Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Polycyclic cycloalkyl radicals include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like.
• haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like.
• the alkyl part of the haloalkyl radical is optionally further substituted as described herein.
• heterocycle refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms.
• Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
• a bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits.
• an aromatic ring e.g., pyridyl
• heterocycloalkyl refers to a saturated ring with carbon atoms and at least one heteroatom.
• exemplary heteroatoms include N, O, Si, P, B, and S atoms.
• Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings.
• the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
• One or more nitrogen atoms, if present, are optionally quaternized.
• heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
• heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thi
• heterocycloalkenyl refers to an unsaturated ring with carbon atoms and at least one heteroatom and there is at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, a heterocycloalkenyl comprises five to seven ring atoms.
• the heterocycloalkenyl may be attached to the rest of the molecule by a single bond.
• monocyclic cycloalkenyls include, e.g., pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydro
• substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
• substituted is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
• 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, phosphoric acid, and the like.
• compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treatment via administration of a compound described herein does not require the involvement of a medical professional.
• Compounds [0055] The following is a discussion of compounds and salts thereof that may be used in the methods of the disclosure. In certain embodiments, the compounds and salts are described in Formulas (IIA), (IIB), or (IIC).
• R 11 is selected from: hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -SR 16 , - N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , - N(R 16 )C(O)N(R 16 ) 2 , -OC(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 ,
• R 11 is selected from phenyl, 3-pyridyl, and cyclopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OMe, -OCF 3 , -OCHF 2 , and -CF 3 .
• R 11 is selected from [0065] In certain embodiments, for a compound or salt of Formula (IIA), R 11 is selected from [0066] In certain embodiments, for a compound or salt of Formula (IIA), R 12 is cyclobutyl optionally substituted with one or more substituents independently selected from: halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R 16 ) 2 , -N(R 16 )C(O)R 16 , -C(O)OR 16 , - OC(O)R 16 , -NO 2 , and -CN; and C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)N(R
• R 16 is hydrogen.
• R 11 is selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 15 ; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -NO 2 , -CN, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle; wherein C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are each optionally substituted with one or more R 15 ; R 12 is selected from cyclobutyl
• R 21 is selected from optionally substituted C 1-6 alkyl, optionally substituted carbocycle, and optionally substituted heteroaryl.
• R 21 is selected from optionally substituted C 1-3 alkyl, optionally substituted C 3-6 carbocycle, and optionally substituted 5- or 6-membered heteroaryl; wherein substituents on C 1-3 alkyl are selected from halogen, - OR 26 , -N(R 26 ) 2 , -C(O)R 26 , -C(O)N(R 26 ) 2 , -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO 2 , and - CN, and substituents on C 3-6 carbocycleand 5- or 6-membered heteroaryl are selected from halogen
• R 21 is selected from C 1 - 3 alkyl, substituted phenyl, C 5 carbocycle, and optionally substituted pyridyl; wherein substituents on phenyl and pyridyl are selected from halogen, -OH, -NH 2 , -NO 2 , and -CN.
• R 21 is selected from- C
• R 22 is selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 26 , -N(R 26 ) 2 , -C(O)R 26 , -C(O)N(R 26 ) 2 , -N(R 26 )C(O) R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO 2 , -CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 25 ; and C 3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 26 , -N(R 26 )
• R 22 is selected from: C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, and phenyl optionally substituted with one or more R 25 ; and C 3 - 6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10- membered heterocycle, wherein C 1-6 alkyl, C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 25 .
• R 22 is selected from: C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, and phenyl optionally substituted with one or more substituents independently selected from halogen; and C 3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10- membered heterocycle.
• R 22 is selected from C 1 - 3 alkyl and C 3-6 carbocycle optionally substituted with one or more halogen.
• R 22 is selected from -CH 2 CH 3 .
• R 23 is selected from hydrogen, -OMe,- OH, -NH 2 , -COOH, -NO 2 , and -CN.
• R 23 is hydrogen.
• a compound represented by Formula (IIB): (IIB); or a salt thereof wherein: X 21 and X 22 are independently selected from N and C(R 23 ), wherein at least one of X 21 and X 22 is N; X 23 is selected from S and O; R 21 is selected from optionally substituted C 1-3 alkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl; wherein substituents on C 1-3 alkyl are selected from halogen, -OR 26 , -N(R 26 ) 2 , -C(O)R 26 , -C(O)N(R 26 ) 2 , -N(R 26 )C(O)R 26 , -C(O)OR 26 , - OC(O)R 26 , -NO 2 , and -CN, and substituents on phenyl and 5- or 6-membered heteroaryl are selected from
• R 31 is selected from: hydrogen; C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 36 , -SR 36 , - N(R 36 ) 2 , -C(O)R 36 , -C(O)N(R 36 ) 2 , -N(R 36 )C(O)R 36 , -C(O)OR 36 , -OC(O)R 36 , - N(R 36 )C(O)N(R 36 ) 2 , -OC(O)N(R 36 ) 2 , -N(R 36 )C(O)OR 36 , -S(O)R 36 , -S(O) 2 R 36 , -S(O) 2 R 36 , -S(O) 2 R 36 , -S(O)R 36 , -S(O) 2 R 36 ,
• R 31 is selected from C 1- 3 alkyl, substituted phenyl, and optionally substituted 6-membered heteroaryl; wherein substituents on phenyl and 6-membered heteroaryl are selected from halogen, -OR 36 , -N(R 36 ) 2 , - NO 2 , and -CN.
• R 31 is selected from C 1 - 3 alkyl, substituted phenyl, and optionally substituted pyridyl; wherein substituents on phenyl and pyridyl are selected from halogen, -OH, -NH 2 , -NO 2 , and -CN.
• R 32 is selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 36 , -N(R 36 ) 2 , -C(O)R 36 , -C(O)N(R 36 ) 2 , -N(R 36 )C(O) R 36 , -C(O)OR 36 , -OC(O)R 36 , -NO 2 , -CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 35 ; and C 3 - 6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, -OR 36 , -N(R 36 ) 2 , -C(O)R 36 , -C(O)N(R 36 ) 2
• R 32 is selected from: C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, and phenyl optionally substituted with one or more R 35 ; and C 3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10- membered heterocycle, wherein C 1-6 alkyl, C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 35 .
• R 32 is C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, and phenyl optionally substituted with one or more substituents independently selected from halogen [0118] In certain embodiments, for a compound or salt of Formula (IIC), R 32 is selected from C 1 - 3 alkyl. [0119] In certain embodiments, for a compound or salt of Formula (IIC), R 32 is selected from - CH 2 CH 3 .
• a compound or salt of Formula (III) is selected from and a salt of any one thereof.
• Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.
• a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers.
• the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
• isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
• Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
• the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
• the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
• Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S.
• Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
• Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein.
• the compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt.
• compounds that are inherently charged can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
• an appropriate counterion e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
• the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
• the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof.
• Stereoisomers may also be obtained by stereoselective synthesis.
• the methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs).
• the compounds described herein may be in the form of pharmaceutically acceptable salts.
• active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
• the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
• compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
• prodrug is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure.
• One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
• the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal.
• esters or carbonates are preferred prodrugs of the present disclosure.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims.
• some of the herein-described compounds may be a prodrug for another derivative or active compound.
• Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug.
• the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
• Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.
• the design of a prodrug increases the lipophilicity of the pharmaceutical agent.
• the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed.
• the compounds may be synthesized using conventional techniques.
• these compounds are conveniently synthesized from readily available starting materials.
• Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).
• Methods of administration of a compound or salt of Formula (I), (IIA), (IIB), (IIC), or (III) discussed herein may be used for inhibiting muscle myosin II.
• the compounds and salts thereof may be used to treat activity-induced muscle damage.
• the compounds may be used to treat neuromuscular conditions and movement disorders (such as spasticity).
• Methods of administration of a compound or salt of Formula (I), (IIA), (IIB), (IIC), or (III) discussed herein may be used for the treatment of neuromuscular conditions and movement disorders.
• neuromuscular conditions include but are not limited to Duchenne Muscular Dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophies, tendinitis and carpal tunnel syndrome.
• movement disorders include but are not limited to muscle spasticity disorders, spasticity associated with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or cerebral palsy, or injury or a traumatic event such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis.
• neuromuscular conditions and movement disorders are selected from muscular dystrophies and myopathies.
• muscular dystrophies are diseases that cause progressive weakness and loss of muscle mass where abnormal genes (mutations) interfere with the production of proteins needed to form healthy muscle.
• muscular dystrophies are selected from Becker muscular dystrophy (BMD), Congenital muscular dystrophies (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), Facioscapulohumeral muscular dystrophy (FSHD), Limb-girdle muscular dystrophies (LGMD), Myotonic dystrophy (DM), and Oculopharyngeal muscular dystrophy (OPMD).
• BMD Becker muscular dystrophy
• CMD Congenital muscular dystrophies
• DMD Duchenne muscular dystrophy
• EDMD Emery-Dreifuss muscular dystrophy
• FSHD Facioscapulohumeral muscular dystrophy
• LGMD Limb-girdle muscular dystrophies
• DM Myotonic dystrophy
• Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy
• Congenital muscular dystrophies is selected from Bethlem CMD, Fukuyama CMD, Muscle-eye
• myopathies are diseases of muscle that are not caused by nerve disorders. Myopathies cause the muscles to become weak or shrunken (atrophied). In some embodiments, myopathies are selected from congenital myopathies, distal myopathies, endocrine myopathies, inflammatory myopathies, metabolic myopathies, myofibrillar myopathies (MFM), scapuloperoneal myopathy, and cardiomyopathies.
• congenital myopathies are selected from cap myopathies, centronuclear myopathies, congenital myopathies with fiber type disproportion, core myopathies, central core disease, multiminicore myopathies, myosin storage myopathies, myotubular myopathy, and nemaline myopathies.
• distal myopathies are selected from, gne myopathy/Nonaka myopathy/hereditary inclusion-body myopathy (HIBM), laing distal myopathy, Markesbery-Griggs late-onset distal myopathy, Miyoshi myopathy, Udd myopathy/tibial muscular dystrophy, VCP myopathy / IBMPFD, vocal cord and pharyngeal distal myopathy, and welander distal myopathy.
• endocrine myopathies are selected from, hyperthyroid myopathy, and hypothyroid myopathy.
• inflammatory myopathies are selected from, dermatomyositis, inclusion- body myositis, and polymyositis.
• metabolic myopathies are selected from, von Gierke’s disease, Anderson disease, Fanconi-Bickel syndrome, aldolase A deficiency, acid maltase deficiency (Pompe disease), carnitine deficiency, carnitine palmitoyltransferase deficiency, debrancher enzyme deficiency (Cori disease, Forbes disease), lactate dehydrogenase deficiency, myoadenylate deaminase deficiency, phosphofructokinase deficiency (Tarui disease), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency (Her’s disease), and phosphorylase deficiency (McArdle disease).
• cardiomyopathies are selected from intrinsic cardiomyopathies and extrinsic cardiomyopathies.
• intrinsic cardiomyopathies are selected from genetic myopathies and acquired myopathies.
• genetic myopathies are selected from Hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC), LV non-compaction, ion channelopathies, dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM).
• acquired myopathies are selected from stress cardiomyopathy, myocarditis, eosinophilic myocarditis, and ischemic cardiomyopathy.
• extrinsic cardiomyopathies are selected from metabolic cardiomyopathies, endomyocardial cardiomyopathies, endocrine cardiomyopathies, and cardiofacial cardiomyopathies.
• metabolic cardiomyopathies are selected from Fabry's disease and hemochromatosis.
• endomyocardial cardiomyopathies are selected from endomyocardial fibrosis and Hypereosinophilic syndrome.
• endocrine cardiomyopathies are selected from diabetes mellitus, hyperthyroidism, and acromegaly.
• the Cardiofacial cardiomyopathy is Noonan syndrome.
• a ring is an unsubstituted 5-membered heteroaromatic ring.
• a ring is a 5-membered heteroaromatic ring substituted by one or more substituents independently selected from R 1 .
• a ring has two or more heteroatoms.
• a ring has three heteroatoms.
• a ring is selected from thiophene, oxadiazole, oxazole, thiadiazole, triazole, pyrazole, and thiazole, each of which is optionally substituted with one or more substituents independently selected from R 1 .
• a ring is selected from each of which is optionally substituted with one or more substituents independently selected from R 1 .
• a ring is selected from each of which is optionally substituted with one or more substituents independently selected from R 1 .
• a ring is selected from and [0160] In certain embodiments, for a compound or salt of Formula (I), A ring is selected from [0161] In certain embodiments, for a compound or salt of Formula (I), X is N. In certain embodiments, for a compound or salt of Formula (I), X is CH.
• R 1 is selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 5 ; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -CN, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle; wherein C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are each optionally substituted with one or more R 5 .
• R 1 is selected from: C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 6 , and -CN; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , - and C 1-6 alkyl, optionally substituted with one or more R 5 .
• R 1 is selected from: C 1-6 alkyl; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , - and C 1-6 alkyl optionally substituted with one or more R 5 .
• R 1 is selected from C 1-6 alkyl optionally substituted with halogen or -OR 6 ; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , - and C 1-6 alkyl optionally substituted with one or more R 5 .
• R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen and -OR 6 .
• R 1 is selected from methyl optionally substituted with one or more substituents independently selected from halogen, -OH, - OC 6 H 5 , and -OCH 3 .
• R 1 is selected from pyridine, C3-5 cycloalkyl, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CH 3 , -CN, -OH, -OCH 3 , -OCF 3 , -CF 3 , -CHF 2 , -OCHF 2 , and cyclopropyl.
• R 1 is selected from methyl,
• R 2 is selected from C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 6 , -SR 6 , -N(R 6 ) 2 , CN, C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein C 1-6 alkyl, C 3-10 carbocycle, and 3- to 10-membered heterocycle are each optionally substituted with one or more R 5 .
• R 2 is selected from phenyl, pyridyl, pyrimidyl, thiazole, oxadiazole, and oxazole, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -SR 6 , - N(R 6 ) 2 , CN, and C 1-6 alkyl.
• the compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be administered in an amount less than the amount needed to reduce skeletal muscle contraction by 50% relative to pre- treatment skeletal muscle contraction capacity of the subject.
• the compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be administered in an amount that reduces skeletal muscle contraction by 5% to 45% relative to pre-treatment skeletal muscle contraction capacity of said subject.
• the level of inflammatory markers may be modulated by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 85%, about 35% to about 90%, about
• Involuntary muscle contractions may be reduced by 20% to 90% relative to involuntary muscle contractions prior to the administration of the inhibitor. In some cases, involuntary muscle contractions may be reduced by at least about 20% relative to pre-treatment involuntary muscle contractions. In some cases, involuntary muscle contractions may be reduced by at most about 90% relative to pre-treatment involuntary muscle contractions.
• Inhibition of skeletal muscle contraction may not inhibit smooth muscle contraction. In some cases, the inhibition of skeletal muscle contraction may not appreciably inhibit smooth muscle contraction. As used herein with regard to smooth muscle contraction, the phrase not appreciably refers to the smooth muscle contraction reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5% or even less than 0.1% relative to the smooth muscle contraction prior to the administration of the inhibitor. Smooth muscle contraction in a subject may be evaluated by measuring a subject’s blood pressure. [0230] Neuromuscular coupling in a subject may be measured prior to and following the administration of a compound or salt of Formula (I), (IIA), (IIB), or (IIC).
• Inhibition of skeletal muscle contraction may not impair nerve conduction, neurotransmitter release or electrical depolarization of skeletal muscle in a subject.
• the inhibition of skeletal muscle contraction may not appreciably impair neuromuscular coupling in a subject.
• the phrase not appreciably refers to a level of neuromuscular coupling in the subject reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5% or less than 0.1% relative to the level of neuromuscular coupling in the subject prior to the administration of the inhibitor.
• Neuromuscular coupling in a subject may be evaluated by measuring nerve induced electrical depolarization of skeletal muscle by the recording of electrical activity produced by skeletal muscles after electrical or voluntary stimulation with electromyography (EMG) using surface or needle electrodes .
• EMG electromyography
• the method of treating a neuromuscular condition or movement disorder can comprise administering a compound or salt of Formula (I), (IIA), (IIB), or (IIC) wherein the compound or salt of Formula (I), (IIA), (IIB), or (IIC) may inhibit myosin ATPase activity, native skeletal muscle myofibril ATPase (calcium regulated) or a reconstituted S1 with actin, tropomyosin and troponin.
• In vitro assays may be used to test the effect of the test compound or inhibitor on the myosin ATPase activity.
• Test compounds can be screened for assessing their inhibitory activity of muscle contraction. Inhibitory activity can be measured using an absorbance assay to determine actin-activated ATPase activity.
• Rabbit muscle myosin sub- fragment 1 (S1) can be mixed with polymerized actin and distributed into wells of assay plates without nucleotides. Test compounds can then be added into the wells with a pin array. The reaction can be initiated with MgATP.
• the amount of ATP consumption over a defined time period in the test vessel may be compared to the amount of ATP consumption in a control vessel. The defined period of time may be 5 minutes to 20 minutes.
• Test compounds of skeletal muscle contraction may be tested on skinned fibers.
• Single skeletal muscle fibers, treated so as to remove membranes and allow for a direct activation of contraction after calcium administration may be used.
• An inhibitor compound or salt of Formula (I), (IIA), (IIB), or (IIC) may inhibit contraction of a single skeletal muscle fiber by about 5 % to about 90 % relative to pre-treatment value or an untreated control single skeletal muscle fiber.
• An inhibitor may inhibit contraction of a single skeletal muscle fiber by at least about 5 % relative to pre-treatment value or an untreated control single skeletal muscle fiber.
• An inhibitor may inhibit contraction of a single skeletal muscle fiber by at most about 90 % relative to pre- treatment value or an untreated control single skeletal muscle fiber.
• An inhibitor may inhibit contraction of a single skeletal muscle fiber by about 5 % to about 10 %, about 5 % to about 20 %, about 5 % to about 30 %, about 5 % to about 40 %, about 5 % to about 50 %, about 5 % to about 60 %, about 5 % to about 70 %, about 5 % to about 80 %, about 5 % to about 90 %, about 10 % to about 20 %, about 10 % to about 30 %, about 10 % to about 40 %, about 10 % to about 50 %, about 10 % to about 60 %, about 10 % to about 70 %, about 10 % to about 80 %, about 10 % to about 90 %, about 20 % to about 30 %, about 20 % to about 40 %, about 20 % to about 50 %, about 20 % to about 60 %, about 20 % to about 70 %, about 20 % to about 80 %, about 20 % to about 90 %,
• An inhibitor may inhibit contraction of a single skeletal muscle fiber by about 5 %, about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, or about 90 % relative to pre-treatment capacity or an untreated control single skeletal muscle fiber.
• An inhibitor compound or salt of Formula (I), (IIA), (IIB), or (IIC) may inhibit contraction of a single skeletal muscle by about 5 % to about 90 % relative to pre-treatment value or an untreated control single skeletal muscle.
• An inhibitor may inhibit contraction of a single skeletal muscle by at least about 5 % relative to pre-treatment value or an untreated control single skeletal muscle.
• An inhibitor may inhibit contraction of a single skeletal muscle by about 5 %, about 10 %, about 20 %, about 30 %, about 40 %, about 50 %, about 60 %, about 70 %, about 80 %, or about 90 % relative to pre-treatment capacity or an untreated control single skeletal muscle.
• the effect of a test compound on slow type I skeletal muscle fibers, cardiac muscle bundles or lung muscle fibers may be evaluated.
• a test compound or inhibitor compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be selected so as not to appreciably modulate the function of slow type I skeletal muscle fibers, cardiac muscle bundles or lung muscle fibers and be specific for type II skeletal muscles.
• the ex vivo assays used may be mouse models.
• the mouse models used may be dystrophy mouse models such as an mdx mouse.
• the mdx mouse has a point mutation in its dystrophin gene, changing the amino acid coding for a glutamine to a threonine producing a nonfunctional dystrophin protein resulting in DMD where there is increased muscle damage and weakness.
• Extensor digitorum longus muscles may be dissected from mdx mice and mounted on a lever arm. The muscles may be bathed in an oxygenated Krebs solution to maintain muscle function.
• a test compound or compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be applied to the muscles.
• An isometric (fixed length) contraction step may then be performed wherein the muscles are stimulated with a series of electrical pulses.
• An eccentric (lengthening) contraction step may be performed wherein the muscles are stretched to 10%, 15%, 20%, 25%, or 30% greater than its rested length, while relaxed or while stimulated with an electrical pulse.
• the eccentric contraction step is repeated from 2 to 50 times.
• the eccentric contraction step is repeated from 2 to 40 times.
• the eccentric contraction step is repeated from 2 to 30 times.
• the eccentric contraction step is repeated from 2 to 20 times.
• the eccentric contraction step is repeated from 2 to 10 times.
• the electric pulse may have a frequency of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150 Hz.
• a series of electric pulses may comprise of individual pulses of different frequencies.
• the time period of each pulse in the series of electric pulses may be between 0.1 second to 0.5 seconds for each pulse.
• the time for each pulse may be 0.1, 0.2, 0.3, 0.35, 0.4 or 0.5 seconds.
• Muscle membrane damage may also be measured by incubating muscles in procion orange after the isometric or eccentric contraction. Procion orange is a fluorescent dye that is taken up by muscle fibers with injured membranes.
• the number or proportion of dye-positive fibers may then quantified by histology.
• the test compound may be selected as a compound or salt of Formula (I), (IIA), (IIB), or (IIC).
• the force generated by the muscle may be measured.
• the change in force generated by the muscle before and after an isometric or eccentric set of contractions may be calculated as the test force drop.
• the calculations may be compared to the change in force generated by the muscle contraction from the first pulse to the last pulse in a control sample without exposure to the test compound (control force drop).
• compositions comprising a compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation may be modified depending upon the route of administration chosen.
• Pharmaceutical compositions comprising a compound, salt or conjugate may be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate.
• the pharmaceutical compositions may also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.
• compositions comprising a compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be formulated for administration as an injection.
• formulations for injection may include a sterile suspension, solution or emulsion in oily or aqueous vehicles.
• Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension.
• the suspension may also contain suitable stabilizers.
• Injections may be formulated for bolus injection or continuous infusion.
• compositions may be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• a suitable vehicle e.g., sterile pyrogen-free water
• a compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle.
• a unit dosage injectable form e.g., solution, suspension, emulsion
• Such vehicles may be inherently non-toxic, and non-therapeutic.
• Vehicles may be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin.
• Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used.
• Liposomes may be used as carriers.
• the vehicle may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
• the invention relates to methods and compositions of Formula (I), (IIA), (IIB), or (IIC) formulated for oral delivery to a subject in need.
• a composition is formulated so as to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the mouth or esophagus.
• the composition is formulated to deliver one or more pharmaceutically active agents to a subject through a mucosa layer in the stomach and/or intestines.
• compositions of Formula (I), (IIA), (IIB), or (IIC) are provided in modified release dosage forms.
• suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multi-particulate devices, and combinations thereof.
• the compositions may also comprise non-release controlling excipients.
• compositions of Formula (I), (IIA), (IIB), or (IIC) are provided in enteric coated dosage forms. These enteric coated dosage forms can also comprise non-release controlling excipients.
• compositions are in the form of enteric-coated granules, as controlled-release capsules for oral administration.
• the compositions can further comprise cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate.
• the compositions are in the form of enteric-coated pellets, as controlled-release capsules for oral administration.
• the compositions can further comprise glycerol monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.
• compositions comprising a compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be prepared for storage by mixing a compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and/or a stabilizer.
• This formulation may be a lyophilized formulation or an aqueous solution.
• Acceptable carriers, excipients, and/or stabilizers may be nontoxic to recipients at the dosages and concentrations used.
• Acceptable carriers, excipients, and/or stabilizers may include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non-ionic surfactants or polyethylene glycol.
• buffers such as phosphate, citrate, and other organic acids
• antioxidants including ascorbic acid and methionine
• preservatives polypeptides
• proteins such as serum albumin or gelatin
• hydrophilic polymers amino acids
• compositions of Formula (I), (IIA), (IIB), or (IIC) can further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.
• compositions of Formula (I), (IIA), (IIB), or (IIC) are provided in effervescent dosage forms. These effervescent dosage forms can also comprise non-release controlling excipients.
• compositions of Formula (I), (IIA), (IIB), or (IIC) can be provided in a dosage form that has at least one component that can facilitate the immediate release of an active agent, and at least one component that can facilitate the controlled release of an active agent.
• the dosage form can be capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours.
• the compositions can comprise one or more release controlling and non-release controlling excipients, such as those excipients suitable for a disruptable semi- permeable membrane and as swellable substances.
• compositions of Formula (I), (IIA), (IIB), or (IIC) are provided in a dosage form for oral administration to a subject, which comprise one or more pharmaceutically acceptable excipients or carriers, enclosed in an intermediate reactive layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer.
• the compositions of Formula (I), (IIA), (IIB), or (IIC) provided herein can be in unit-dosage forms or multiple-dosage forms.
• Unit-dosage forms refer to physically discrete units suitable for administration to human or non-human animal subjects and packaged individually.
• Each unit-dose can contain a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients.
• unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules.
• unit-dosage forms may be administered in fractions or multiples thereof.
• a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which can be administered in segregated unit-dosage form.
• Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons.
• the multiple dosage forms comprise different pharmaceutically active agents.
• the compositions of Formula (I), (IIA), (IIB), or (IIC) may also be formulated as a modified release dosage form, including immediate-, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, extended, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
• combination therapies for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
• the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
• Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
• Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents.
• each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
• the therapeutic agents are administered by the same route or by different routes.
• a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally.
• all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.
• the components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously.
• a compound or salt of the disclosure may be administered in combination with an oral corticosteroid.
• a compound or salt of the disclosure is administered in combination with deflazacort.
• a compound or salt of the disclosure is administered in combination with prednisone.
• a compound or salt of the disclosure is administered in combination with a morpholino antisense oligomer.
• a compound or salt of the disclosure is administered in combination with and exon skipping therapy.
• the additional therapeutic agent is eteplirsen or ataluren.
• a compound or salt of the disclosure is used in combination with a gene therapy.
• the compound or salt of the disclosure is used in combination with adeno-associated virus (AAV) containing genes encoding replacement proteins, e.g., dystrophin, or truncated version thereof, e.g., microdystrophin.
• AAV adeno-associated virus
• a compound or salt of the disclosure is administered in combination with vamorolone.
• Example 1 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydropyridazin-1-yl]-N- ethylacetamide (Compound 15)
• Step 1 6-oxo-1,6-dihydropyridazine-3-carboxylate
• N-hydroxycyclopropanecarboximidamide 157.22 mg, 1.57 mmol
• DIC 270.24 mg, 2.14 mmol
• HOBt 289.35 mg, 2.14 mmol
• Step 3 methyl 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydropyridazin-1- yl]acetate
• 6-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydropyridazin-3- one (205 mg, 1.00 mmol) in DMF (5 mL) were added Cs 2 CO 3 (654.23 mg, 2.00 mmol) and methyl 2-bromoacetate(153.58 mg, 1.00 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at 0 °C.
• Step 4 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethyl acetamide [0267] A solution of methyl 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydro- pyridazin-1-yl]acetate (120 mg, 0.43 mmol) in ethanamine 35% in EtOH (5 mL) was stirred for 4 h at 80 °C. The resulting mixture was concentrated under reduced pressure.
• Example 2 2-(3-(4-(3-chlorophenyl)thiazol-2-yl)-6-oxopyridazin-1(6H)-yl)-N-ethylacet- amide (Compound 81) Step 1: 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide [0269] To a stirred solution of 2-(3-bromo-6-oxopyridazin-1-yl)-N-ethylacetamide (1.00 g, 0.38 mmol) in DMA (10.00 mL) were added Zn(CN) 2 (496.70 mg, 0.42 mmol), XantPhos (222.47 mg, 0.038 mmol) and DIPEA (49.69 mg, 0.038 mmol).
• Step 2 2-(3-carbamothioyl-6-oxopyridazin-1-yl)-N-ethylacetamide
• 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide 200.00 mg, 0.097 mmol
• EtOH 2.00 mL
• P 2 S 5 431.17 mg, 0.19 mmol
• the resulting solution was stirred for 3 h at 80°C.
• the reaction was quenched by the addition of H 2 O (20 mL) at 0 °C.
• the aqueous layer was extracted with EtOAc (3x15 mL).
• Step 3 2-(3-(4-(3-chlorophenyl)thiazol-2-yl)-6-oxopyridazin-1(6H)-yl)-N-ethylacetamide
• 2-(3-carbamothioyl-6-oxopyridazin-1-yl)-N-ethylacetamide 100.00 mg, 0.083 mmol
• 2-bromo-1-(3-chlorophenyl)ethanone 106.89 mg, 0.092 mmol
• Example 3 2-[3-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacet- amide (Compound 25)
• Step 1 2-bromo-5-(3-chlorophenyl)-1,3-thiazole
• LDA 492.75 mg, 1.53 mmol
• CBr4 1525.42 mg, 1.533 mmol
• Step 2 N-ethyl-2-[6-oxo-3-(trimethylstannyl)pyridazin-1-yl]acetamide
• 2-(3-bromo-6-oxopyridazin-1-yl)-N-ethylacetamide (1.00 g, 3.85 mmol) in Dioxane (5.00 mL) were added hexamethyldistannane (2.52 g, 7.69 mmol) and Pd(dppf)Cl 2 (281.32 mg, 0.38 mmol).
• the reaction was stirred for 1 h at 100°C under Argon atmosphere.
• the resulting mixture was concentrated under vacuum.
• Step 3 2-[3-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide [0274] To a stirred solution of N-ethyl-2-[6-oxo-3-(trimethylstannyl)pyridazin-1-yl]acetamide (200.00 mg, 0.58 mmol) in dioxane (2.00 mL) were added Pd(dppf)Cl 2 (212.70 mg, 0.29 mmol) and 2-bromo-5-(3-chlorophenyl)-1,3-thiazole (319.25 mg, 1.16 mmol).
• the reaction was stirred for 3 h at 100°C under Argon atmosphere.
• the reaction was quenched by the addition of H 2 O (20 mL) at room temperature.
• the aqueous layer was extracted with EtOAc (3x10 mL).
• the combined organic layers were washed by water (20 mL), dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure.
• the crude product was first purified by silica gel column chromatography and then further purified by Prep-HPLC to give the title compound as a off- white solid (17.1 mg, 7.85%).
• Example 4 2-benzyl-6-(5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)pyridazin-3(2H)-one (Compound 73)
• Step 1 3-chlorobenzohydrazide [0275] To a stirred solution of methyl 3-chlorobenzoate (3.00 g, 17.58 mmol) in MeOH (10.00 mL) was added Hydrazine Monohydrate (3.0 mL). The reaction mixture was stirred for 2 h at 50°C.
• Step 3 6-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2H-pyridazin-3-one [0277] To a stirred solution of N-(3-chlorobenzoyl)-6-oxo-1H-pyridazine-3-carbohydrazide (330 mg, 1.13 mmol) in toluene (3.00 mL) was added POCl 3 (0.32 mL, 3.43 mmol). The reaction mixture was stirred overnight at 100°C. The reaction was quenched by the addition of water (15 mL) at room temperature. The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were concentrated under reduced pressure.
• Step 4 2-benzyl-6-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-one [0278] To a stirred solution of 6-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2H-pyridazin-3-one (120.00 mg, 0.44 mmol) in DMF(2.0 mL) were added benzyl bromide (82.20 mg, 0.48 mmol) and K 2 CO 3 (181.15 mg, 1.31 mmol).
• the reaction mixture was stirred for 2 h at room temperature.
• the resulting mixture was diluted with water (10 mL).
• the precipitated solids were collected by filtration.
• the crude product was purified by Prep-HPLC to give the title compound as a white solid (30 mg, 18.82%).
• Example 5 2-[3-[5-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N- ethylacetamide
• Step 1 2-[3-[5-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide
• To a stirred solution of 5-(3-chlorophenyl)-1,3-oxazole (200.00 mg, 1.11 mmol) in DMA (2.00 mL) were added 2-(3-bromo-6-oxopyridazin-1-yl)-N-ethylacetamide (318.6 mg, 1.23 mmol), K 2 CO 3 (384.76 mg, 2.78 mmol), PPh 3 (58.42 mg,
• the resulting reaction mixture was irradiated under microwave radiation conditions for 1 h at 120°C.
• the reaction was diluted by the addition of H 2 O (20 mL).
• the aqueous layer was extracted with EtOAc (3x10 mL).
• the organic layers were combined and concentrated under reduced pressure.
• the crude product was purified by silica gel column chromatography and then further purified by Prep-HPLC to give the title compound as a white solid (35 mg, 8.76%).
• Example 6 2-[3-[4-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N- ethylacetamide (Compound 30) Step 1: 1-[(ethylcarbamoyl)methyl]-6-oxopyridazine-3-carboxamide [0281] A solution of 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide (200.00 mg, 0.10 mmol) in sulfuric acid (2.0 mL) was stirred for 1 h at 50°C. The pH value of the solution was adjusted to 7 with NaOH (1 mol/L).
• Example 7 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-oxopyridazin-1-yl]-N- ethylacetamide (Compound 24)
• Step 1 benzoylhydrazine, M-chloro [0283] To a stirred solution of methyl 3-chlorobenzoate (600.00 mg, 3.53 mmol) in methanol (5.00 mL) was added Hydrazine Monohydrate (1.0 mL). The resulting solution was stirred for 1 h at 70°C.
• Step 3 methyl 2-(3-[[(3-chlorophenyl)formohydrazido]carbonyl]-6-oxopyridazin-1-yl)acetate
• 3-chloro-N-(6-oxo-1H-pyridazine-3-carbonyl)benzohydrazide 175.00 mg, 0.601 mmol
• K 2 CO 3 167.43 mg, 1.20 mmol
• methyl 2-bromoacetate 82.79 mg, 0.54 mmol
• Step 4 methyl 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-oxopyridazin-1-yl]acetate
• methyl 2-(3-[[(3-chlorophenyl)formohydrazido]carbonyl]-6- oxopyridazin-1-yl)acetate 130.00 mg, 0.36 mmol
• Toluene (2.00 mL) were added bis(4- methoxyphenyl)-1,3,2lambda5,4lambda5-dithiadiphosphetane-2,4-dithione (288.31 mg, 0.71 mmol) and TEA (108.20 mg, 1.069 mmol).
• Step 5 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide [0287] To a stirred solution of methyl 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6- oxopyridazin-1-yl]acetate (47.42 mg, 0.131 mmol) in methanol (1.00 mL) was added ethylamine in EtOH (35%) (1 mL, 0.66 mmol). The resulting solution was stirred for 1 h at 70°C.
• Example 8 2-[3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-oxopyridazin-1-yl]- N-ethylacetamide (Compound 32) Step 1: methyl 6-oxo-1H-pyridazine-3-carboxylate [0289] To a stirred solution of 6-methoxypyridazine-3-carboxylic acid (1.50 g, 9.732 mmol) in MeOH (50.00 mL) was added H2SO4 (1.00 mL).
• Step 2 6-oxo-1H-pyridazine-3-carbohydrazide
• methyl 6-oxo-1H-pyridazine-3-carboxylate 800.00 mg, 5.19 mmol
• EtOH 5.00 mL
• Hydrazine Monohydrate 1.0 mL
• the reaction mixture was stirred for 3 h at 40°C.
• the reaction mixture was allowed to cool down to room temperature.
• the precipitated solids were collected by filtration and washed with ACN (2x2 mL) to give the title compound as a white solid (650 mg, 81.25%)MS m/z: 155 [M+H] + .
• Step 3 N'-[bicyclo[1.1.1]pentane-1-carbonyl]-6-oxo-1H-pyridazine-3-carbohydrazide [0291] To a stirred solution of 6-oxo-1H-pyridazine-3-carbohydrazide (500.00 mg, 3.24 mmol) in DMF (8.00 mL) were added bicyclo[1.1.1]pentane-1-carboxylic acid (363.30 mg, 3.24 mmol), PyBOP (2.19 g, 4.21 mmol) and DIPEA (1.26 g, 9.72 mmol). The reaction mixture was stirred for 4 h at room temperature.
• Step 4 6-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H-pyridazine-3-thione [0292] To a stirred solution of N-[bicyclo[1.1.1]pentane-1-carbonyl]-6-oxo-1H-pyridazine-3- carbohydrazide (400.00 mg, 1.61 mmol) in Toluene (5.00 mL) was added Lawesson Reagent (977.60 mg, 2.42 mmol). The reaction mixture was stirred for 1 h at 60 o C. The reaction mixture was allowed to cool down to room temperature. The reaction was diluted by the addition of H 2 O (30 mL).
• Step 5 3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-(methylsulfanyl)pyridazine [0293] To a stirred solution of 6-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H- pyridazine-3-thione (300.00 mg, 1.14 mmol) in DMF (5.00 mL) were added CH 3 I (194.77 mg, 1.37 mmol) and K2CO3 (316.08 mg, 2.29 mmol). The reaction mixture was stirred for 2 h at room temperature.
• Step 6 3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-methanesulfonylpyridazine [0294] To a stirred solution of 3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6- (methylsulfanyl)pyridazine (280.00 mg, 1.01 mmol) in DCM (6.00 mL) was adde M-CPBA (524.48 mg, 3.04 mmol). The reaction mixture was stirred for 2 h at 40°C. The reaction mixture was allowed to cool down to room temperature.
• Step 7 6-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H-pyridazin-3-one [0295] To a stirred solution of 3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6- methanesulfonylpyridazine (220.00 mg, 0.71 mmol) in THF (2.00 mL) were added H 2 O (1.00 mL) and KOH (160.11 mg, 2.85 mmol). The reaction mixture was stirred for 2 h at 70°C. The reaction mixture was allowed to cool down to room temperature.
• Step 9 2-[3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-oxopyridazin-1-yl]-N- ethylacetamide [0297] To a stirred solution of methyl 2-[3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)- 6-oxopyridazin-1-yl]acetate (160 mg, 0.50 mmol) in EtOH (4 mL) were added DMAP (6.14 mg, 0.05 mmol) and ethylamine in EtOH (35%) (1 mL).
• Plasma and serum for affected individuals were received from the Newcastle MRC Centre Biobank for Rare and Neuromuscular Diseases (Duchenne muscular dystrophy), and a Becker muscular dystrophy biomarker study at Binghamton University – SUNY (Becker muscular dystrophy). Upon receipt, all samples were aliquoted into working volumes of 50 – 100 ⁇ L and stored at -80°C to minimize freeze-thaw damage. Red top serum vacutainer tubes, containing silica act clot activator, were used for the blood collection. If a subject required MLPA testing, an EDTA tube would be added for those collections, but was not used for any other analysis.
• the serum tubes were left to clot for 30 minutes, they were processed in a centrifuge at 1000-1300xg for 10 minutes.
• the serum (top layer) fluid was then pipetted from the vacutainer tube and transferred into cryovials and immediately frozen on dry ice for shipment and later storage at -80°C.
• Serum samples were sent frozen on dry ice to Binghamton University and stored at -80°C. Samples were collected from 2017 to 2019 and analyzed in 2019.
• Plasma samples from the Newcastle MRC Centre Biobank were collected from patients attending clinics at The John Walton Muscular Dystrophy Research Centre. Blood was drawn into vacutainers, gently inverted 5-10 times to ensure adequate mixing of blood with EDTA and then centrifuged at 1,500xg for 10 minutes.
• Plasma CK activity was assayed using a coupled-reaction kit purchased from Pointe Scientific (Canton, MI). Plasma was diluted 25-fold with phosphate-buffered saline (PBS), of which 2 ⁇ L was added to the 384-well plate.
• PBS phosphate-buffered saline
• the CK assay reagent 70 ⁇ L, 4:1 kit Buffer A:Buffer B was added using the Multidrop Combi (ThermoFisher, Inc., Waltham, MA) and the reaction progress monitored by absorbance at 340 nm for 30 min with the SpectraMax M3 plate reader (Molecular Devices, San Jose, CA) over approximately 20 – 30 min. Following the termination of the reaction, pathlength correction values were measured with near-IR absorbance at 900 nm and 975 nm. The raw absorbance data were processed in Microsoft Excel to exclude points with A340 > 2.5 and to correct for pathlength using a system-specific K-Factor of 0.168.
• TNNI ELISAs Plasma concentrations of TNNI isoforms for slow and fast muscle were measured by capture ELISA.
• the slow isoform (TNNI1) was measured using a commercially available test kit (LSF7068, LifeSpan Biosciences, Inc, Seattle, WA) and was performed according to the manufacturer’s instructions.
• the fast isoform (TNNI2) was assayed as described previously. Briefly, high-binding ELISA plates were coated with ⁇ -TNNI2 monoclonal antibody (Clone 7G2, OriGene, Inc., Rockville, MD) at a concentration 6.4 ⁇ g/mL overnight at 4°C. The wells were blocked with 1% w/v non-fat dry milk in PBS for 30 min at 37°C., followed by incubation for 2 h at 37°C with the samples or recombinant human TNNI2 as a standard curve.
• ⁇ -TNNI2 monoclonal antibody (Clone 7G2, OriGene, Inc., Rockville, MD) at a concentration 6.4 ⁇ g/mL overnight at 4°C.
• the wells were blocked with 1% w/v non-fat dry milk in PBS for 30 min at 37°C., followed by incubation for 2 h at 37°C with the samples or recombinant human TNNI2 as
• the wells were washed with PBS containing 0.1% Tween-20 (PBS-T) and incubated with 1 ⁇ g/mL polyclonal ⁇ -TNNI2 antibody (PA5-76303, ThermoFisher, Inc.) for 90 min at 37°C.
• the detection antibody HRP-conjugated goat- ⁇ -rabbit IgG, 0.08 ⁇ g/mL, Pierce Biosciences
• the HRP was visualized with Ultra-TMB colorimetric reagent (ThermoFisher) followed by quenching with 2 N H2SO4 and measurement of the absorbance at 410 nm.
• BMD Becker muscular dystrophy
• D, E, and F Becker muscular dystrophy
• Bars represent the mean +/- the standard error for the population. ****: p ⁇ 0.0001, ns: non-significant.
• Figure 6 Plasma fast troponin I (A), myblobin (B), and creatine kinase (C) in healthy control subjects (Controls), and in subjects with McArdle disease (McA) or Becker muscular dystrophy (BMD) after excersise. Data are expressed as mean + SE.

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