid. LRMS (ES) m / z 318 [M+H],Step 9: Preparation of (S)-6-(5-methyl-l,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-amine hydrochloride

[0140] To a solution of tert-butyl AX3S')-6-(5-mcthyl- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydro- l-benzofuran-3-yl] carbamate (1.20 mg, 19.7 mmol, 1.0 equiv) in DCM (6 mL )was added HCI (4 M in dioxane, 6 mL). The resulting solution was stirred for overnight at room temperature, then concentrated under reduced pressure to afford 873 mg of (3S)-6-(5-methyl- l,2,4-oxadiazol-3-yl)-2,3-dihydro-l-benzofuran-3-amine hydrochloride (Intermediate2.1) as a white solid. LRMS (ES) m / z 201 [M+H- 17],

[0141] Intermediates in the following table were prepared in a similar manner as Intermediate 2.1 using the appropriate starting materials.Example S3: Synthesis of (R)-5-(3-methyl-l,2,4-oxadiazol-5-yl)-2,3-dihydro-lH-inden-l- amine hydrochloride (Intermediate 3.1)Step 1: Preparation of (lR)-l-[[(tert-butoxy)carbonyl]amino]-2,3-dihydro-lH-indene-5- carboxylic acid

[0142] To a solution of tert-butyl A-[(17 )-5-bromo-2,3-dihydro-177-inden-l-yl]carbamate (10 g, 32.2 mmol, 1.0 equiv) in THF (300 mL) cooled to -78 °C was added MeLi (30.1 mL, 1.6 M, 1.5 equiv) dropwise. The mixture was stirred at -78 °C for 10 min and n-BuLi (25.7 mL, 2.5 M, 2.0 equiv) was added dropwise at -78 °C. The mixture was stirred for an additional hour at -78 °C and dry ice (30 g) was added. The mixture was then stirred for 30 min at -78 °C and quenched by adding saturated NH4CI solution (30 mL) at -78 °C slowly. The resulting solution was warmed to r.t. and extracted with EtOAc (2 x 400 mL). The combined organic layers were concentrated under reduced pressure and triturated with a mixture of EA, PE, and ethyl ether (1 / 20 / 10) to afford 6.2 g (70%) of (17?)- l-[[(tert- butoxy)carbonyl]amino]-2,3-dihydro-177-indene-5-carboxylic acid as a white solid.Step 2: Preparation of tert-butyl N-[(lR)-5-(3-methyl-l, 2, 4-oxadiazol-5-yl)-2,3-dihydro-lH- inden-1 -yl ]carbamate

[0143] (17?)-l-[(tert-butoxycarbonyl)amino]-2,3-dihydro-177-indene-5-carboxylic acid (2.081 g, 7.504 mmol, 1.1 equiv.) was dissolved in anhydrous DMSO (8 mL) and CDI (1.327 g, 8.186 mmol, 1.2 equiv.) was added all at once. The resulting mixture was stirred at r.t. for 30 min and then acetamide, oxime (0.505 g, 6.82 mmol, 1 equiv.) was added. The resulting mixture was stirred at r.t. o / n. powdered NaOH (0.327 g, 8.186 mmol, 1.2 equiv.) was then added and the resulting mixture was stirred at r.t. for 2 h. Water was added (100 ml) and the resulting precipitate was sonicated and then filtered. The white filtered solid was dried under high vacuum to give tert-butyl 7V-[( 17?)-5-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-2,3-dihydro- 177- inden-l-yl]carbamate (2 g, 93%).Step 3: Preparation of (R)-5-(3-methyl-l,2,4-oxadiazol-5-yl)-2,3-dihydro-lH-inden-l-amine hydrochloride

[0144] Tert-Butyl 7V-[( 17?)-5-(3-methyl- 1 ,2,4-oxadiazol-5-yl)-2,3-dihydro- 177-inden- 1- yl]carbamate (2 g, 6.342 mmol, 1 equiv) was combined with HC1 (31 mL, 4M in 1,4-dioxane) and stirred at r.t. for 1.5 h. The resulting off-white precipitate was filtered and the filtered solid washed with excess diethyl ether, collected, dried under high vacuum to give (7?)-5-(3- methyl- 1 ,2,4-oxadiazol-5 -yl)-2,3-dihydro- 177-inden- 1 -amine hydrochloride (Intermediate 3.1, 1.1 g, 69%).

[0145] Intermediate 3.2 was prepared in a similar manner as Intermediate 3.1 using the appropriate starting materials.Example S4: Synthesis of (lR)-l-amino-N-cyclobutyl-2,3-dihydro-lH-indene-5- carboxamide hydrochloride (Intermediate 4.1)Step 1: Preparation of tert-butyl N-[(lR)-5-(cyclobutylcarbamoyl)-2,3-dihydro-lH-inden-l- yl ]carbamate

[0146] AUV-Diisoproylethylamine (0.07 g, 0.094 mL, 0.742 g / mL, 0.54 mmol, 1.5 equiv.) was added to a solution of cyclobutylamine (0.026 g, 0.361 mmol, 1 equiv.), (17?)-l-[(tert- butoxycarbonyl)amino]-2,3-dihydro-177-indene-5-carboxylic acid (100 mg, 0.361 mmol, 1 equiv.), A-hydroxybenzotriazole (0.049 g, 0.361 mmol, 1 equiv.), HATU (0.137 g, 0.361 mmol, 1 equiv.) in dimethylformamide (2 mL) before the reaction was sonicated and stirred for 15 min. The mixture was diluted with sodium bicarbonate then extracted with ethyl acetate (2 x 15mL). The organic layers were combined, washed with water (1 xl5mL) and ammonium chloride (lxl5mL), then dried using sodium sulfate, filtered, and solvent evaporated by rotoary evaporation. The was dried in vacuo to provide tert-butyl A / -[( l / ?)-5- (cyclobutylcarbamoyl)-2,3-dihydro-177-inden-l-yl]carbamate (0.119 g, 0.36 mmol, Yield 99.87%) as a white foam. LCMS-ESI (POS.) m / z: 331.2 (M+H).Step 2: Preparation of (lR)-l-amino-N-cyclobutyl-2,3-dihydro-lH-indene-5-carboxamide hydrochloride

[0147] Tert-butyl W|( I / ?)-5-(cyclobutylcarbamoyl)-2,3-dihydro- 1 / 7-indcn- 1 - yl]carbamate (0.119 g, 0.36 mmol, 1 equiv.) was combined with HC1 solution (4.0 M in dioxane, 1.8 mL, 4 M, 7.2 mmol, 20 equiv.). The subsequent precipitate was filtered, washed with ether and hexane, then dried on Schlenk line overnight to provide ( l / ?)- l -amino- / V- cyclobutyl-2,3-dihydro-177-indene-5-carboxamide hydrochloride (Intermediate 4.1) as a hygroscopic sticky orange solid.

[0148] Intermediate 4.2 was prepared in a similar manner as Intermediate 4.1 using the appropriate starting materials.Example S5: Synthesis of phenyl (S)-(6-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydrobenzofuran-3-yl)carbamate (Intermediate 5.1)

[0149] To a stirred solution of (5')-6-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydrobenzofuran-3 -amine (Intermediate 2.3, 853 mg, 3.01 mmol, 1 equiv) in THF (3 mL) was added pyridine (477 mg, 6.03 mmol, 2.01 equiv) and phenyl chloroformate (706 mg, 4.51 mmol, 1.50 equiv) at room temperature. The resulting mixture was stirred for 2 h at room temperature before being concentrated under reduced pressure. The residue was resolved by reversed-phase flash chromatography (3%->100% MeOH in Water w / 0.1% TFA), to give phenyl (S)-(6-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (Intermediate 5.1, 560 mg, 51%) as a light brown solid.LRMS (ES) m / z 368 [M+H],

[0150] Intermediates 5.2-5.6 in the following table were prepared in a similar manner asIntermediate 5.1 using the appropriate starting materialsExample S6: Synthesis of (R)-l-(5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l- yl)-3-(3-methylpyridin-2-yl)urea (Compound 8)1 : triphosgene, NaHCO3,

[0151] Triphosgene (74 mg, 0.25 mmol, 0.33 equiv) in CH2CI2 (1 mL) was added rapidly to a vigorously stirring solution of (lR)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177- inden-l-amine hydrochloride (200 mg, 0.75 mmol, 1 equiv.) in CH2CI2 (3 mL) and sodium bicarbonate (3 mL) at 0 °C. After 15 min, CH2CI2 was removed, aqueous extracted with CH2CI2 (3 x 5 mL), organics combined, dried over sodium sulfate, filtered, and concentratedby rotary evaporation. The crude isocyanate was diluted with CH2Q2 (7.5 mL) to create a 0.1 M stock solution.

[0152] 3-Methylpyridin-2 -amine (41 mg, 0.376 mmol, 2 equiv) was added to a stirring solution of crude isocyanate (1.8 mL, 0.18 mmol, 1 equiv) at rt. After 12 h, solvent was removed by rotary evaporation, crude suspended in DMF (~2mL), filtered through a 0.4pm syringe filter, and (R)-l-(5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177-inden-l-yl)-3-(3- methylpyridin-2-yl)urea (Compound 8) isolated by reverse phase HPLC (5- >95% MeCN / thO w / 0.1% formic acid) as a white solid (25 mg, 38%). LCMS-ESI (POS.) m / z.364.1 (M+H)+.JH NMR (400 MHz, DMSO-d6) 8 9.87 (d, J = 7.9 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J = 4.9 Hz, 1H), 7.95 - 7.78 (m, 2H), 7.57 (d, J = 7.4 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 6.90 (dd, J = 7.3, 5.1 Hz, 1H), 5.40 (q, J = 8.2 Hz, 1H), 3.12 - 2.86 (m, 4H), 2.66 - 2.55 (m, 1H), 2.26 (s, 3H), 1.92 (p, J = 9.6 Hz, 1H), 1.35 (t, J = 7.6 Hz, 3H).

[0153] Compounds in the following table were prepared in a similar manner as Compound 8 using the appropriate starting materials and the Intermediate specified in the table.Example S7: Synthesis of (R)-N-(5-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro- !H-inden-l-yl)-6-methyl-2,3-dihydro-lH-pyrrolo[3,2-b]pyridine-l-carboxamide (Compound 64)

[0154] Triphosgene (0.053 g, 0.177 mmol, 0.33 equiv.) in DCM (1.5 mL, 0.35 M, 10Vols), was added dropwise to stirring solution of saturated NaHCOa (1.5 mL, 0.532 mmol, 1 equiv.) at 0 °C. (R)-5-(5-(Methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177-inden-l- amine hydrochloride (0.15 g, 0.532 mmol, 1 equiv.) in DCM (1.5 mL, 0.355 M, 10 Vols) wasthen added and the reaction stirred vigorously for 20 min. The organic layer was separated and the aqueous phase extracted with DCM, the combined organic layers were dried with sodium sulfate, filtered, and concentrated by rotary evaporation to give 3-|( l / ?)- l -isocyanato- 2,3-dihydro-177-inden-5-yl]-5-(methoxymethyl)-l,2,4-oxadiazole.

[0155] To a solution of 3-[(lR)-l-isocyanato-2,3-dihydro-177-inden-5-yl]-5- (methoxymethyl)-l,2,4-oxadiazole (0.149 g, 0.548 mmol, 1 equiv.) in methylene chloride (1 mL, 0.548 M, 6.722 Vols) was added a solution of 6-methyl-177,277,377-pyrrolo[3,2- b]pyridine dihydrochloride (0.114 g, 0.548 mmol, 1 equiv.) and V,V-diisopropylcthylaminc (0.248 g, 0.334 mL, 0.742 g / mL, 1.919 mmol, 3.5 equiv.) in DCM (1 mL, 0.548 M, 6.722 Vols). The mixture was stirred at rt overnight before the solvent was removed, and the reaction resolved by reverse phase HPLC (10-100% ACN in water, 0.1% formic acid) to (R)- V-(5-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177-inden-l-yl)-6-methyl-2,3- dihydro- 1 / 7-pyiTOlo|3,2-b|pyridinc- 1 -carboxamide (Compound 64) 45 mg, 20%) as a tan solid. LCMS-ESI (POS.) m / z: 406.1 (M+H).JH NMR (400 MHz, DMSO-d6) 8 7.97 - 7.87 (m, 3H), 7.81 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.39 (q, J = 8.4 Hz, 1H), 4.83 (s, 2H), 3.98 (t, J = 8.8 Hz, 2H), 3.44 (s, 3H), 3.20 - 3.02 (m, 3H), 2.91 (dt, J = 16.5, 8.7 Hz, 1H), 2.46 (dd, J = 8.0, 2.4 Hz, 1H), 2.25 (s, 3H), 2.05 (dq, J = 12.3, 9.2 Hz, 1H).

[0156] Compounds in the following table were prepared in a similar manner as Compound 64 using the appropriate starting materials and the Intermediate specified in the table.Example S8: Synthesis of (R)-N-(5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l- yl)-6-methylindoline-l -carboxamide (Compound 28)

[0157] Phosgene in CH2CI2 (1.6 mL, 2.26 mmol, 2 equiv, 15 wt% in toluene) was added rapidly to a vigorously stirring solution of (17?)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro- l / 7-indcn- 1 - amine hydrochloride (300 mg, 1.13 mmol, 1 equiv.) in CH2CI2 (6 mL) and sodium bicarb (6 mL) at 0 °C. After 15 min, CH2CI2 was removed, aqueous extracted with CH2Q2 (3 x 10 mL), organics combined, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude isocyanate was diluted with CH2Q2 (11.3 mL) to create a 0.1 M stock solution.

[0158] 6-Methyl-2,3-dihydro-177-indole (50 mg, 0.376 mmol, 2 equiv) was added to a stirring solution of crude isocyanate (1.8 mL, 0.18 mmol, 1 equiv) at rt. After 12 h, solventwas removed by rotary evaporation, crude suspended in DMF (~2mL), filtered through a 0.4pm syringe filter, and (R)-A-(5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177-inden-l- yl)-6-methylindoline-l -carboxamide (Compound 28) isolated by reverse phase HPLC (5- >95% MeCN / H2<D w / 0.1% formic acid) as a white solid (30 mg, 43%). LCMS-ESI (POS.) m / z 389.2 (M+H)+.1H NMR (400 MHz, DMSO-tfe) 8 7.84 - 7.74 (m, 2H), 7.70 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 6.93 (dd, J = 19.0, 7.9 Hz, 2H), 6.60 (d, J = 7.4 Hz, 1H), 5.30 (q, J = 8.2 Hz, 1H), 3.85 (t, J = 8.5 Hz, 2H), 3.05 - 2.89 (m, 5H), 2.82 (dt, J = 16.5, 8.8 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.19 (s, 3H), 1.96 (p, J = 9.6 Hz, 1H), 1.27 (t, J = 7.3 Hz, 3H).Example S9: Synthesis of (R)-l-(5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l- yl)-3-(6-isopropylpyridin-2-yl)urea (Compound 55)

[0159] Phosgene in CH2Q2 (0.8 mL, 1.129 mmol, 2 equiv, 15 wt%) was added rapidly to a vigorously stirring solution of (lR)-5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177-inden- 1-amine hydrochloride (150 mg, 0.56 mmol, 1 equiv.) in CH2CI2 (3 mL) and sodium bicarbonate (3 mL) at 0 °C. After 15 min, CH2Q2 was removed, aqueous extracted with CH2CI2 (3 x 5 mL), organics combined, dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude isocyanate was diluted with CH2Q2 (5.6 mL) to create a 0.1M stock solution.

[0160] 6-Isopropylpyridin-2-amine (51 mg, 0.376 mmol, 2 equiv) was added to a stirring solution of crude isocyanate (1.8 mL, 0.18 mmol, 1 equiv) at rt. After 12 h, solvent was removed by rotary evaporation, crude suspended in DMF (~2mL), filtered through a 0.4pm syringe filter, and (R)-l-(5-(5-ethyl-l,2,4-oxadiazol-3-yl)-2,3-dihydro-177-inden-l-yl)-3-(6- isopropylpyridin-2-yl)urea (Compound 55) isolated by reverse phase HPLC (5->95% MeCN / thO w / 0.1% formic acid) as a white solid (24 mg, 33%). LCMS-ESI (POS.) m / z: 392.1 (M+H).JH NMR (400 MHz, DMSO-rfc) 8 9.35 (d, J = 19.1 Hz, 2H), 7.95 - 7.80 (m,2H), 7.59 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 6.9 Hz, 1H), 5.34 (d, J = 7.9 Hz, 1H), 3.11 - 2.86 (m, 4H), 2.79 (d, J = 8.6 Hz, 1H), 2.58 (q, J = 9.8, 8.5 Hz, 1H), 1.95 - 1.78 (m, 1H), 1.35 (t, J = 7.2 Hz, 3H), 1.00 (dd, J = 13.1, 6.3 Hz, 6H).

[0161] Compounds in the following table were prepared in a similar manner asCompound 55 using the appropriate starting materials and the Intermediate specified in the tableExample S10: Synthesis of l-((lr,3S)-3-methoxycyclobutyl)-3-((S)-6-(5-(methoxymethyl)- l,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)-l-methylurea ( Compound 25)

[0162] To a stirred solution of phenyl ( .S%(6-(5-( methoxy methyl)- 1 ,2, 4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)carbamate (Intermediate 5.1, 90 mg, 0.245 mmol, 1 equiv) and (lr,3r)-3-methoxy-A-methylcyclobutan-l-amine (43 mg, 0.373 mmol, 1.52 equiv) in DMSO (2 mL) was added triethylamine (75 mg, 0.741 mmol, 3.03 equiv) at room temperature. The resulting mixture was stirred for 2 h at 70 °C. The resulting mixture was cooled to room temperature. The crude material was resolved by reverse-phase HPLC (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: Water [10 mmol / L NH4HCO3+0.1%NH3.H2<D], Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 53% B in 9 min, 53% B; Wave Length: 254 nm;) to afford l-((lr,35)-3- methoxycyclobutyl)-3-((5')-6-(5-(methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3- dihydrobenzofuran-3-yl)-l-methylurea (Compound 25, 34.3 mg, 35%) as a light brown oil. LCMS-ESI (POS.) m / z 389 (M+H)+.JH NMR (400 MHz, DMSO-rfe) 8 7.61 - 7.52 (m, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.35 (s, 1H), 6.94 (d, J = 7.6 Hz, 1H), 5.55-5.45 (m, 1H), 4.87 - 4.66 (m, 4H), 4.35 - 4.23 (m, 1H), 3.81 (t, J = 6.8 Hz, 1H), 3.42 (s, 3H), 3.12 (s, 3H), 2.75 (s, 3H), 2.32 - 2.17 (m, 2H), 2.14 - 2.01 (m, 2H).

[0163] Compounds in the following table were prepared in a similar manner as Compound 25 using the appropriate starting materials and the Intermediate specified in the table.Example Sil: Synthesis of (S)-l-(3-methoxybicyclo[l.l.l]pentan-l-yl)-3-(6-(5- (methoxymethyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)urea ( Compound 66)

[0164] To a stirred solution of 3-methoxybicyclo[l.l.l]pentan-l-amine hydrochloride(38 mg, 0.24 mmol, 1 equiv.) and triethylamine (75 mg, 0.74 mmol, 3 equiv). in THF(2 mL) was added triphosgene (30 mg, 0.097 mmol, 0.4 equiv.) at 0 °C before being warmedto rt for 1 h. To the above mixture was added (3S)-6-[5-(methoxymethyl)-l,2,4-oxadiazol-3- yl]-2,3-dihydro-l-benzofuran-3-amine hydrochloride (Intermediate 2.3, 70 mg, 0.242 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred overnight at room temperature before the resulting mixture was concentrated under reduced pressure. The residue was resolved by silica gel column chromatography, eluted with DCM / MeOH (6%) to afford crude product. The resultant mixture was resolved by reverse-phase HPLC (XBridge Prep Phenyl OBD Columnl9*250 mm, 5pm; Mobile Phase A: Water[10 mmol / L NH4HC03+0.05%NH3.H20], Mobile Phase B: ACN[1% 2mM NH3-MeOH]; Flow rate: 20 mL / min mL / min; Gradient: 45% B to 53% B in 18 min; Wave Length: 254nm / 220nm nm; RTl(min): 16.) to give (S)-l-(3-methoxybicyclo[l.l.l]pentan-l-yl)-3-(6-(5-(methoxy methyl)- 1 ,2,4-oxadiazol-3-yl)-2,3-dihydrobenzofuran-3-yl)urea (Compound 66, 3.8 mg, 4%) as a white solid. LCMS-ESI (POS.) m / z 387 (M+H)+.JH NMR (400 MHz, DMSO-tfe) 8 7.65 - 7.55 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.40 - 7.30 (m, 1H), 6.57 (s, 1H), 6.51 (d, J= 7.3 Hz, 1H), 5.46 - 5.33 (m, 1H), 4.82 (d, J= 3.0 Hz, 2H), 4.78 - 4.66 (m, 1H), 4.31 - 4.20 (m, 1H), 3.43 (s, 3H), 3.19 (s, 3H), 2.02 (s, 6H).

[0165] Compounds in the following table were prepared in a similar manner as Compound 66 using the appropriate starting materials and the Intermediate specified in the table.Biological Example B-lCardiac Myofibril Assays (CDMF)

[0166] To evaluate the effect of compounds on the ATPase activity of full-length cardiac myosin in the context of the native sarcomere, skinned myofibril assays were performed. Bovine cardiac myofibrils were obtained by homogenizing bovine cardiac left ventricular tissue in the presence of a detergent such as triton X-100. Such treatment removes membranes and a majority of the soluble cytoplasmic proteins but leaves intact the cardiac sarcomeric acto-myosin apparatus. Myofibril preparations retain the ability to hydrolyze ATP in an Ca2+regulated manner. ATPase activities of such myofibril preparations in the presence and absence of compounds were assayed at Ca2+concentrations activating to a defined fraction of the maximal rate (i.e., 25%, 75%). Small molecule agents were assessed for their ability to inhibit the steady-state ATPase activity of bovine cardiac myofibrils using pyruvate kinase and lactate dehydrogenase (PK / LDH)-coupled enzyme system. This assay regenerates myosin-produced ADP into ATP by oxidizing NADH, producing an absorbance change at 340 nm. Prior to testing small molecule agents, the bovine cardiac myofibrils were assessed for their calcium responsiveness and the calcium concentration that achieves either a 50% (pCaso) or 75% (pCa?s) activation of the myofibril system was chosen as the final condition for assessing the inhibitory activity of the small molecule agents. All enzymatic activity was measured in a buffered solution containing 12 mM PIPES (piperazine-N,N'- bis(2-ethanesulfonic acid), 2 mM magnesium chloride at pH 6.8 (PM 12 buffer). Final assay conditions were 1 mg / mL of bovine cardiac myofibrils, 4 U / mL pyruvate kinase, 6 U / mL lactate dehydrogenase, 50 pM ATP, 0.1 mg / mL BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT, 0.5 mM NADH, 1.5 mM PEP, 0.6 mM EGTA, and an amount of CaCh sufficient to achieve either 50% or 75% activation of the myofibril ATPase activity.Results for compounds tested are provided in Table 2. Compounds tested were prepared in accordance with the synthetic procedures described herein.Preparation and Assay of Fast Skeletal Myofibrils (FSKMF)

[0167] Rabbit skeletal myofibrils were prepared based upon the method of Herrmann et al. (Biochem. 32(28):7255-7263(1993). Myofibrils were prepared from rabbit psoas muscle purchased from Pel-Freez Biologicals (Arkansas) within 2 days of ordering, stored on ice. Minced muscle was homogenized in 10 volumes of ice-cold “standard” buffer (50 mM Tris, pH 7.4, 0.1 M KO Ac, 5 mM KC1, 2 mM dithiothreitol (DTT), 0.2 mM phenylmethylsulfonyl fluoride (PMSF), 10 pM leupeptin, 5 p M pepstatin, and 0.5 mM sodium azide) containing 5 mM ethylenediaminetetraacetic acid (EDTA) and 0.5% Triton X-100 using an Omni-Macro homogenizer. Myofibrils were recovered by low speed centrifugation (3000 rpm for 10 minutes) and washed 2 times in the Triton X-100 containing buffer to ensure removal of cellular membrane. Following the Triton washes, myofibrils were washed 3 times in “standard” buffer containing 2 mM magnesium acetate. A final wash in assay buffer (12 mM piperazine- l,4-bis(2-ethanesulfonic acid) (PIPES), pH 6.8, 60 mM KC1, 1 mM DTT) was performed and brought to 10% sucrose for flash freezing in liquid nitrogen and storage at - 80°C.

[0168] Inhibitors of FSKMF were identified by measuring the enzymatic activity of muscle myofibril preparations using the proprietary PUMA (trademark) (see, e.g., U.S. Patent Nos. 6,410,254, 6,743,599, 7,202,051, and 7,378,254) assay system. Myofibril preparations consisted of rabbit skeletal muscle (approximately 90% fast fibers) that had been mechanically homogenized and washed with a detergent (Triton X-100) to remove cellular membranes. This preparation retained all of the sarcomeric components in a native conformation and the enzymatic activity was still regulated by calcium. Compounds were tested using a myofibril suspension and a level of calcium sufficient to increase enzymatic activity of the myofibrils to 25% of their maximal rate (termed pCa25). Enzymatic activity was tracked via a pyruvate kinase and lactate dehydrogenase-coupled enzyme system. This assay regenerates myosin-produced ADP into ATP by oxidizing NADH, producing an absorbance change at 340 nm. The buffering system was 12 mM PIPES, 2 mM MgCh, 1 mM DTT at pH 6.8 (PM12 buffer). Results for compounds tested are provided in Table 2.Compounds tested were prepared in accordance with the synthetic procedures described herein.Table 2Biological Example B-2Lack of Inhibition of FSKMF by Comparator Compounds

[0169] As shown in Biological Example B-l, compounds of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Illa), or (Illb) preferentially inhibit FSKMF over CDMF. This is an unexpected effect with many potential applications in diseases associated with aberrant muscle contraction. To demonstrate the surprising nature of these results, the following comparative examples are provided. The comparator compounds of Table 3 are selective inhibitors of CDMF, and when tested in the FSKMF assay described in Biological Example B-3, showed no activity or low activity.Table 3

[0170] While the foregoing written description of the compounds, uses, and methods described herein enables one of ordinary skill to make and use the compounds, uses, and methods described herein, those of ordinary skill will understand and appreciate the existenceof variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The compounds, uses, and methods provided herein should therefore not be limited by the above-described embodiments, methods, or examples, but rather encompasses all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein.

[0171] All references disclosed herein are incorporated by reference in their entirety.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein:X is -CH2- or -O-;R1is 5- to 6-membered heteroaryl or -C(0)NRN-(C3-CS cycloalkyl), wherein the 5- to 6- membered heteroaryl is optionally substituted with 1-4 independently selected R1Asubstituents;RNis hydrogen or Ci-Ce alkyl; each R1Ais independently Ci-Ce alkyl optionally substituted with 1-3 independently selected Ci-C6alkoxy substituents;R2is hydrogen or Ci-Ce alkyl;R3is Ci-C6alkyl, C3-C8 cycloalkyl, Ce-Cio aryl, 4- to 10-membered heterocyclyl, or 5- to 10- membered heteroaryl, wherein each Ci-Ce alkyl, Ca-Cs cycloalkyl, Ce-Cio aryl, 4- to 10- membered heterocyclyl, 5-membered heteroaryl, and 7- to 10-membered heteroaryl of R3is optionally substituted with 1-5 independently selected R3Asubstituents, and wherein each 6- membered heteroaryl of R3is substituted with 1-4 independently selected R3Asubstituents; or R2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents;each R3Ais independently halogen, Ci-Ce alkyl, Ca-Cs cycloalkyl, Ci-Ce alkoxy, or 4- to 10- membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Aare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents; each R3Bis independently Ci-Ce alkyl, Ca-Cx cycloalkyl, Ci-Ce alkoxy, or 4- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl and Ca-Cx cycloalkyl of R3Bare each optionally substituted with 1-5 independently selected halogen or Ci-Ce alkoxy substituents; andR4is hydrogen or halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula (la):

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is 5- to 6-membered heteroaryl optionally substituted with 1-4 independently selected R1Asubstituents.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is 5-membered heteroaryl optionally substituted with 1-4 independently selected R1Asubstituents.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R1is oxadiazolyl optionally substituted with 1 R1Asubstituent.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R1is 1,2,4-oxadiazolyl optionally substituted with 1 R1Asubstituent.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R1Ais unsubstituted Ci-Ce alkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R1Ais unsubstituted methyl or ethyl.

13. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R1Ais Ci-Ce alkyl substituted with 1-3 independently selected Ci-Ce alkoxy substituents.

14. The compound of any one of claims 1-10 or 13, or a pharmaceutically acceptable salt thereof, wherein R1Ais -CH2OCH3.

15. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is -C(O)NRN-(C3-CS cycloalkyl).

16. The compound of any one of claims 1-4 or 15, or a pharmaceutically acceptable salt thereof, wherein R1is -C(O)NRN-cyclobutyl.

17. The compound of any one of claims 1-4, 15, or 16, or a pharmaceutically acceptable salt thereof, wherein RNis hydrogen.

18. The compound of any one of claims 1-4, 15, or 16, or a pharmaceutically acceptable salt thereof, wherein RNis methyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R2is Ci-Ce alkyl.

21. The compound of any one of claims 1-18 or 20, or a pharmaceutically acceptable salt thereof, wherein R2is methyl or ethyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is Ce-Cio aryl optionally substituted with 1-5 independently selected R3Asubstituents.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is Ci-Ce alkyl optionally substituted with 1-5 independently selected R3Asubstituents.

24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is Ca-Cx cycloalkyl optionally substituted with 1-5 independently selected R3Asubstituents.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Asubstituents.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R3is substituted with 1-5 independently selected R3Asubstituents.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R3is unsubstituted.

28. The compound of any one of claims 1-21 or 24, or a pharmaceutically acceptable salt thereof, wherein R3is cyclobutyl optionally substituted with 1-5 independently selected R3Asubstituents.

29. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is 5-membered heteroaryl optionally substituted with 1-4 independently selected R3Asubstituents.

30. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is 7- to 10-membered heteroaryl optionally substituted with 1-5 independently selected R3Asubstituents.

31. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is 6-membered heteroaryl substituted with 1-4 independently selected R3Asubstituents.

32. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of:is substituted with 1-4 independently selected R3Asubstituents.

33. The compound of any one of claims 1-26 or 28-32, or a pharmaceutically acceptable salt thereof, wherein R3Ais halogen, Ci-Ce alkyl, or Ci-Ce alkoxy.

34. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R2and R3are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents.

35. The compound of any one of claims 1-18 or 34, or a pharmaceutically acceptable salt thereof, wherein R2and R3are taken together with the nitrogen atom to which they are attached to form an 8- to 10-membered heterocyclyl optionally substituted with 1-5 independently selected R3Bsubstituents.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein the 8- to 10-membered heterocyclyl is unsubstituted.

37. The compound of any one of claims 1-18 or 34-36, or a pharmaceutically acceptable salt thereof, wherein R2and R3are taken together with the nitrogen atom to which they areattached to form a moiety selected from the group consisting of:each of which is optionally substituted with 1-5 independently selected R3Bsubstituents.

38. The compound of any one of claims 1-18, 34, 35 or 37, or a pharmaceutically acceptable salt thereof, wherein R2and R3are taken together with the nitrogen atom to which they are attached to form39. The compound of any one of claims 1-18, 34, 35, 37, or 38, or a pharmaceutically acceptable salt thereof, wherein R3Bis Ci-Ce alkyl.

40. The compound of any one of claims 1-18, 34, 35, or 37-39, or a pharmaceutically acceptable salt thereof, wherein R3Bis methyl.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein the ratio of the ICis(CDMF) of the compound to the ICis(FSKMF) of the compound is at least 5.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein the ratio of the ICis(CDMF) of the compound to the ICis(FSKMF) of the compound is at least 10.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein the ratio of the ICis(CDMF) of the compound to the ICis(FSKMF) of the compound is at least 50.

45. A compound selected from the group consisting of the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound according to any one of claims 1-45, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

47. A method of treating a neuromuscular disease in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

48. The method of claim 47, wherein the neuromuscular disease is tremor, spasticity, distal arthrogryposis, muscular dystrophy, multiple sclerosis, or cerebral palsy; or wherein the neuromuscular disease is associated with movement, gait, hypertonia, hypercontractility, muscle stiffness, spasms, involuntary contractions, tendinitis, carpal tunnel syndrome, stroke, physical trauma, brain injury, or spinal cord injury.

49. The method of claim 47, wherein the neuromuscular disease is resting tremor, action tremor, essential tremor, dystonic tremor, orthostatic tremor, distal arthrogryposis associated with a mutation in myosin binding protein Cl (MYBPC1), Duchenne Muscular Dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, or limb girdle muscular dystrophy.

50. A method of inhibiting fast skeletal muscle myosin, comprising contacting the fast skeletal muscle myosin with a compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 46.

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