Methods of treating cardiomyopathy

Abstract

A method of treating dystrophic cardiomyopathy in a subject in need thereof, comprising administering to the subject a cardiac troponin I interacting kinase (TNNI3K) inhibitor.

Description

METHODS OF TREATING CARDIOMYOPATHY CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the benefit of priority to US provisional application No. 63 / 594,570, filed on October 31, 2023, which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Muscular dystrophy (MD) refers to diseases caused by mutations in genes, usually those involved in making muscle proteins. Dystrophin, a muscle protein, exists in muscle cells and works to strengthen the muscle fibers and protect them from injury. Dystrophin is an integral part of the muscular structure, the lack of functional dystrophin destabilizes the muscle sarcolemma, causing progressive muscle damage, as well as respiratory and cardiac complications. Continuous muscle damage, as is the case in muscular dystrophies, can release muscle intrinsic factors such as cTnI which are otherwise absent from circulation, triggering immune cell infiltration and muscle inflammation. Myocarditis is the immune cell infiltration and inflammation of the heart muscle and is a sign and symptom usually associated with muscular dystrophy. Myocarditis, when unresolved, can lead to cardiomyopathy, a group of diseases that affect the heart muscle and impair the function of the heart. SUMMARY

[0003] Described herein are methods for reducing cTnI or phospho-cTnI level in the serum, thereby treating cardiomyopathy.

[0004] Disclosed herein is a method for treating muscular dystrophy in a subject in need thereof, comprising administering to the subject a TNNI3K inhibitor having a structure ofpharmaceutically acceptable salt thereof.

[0005] In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy (DMD).

[0006] Disclosed herein is a method for treating cardiomyopathy in a subject in need thereof, comprising administering to the subject a cardiac troponin I interacting kinase (TNNI3K) inhibitor.

[0007] In some embodiments, the TNNI3K inhibitor comprises of a small molecule, an antibody, an antisense oligomer conjugate, an siRNA.

[0008] In some embodiments, the TNNI3K inhibitor comprises of a small molecule, or a pharmaceutically acceptable salt thereof.

[0009] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein: R1is (C1-C4)alkyl; R2is hydrogen or halogen; R3is hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, aryl, hydroxyl, -(C1-C4)alkylhydroxyl, (C1-C4)alkoxy, -(C1-C4)alkylene-(C1-C4)alkoxy, (C1- C4)haloalkoxy, (C3-C6)cycloalkyloxy, -S-(C1-C4)alkyl, amino, -NH(C1-C4)alkyl, or -N((C1- C4)alkyl)2; R4is hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1- C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene-(C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3- C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(C3-C8)cycloalkyl, -S(=O)2(C1-C8)alkyl, - S(=O)2(C1-C8)haloalkyl, -S(=O)2(C3-C8)cycloalkyl, phenyl, 5-membered heteroaryl, amino, -NHRa, or -NRaRb; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1-C6)alkoxy, (C1- C4)haloalkoxy, -(C1-C4)alkylhydroxyl, and -N(Ra)(Rb); R5is hydrogen; or R4and R5taken together with intervening atoms to form a 5 or 6 membered ring, which ring may be unsubstituted, or substituted with one to three substituents    independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1-C4)alkylhydroxyl, oxo, hydroxyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, and -S-(C1-C8)alkyl; each R6and R7is independently hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, heteroaryl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene-(C1-C4)alkoxyl, (C1-C4)haloalkoxy, (C3-C6)cycloalkyloxy, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(=O)2(C1- C8)alkyl , -NHRc, or -NRcRd; or R6and R7are taken together with the atoms to which they are attached, to form a (C3- C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl, wherein any said (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one to five substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, - C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, SRa, -S(=O)2(C1- C8)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1- C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORe, -(C1-C2)alkylhydroxyl, and -(C1- C2)alkylene-ORa; or two of the substituents are taken together with the atoms to which they are attached, to form a (C4-C8)cycloalkyl, (C4-C8)heterocycloalkyl, aryl, or heteroaryl; each Reis, independently, (C1-C8)alkyl or a 5-6 membered heterocycloalkyl, wherein said (C1-C8)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, and -N(Ra)(Rb); each Rcand Rdis independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, - CO2H, -CO2Ra, -C(=O)NH2, C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1- C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, - NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1- C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1- C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, - S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, - NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa;    each Raand Rbis independently selected from (C1-C4)alkyl, aryl, heterocycloalkyl, or - (C1-C2)alkylene-heterocycloalkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C6)alkoxy, amino, - NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -CO2H, -CO2(C1-C6)alkyl, -C(=O)NH2, -C(=O)NH(C1- C6)alkyl, and C(=O)N((C1-C6)alkyl)2, wherein any heterocycloalkyl is optionally substituted by (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached to form a 5-7 membered heterocyclic ring, wherein said ring is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino, - NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, -(C1-C4)alkylhydroxyl, oxo, (C1-C4)alkoxy, (C1- C4)haloalkoxy, and (C1-C4)alkoxy(C1-C4)alkyl; or a salt thereof.

[0010] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (I-A), or a pharmaceutically acceptable salt thereof,Formula (I-A) wherein: Rcis hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, - C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1-C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, - (C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted    with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, - C(=O)NHRa, -C(=O)NRaRb, SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, - ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa.

[0011] In some embodiments of the methods provided herein, the TNNI3K inhibitor is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments of the methods provided herein, the TNNI3K inhibitor is 3-((6- ((5-chloropyridin-2-yl)amino)pyrimidin-4-yl)amino)-4-(ethylsulfonyl)-N- methylbenzenesulfonamide, having a chemical structure of:or a pharmaceutically acceptable salt thereof.

[0013] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (I-B), or a pharmaceutically acceptable salt thereof,Formula (I-B) wherein: each R8, R9, and R10are each, independently, H, halogen, nitro, amino, -NH(C1-C4)alkyl, - N((C1-C4)alkyl)2, hydroxyl, or ORe; and    each Reis, independently, (C1-C8)alkyl or a 5-6 membered heterocycloalkyl, wherein said (C1-C8)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, and -N(Ra)(Rb); or R9and R10are taken together with the intervening atoms to form a five or six membered heterocycle.

[0014] In some embodiments of the methods provided herein, the TNNI3K inhibitor is selected from the compounds of Table 2, or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments of the methods provided herein, the TNNI3K inhibitor is 3-((6,7- dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide, having the chemical structure of:or a pharmaceutically acceptable salt thereof.

[0016] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (II), or a pharmaceutically acceptable salt thereof,Formula (II) wherein: R11is halogen, (C1-C4)alkyl, or -ORf; R12is H, halogen, (C1-C4)alkyl, or -ORf; and Rfis (C1-C4)alkyl which is optionally substituted with one to three halogen.

[0017] In some embodiments of the methods provided herein, the TNNI3K inhibitor is selected from the compounds of Table 3, or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments of the methods provided herein, the TNNI3K inhibitor is 1-(3,5- dichloro-4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, having the structure of:or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments of the methods provided herein, the TNNI3K inhibitor is selected from the compounds of Table 4, or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments of the methods provided herein, the cardiomyopathy is dystrophic cardiomyopathy.

[0021] In some embodiments of the methods provided herein, the cardiomyopathy is associated with Duchenne muscular dystrophy (DMD).

[0022] In some embodiments of the methods provided herein, the cardiomyopathy is associated with Becker muscular dystrophy (BMD).

[0023] In some embodiments of the methods provided herein, the the cardiomyopathy is associated with X-Linked DMD / BMD mutations of female carriers.

[0024] In some embodiments of the methods provided herein, the subject has a muscular dystrophy, wherein the muscular dystrophy is selected from Becker muscular dystrophy (BMD), congenital muscular dystrophy, Duchenne muscular dystrophy (DMD), distal muscular dystrophy, Emery–Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb–girdle muscular dystrophy (LGMD), myotonic muscular dystrophy, X-Linked Cardiomyopathy (Carriers), and oculopharyngeal muscular dystrophy.

[0025] In some embodiments of the methods provided herein, the muscular dystrophy is Duchenne muscular dystrophy (DMD).

[0026] In some embodiments of the methods provided herein, the muscular dystrophy is Becker muscular dystrophy (BMD).

[0027] In some embodiments of the methods provided herein, the muscular dystrophy is X- linked DMD / BMD mutations of female carriers.

[0028] In some embodiments of the methods provided herein, the subject is a human of at least 2 years of age with elevated cardiac troponin (cTnI) based on a high sensitivity cardiac troponin assay.

[0029] In some embodiments of the methods provided herein, the subject is a boy of age 8 or above.

[0030] In some embodiments of the methods provided herein, the subject is a boy of age 10 or above.

[0031] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces serum cTnI levels in the subject.

[0032] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces cTnI Ca++sensitivity in the subject.

[0033] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces immunogenic cTnI epitopes in the subject.

[0034] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces immunogenic cTnI phospho-epitopes in the subject.

[0035] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces cardiac inflammation in the subject.

[0036] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor stabilizes or reduces cardiac fibrosis in the subject.

[0037] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces ischemic damage in the subject.

[0038] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces non-ischemic damage in the heart.

[0039] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces dystrophic cardiomyopathy in the subject.

[0040] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces loss of cardiac function in the subject.

[0041] In some embodiments of the methods provided herein, the TNNI3K inhibitor is administered orally.

[0042] In some embodiments of the methods provided herein, the administering of the TNNI3K inhibitor does not substantially change the subject’s weight.

[0043] In some embodiments of the methods provided herein, the administering of the TNNI3K inhibitor produces an anti-fibrotic effect.    INCORPORATION BY REFERENCE

[0044] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0045] Muscular dystrophy (MD) is a group of diseases caused by abnormal genes (mutations), interfering with the production of proteins dystrophin needed to form healthy muscle. MD has been mapped to at least 29 different genetic loci that give rise to at least 34 different clinical disorders. Duchenne muscular dystrophy (DMD and Becker muscular dystrophy (BMD) are X- linked disorders affecting the synthesis of dystrophin, a large sarcolemmal protein that is absent in DMD and reduced in amount or abnormal in size in BMD patients. DMD and BMD are responsible for over 80% of all muscular dystrophies. X-linked DMD / BMD mutations of female carriers is caused by X inactivation, in which one of the two X chromosomes in female cells becomes transcriptionally inactive, may result in cardiomyopathy if the active X Chromosome has the abnormal dystrophin gene.

[0046] The Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X- linked DMD / BMD mutations female carriers are usually associated with a heart condition called cardiomyopathy. Cardiomyopathy weakens the cardiac muscle, preventing the heart from pumping blood efficiently, which typically begins in adolescence. Later, the heart problems develop into dilated cardiomyopathy. Cardiomyopathy has become the leading cause of death in Duchenne muscular dystrophy (DMD). Cardiac inflammation (H&E), fibrosis (Masson) and IgG deposition are hallmarks of dystrophic cardiomyopathy, where fibrosis is non-ischemic, diffuse, and widespread . Chronic inflammation in both skeletal and cardiac muscle leads to fibrotic tissue deposition that impairs muscle function.

[0047] Cardiac Troponin I (cTnI)) is a protein encoded by the TNNI3 gene in human. cTnI plays a role in the development of cardiomyopathy. Studies show that serum cTnI levels strongly correlate with extent of immune infiltration from isoproterenol-induced cardiac injury, establishing a link between leaking cTnI and cardiomyopathy. Serum cTnI levels are significantly elevated in DMD. Serum cTnI levels are elevated early and remain elevated throughout life in DMD patients, and the levels decline with age as cardiomyocytes become depleted and fibrotic.

[0048] Troponin I interacting kinase (TNNI3K), is a protein kinase encoded by TNNI3K gene. The gene is localized in human chromosome 1 (1p31.1), and mainly expressed in the heart. TNNI3K exhibits highly selective expression for cardiac tissues, and interacts with components of the sarcomere, including troponin I. TNNI3K has been linked to the progression of dilated cardiomyopathy, cardiac hypertrophy, and ischemia / reperfusion injury. Inhibition of the kinase activity of TNNI3K can disrupt these signaling pathways, and enable the mitigation, or reversal of cardiomyopathies. Inhibition of TNNI3K reduces cTnI Ca++sensitivity, immunogenic cTnI epitopes and / or cTnI phospho-epitopes, ischemic damage, and limits loss of cardiac function after injury.

[0049] Increased TNNI3K expression correlates with dilated cardiomyopathy, and heart failure in the context of cardiac stress, such as calsequestrin (Csq) transgene mediated depression of contractile function, or via surgical transverse aortic constriction (TAC). High levels of TNNI3K are associated with slower cardiac conduction, faster progression of cardiac disease, and worse recovery after reperfusion injury. These effects are ameliorated in absence of the kinase function of the protein, or by inhibition of TNNI3K through inhibitors, or both.

[0050] However, despite the previous studies on TNNI3K inhibitors, it is unpredictable whether TNNI3K inhibitor will have any efficacy in treating muscular dystrophy such as DMD. Initial work with TNNI3K inhibitors (e.g., Compound 321) tested models of ischemic heart attacks that result in a focal area of damage (M. Lindsey et al., “Guidelines for experimental models of myocardial ischemia and infarction.” Am. J. of Physiol. Heart and Circulatory Physiol. Vol. 314,4 (2018): H812-H838. Doi:10.1152 / ajpheart.00335.2017) and regional fibrosis whereas in DMD, the cardiac fibrosis is non-ischemic and diffuse and widespread (T. Meyers and D. Townsend, “Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy”, Int J Mol Sci.2019 Aug 22;20(17):4098. doi: 10.3390 / ijms20174098; A. Tandon et al., Myocardial fibrosis burden predicts left ventricular ejection fraction and is associated with age and steroid treatment duration in Duchenne muscular dystrophy, J. of the Am. Heart Association Vol.4,4 (2015). Doi: 10.1161 / JAHA.114.001338 ). So there was no expectation of an anti-fibrotic effect of TNNI3K inhibitors in DMD patients based on the prior studies.

[0051] Thus, the instant application unexpectedly identified a method of treating muscular dystrophy (such as DMD) by using TNNI3K inhibitors.    Definitions

[0052] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0053] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.

[0054] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and / or precluding the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.

[0055] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” and “physiologically acceptable excipient” refer to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2009.

[0056] The terms “about” and “approximately” mean an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms “about” and “approximately” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “about” and    “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0057] The terms “active ingredient” and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition. As used herein, “active ingredient” and “active substance” may be an optically active isomer of a compound described herein.

[0058] The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent” refer to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition.

[0059] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0060] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a patient. In some embodiments, a therapeutic agent such as a TNNI3K inhibitor to the treatment and / or the amelioration of muscular dystrophy.

[0061] “Administering,” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, the term “administering,” when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue; providing a composition systemically to a patient by, e.g., oral administration whereby the therapeutic reaches the target tissue or cells. “Administering” a    composition may be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

[0062] The term “animal” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals. As used herein, the terms “patient,” “subject” and “individual” are intended to include living organisms in which certain conditions as described herein can occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats, and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In certain instances, the human is an adult. In certain instances, the human is child. In some instances, the human is at least the age of 18 years. In some instances, the human is at least the age of 14 years. In some instances, the human is at least the age of 12 years. In some instances, the human is at least the age of 10 years. In some instances, the human is at least the age of 8 years. In some instances, the human is at least the age of 6 years. In some instances, the human is at least the age of 4 years. In further instances, the human is at least the age of 2 years. In some instances, the human is at least the age of 6 months old. Other examples of subjects include experimental animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cows. The experimental animal can be an animal model for a disorder, e.g., a transgenic mouse with hypertensive pathology.

[0063] The term “pharmaceutical composition” shall mean a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0064] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or    displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0065] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.

[0066] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0067] “oxo” refers to =O;

[0068] “amino” refers to -NH2;

[0069] “amine” refers to any group contains a nitrogen atom with a lone pair (e.g., -NH2, - NHCH3, -N(CH3)2, and the like);

[0070] “cyano” refers to -CN;

[0071] “nitro” refers to -NO2;

[0072] “phenyl” refers to substituted or unsubstituted benzene ring;

[0073] “hydroxy” or “hydroxyl” refers to -OH;

[0074] “carboxyl” refers to -COOH.

[0075] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about twenty carbon atoms, more preferably one to twelve carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1- propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl- 2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms,    3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10 alkyl. In some embodiments, the alkyl is a C1-C6alkyl. In some embodiments, the alkyl is a C1-C5alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0076] The term “alkylamine” refers to a group consisting of an alkyl group (e.g., a C1-12alkyl) and an amine (e.g., -NH2, -NHCH3, -N(CH3)2, and the like), or a radical thereof. Examples of alkylamines include -CH2NH2, -CH2NHCH2, -CH2N(CH3)2, -CH2CH2NH2, -CH2NHCH2CH3, - NHCH2CH3, and the like. The term “aminoalkyl” is used interchangeably with “alkylamine”, wherein both terms are meant to include both alkyl radicals and nitrogen radicals. Alkyl amides are not encompassed in the term alkylamine as used herein.

[0077] The term “alkylhydroxyl” refers to a group consisting of an alkyl group (e.g., a C1-12 alkyl) and one or more hydroxyl groups (e.g., -OH and the like), or a radical thereof. Examples of alkylhydroxyl include -CH2OH, -CH2CH2OH, -CH(OH)-CH3, -CH(OH)-CH2CH3, - C(OH)(CH3)2, and the like.

[0078] The term “alkylcyano” refers to a group consisting of an alkyl group (e.g., a C1-12alkyl) and one or more cyano (e.g., -CN, and the like), or a radical thereof. Examples of alkylcyano include -CH2CN, -CH2CH2CN, -CH(CN)-CH3, -CH(CN)-CH2CH3, -C(CN)(CH3)2, and the like. The term “alkylcyano” is meant to include both alkyl radicals and cyano radicals.

[0079] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl”, means that the alkenyl group may consist of 2 carbon    atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0080] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0081] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, - COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0082] “Alkoxy” refers to a radical of the formula -O-alkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally    substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, - CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0083] The term “haloalkoxy” refers to a group consisting of one or more alkoxy groups (e.g., a -O- alkyl, where alkyl is defined as above) and one or more halogens (e.g., F, Cl,Br, I and the like), or a radical thereof. Examples of haloalkoxy include -OCF3, -OCH2CH2Cl, -CH2OCF3, - CH2OC(F)2-CH3, and the like. The term “haloalkoxy” is meant to include both alkoxy radicals and halogen radicals.

[0084] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, - OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0085] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated    cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis- decalinyl, trans-decalinyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0086] “Cycloalkyloxy” refers to a group containing a saturated carbocyclic ring attached through an oxygen linking atom. Examples of "cycloalkyloxy" moieties include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0087] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro, bromo or chloro. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is bromo or chloro. In some embodiments, halogen is fluoro or bromo. In some embodiments, halogen is bromo. In some embodiments, halogen is chloro. In some embodiments, halogen is fluoro. In some embodiments, halogen is iodo. In some embodiments, halogen is a combination of one or more atoms selected from to bromo, chloro, fluoro or iodo.

[0088] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0089] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10fully saturated heterocycloalkyl or C2-C10heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6fully saturated heterocycloalkyl or C2-C6heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, 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, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3- dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, hexahydro-1H-1,4-diazepinyl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, - CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0090] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms    selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, indolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzoisothiazolyl, dihydroquinolinyl, tetrahydroisoquinolinyl, dihydrobenzodioxinyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl,    ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0091] The term “alkylheteroaryl” refers to a group consisting of an alkyl group (e.g., a C1-12alkyl) and a heteroaryl (e.g., a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring, and the like), or a radical thereof. Examples of alkylheteroaryl include -CH2-pyridazinyl, -CH2CH2-imidazolyl, and the like. The term “alkylheteroaryl” is meant to include both alkyl radicals and heteroaryl radicals.

[0092] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, oxo, -OH, -O(alkyl), -CO2H, - CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -OCH3, -CO2H, - CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -S(C1-C4alkyl), -S(=O)(C1-C4alkyl), and -S(=O)2(C1-C4alkyl). In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O). Method of treatment

[0093] In one aspect, a method described herein is useful for treatment of cTnI-mediated or phospho-cTnI-mediated diseases or disorders, by lowering serum cTnI and / or serum phospho- cTnI levels. In some embodiments, a method described herein is useful for treatment of cTnI - mediated or phospho-cTnI-mediated diseases or disorders, by inhibition of cTnI or phospho- cTnI activity. In some embodiments, a method described herein is useful for lowering serum cTnI and / or serum phospho-cTnI levels. Such diseases or disorders are selected from cardiomyopathy, heart failure, such as congestive heart failure, cardiac hypertrophy, and heart    failure or congestive heart failure resulting from cardiac hypertrophy, myocardial ischemia, or myocardial infarction. In one aspect, a method described herein is useful for the treatment of heart failure in the context of cardiac stress, such as calsequestrin (Csq) transgene mediated depression of contractile function, or via surgical transverse aortic constriction (TAC). In another aspect, a method described herein is useful for the treatment of dystrophic cardiomyopathy, dilated cardiomyopathy. In one aspect, a method described herein is useful for treatment of cTnI mediated diseases or disorders, by lowering the serum cTnI and / or serum phospho-cTnI levels. In some embodiments, the heart failure in the context of cardiac stress is dystrophic cardiomyopathy. In some embodiments, a method described herein is useful for treatment of cTnI -mediated diseases or disorders, by inhibition of cTnI or phospho-cTnI activity. In some embodiments, a method described herein is useful for lowering serum cTnI. In some embodiments, a method described herein is useful for lowering serum phospho-cTnI levels. In some embodiments, such diseases or disorders can be dystrophic cardiomyopathy.

[0094] In one aspect, a method described herein is useful for treatment of phospho-cTnI mediated diseases or disorders, by lowering the serum cTnI and / or serum phospho-cTnI levels. In some embodiments, a method described herein is useful for treatment of phospho-cTnI mediated diseases or disorders, by inhibition of cTnI or phospho-cTnI activity. In some embodiments, a method described herein is useful for lowering serum cTnI. In some embodiments, a method described herein is useful for lowering serum phospho-cTnI levels.

[0095] In some embodiments, a method described herein is useful for lowering serum cTnI level. In some embodiments, described herein is a method of lowering serum cTnI level in a subject by administering a herein described compound. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 5%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 10%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 15%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 20%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 25%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 30%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 35%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 40%. In some embodiments, the    administering of a compound described herein lowers a serum cTnI level in the subject by at least 45%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 50%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 55%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 60%. In some embodiments, the administering of a compound described herein lowers a serum cTnI level in the subject by at least 70%.

[0096] In some embodiments, a method described herein is useful for lowering serum phospho- cTnI level. In some embodiments, described herein is a method of lowering serum phospho-cTnI level in a subject by administering a herein described compound. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 5%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 10%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 15%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 20%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 25%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 30%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 35%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 40%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 45%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 50%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 55%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 60%. In some embodiments, the administering of a compound described herein lowers a serum phospho-cTnI level in the subject by at least 70%.

[0097] In one aspect, a method described herein is useful for the treatment of muscular dystrophy associated cardiomyopathy. In one aspect, a method described herein is useful for the treatment of dystrophic cardiomyopathy. In one aspect, a method described herein is useful for    the treatment of DMD associated cardiomyopathy. In one aspect, a method described herein is useful for the treatment of BMD associated cardiomyopathy. In one aspect, a method described herein is useful for the treatment of X-linked DMD / BMD mutations of female carriers associated cardiomyopathy. In some embodiments, a method described herein is useful for the treatment of myocarditis.

[0098] In some embodiments, the disclosed method herein can modulate or inhibit the activity of TNNI3K, thus reducing, alleviating, or preventing a disease condition. The disease condition includes but is not limited to dystrophic cardiomyopathy.

[0099] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces dystrophic cardiomyopathy in the subject.

[0100] In some embodiments, administering of the TNNI3K inhibitor in the subject reduces, alleviate, or stabilize Duchenne muscular dystrophy (DMD) associated cardiomyopathy. In some embodiments, administering of the TNNI3K inhibitor in the subject reduces, alleviate, or stabilize Becker muscular dystrophy (BMD) associated cardiomyopathy. In some embodiments, administering of the TNNI3K inhibitor in the subject reduces, alleviate, or stabilize X-linked Female Carriers associated cardiomyopathy.

[0101] In some embodiments, administering of the TNNI3K inhibitor reduces non-ischemic damage in the heart.

[0102] In some embodiments, administering of the TNNI3K inhibitor produces an anti-fibrotic effect.

[0103] In some embodiments, administering of the TNNI3K inhibitor reduces the cardiac fibrosis associated with DMD.

[0104] In some embodiments, administering of the TNNI3K inhibitor reduces the cardiac fibrosis associated with DMD while not impacting skeletal muscle fibrosis associated with DMD.

[0105] In some embodiments, administering of the TNNI3K inhibitor reduces inflammatory cells in the heart.

[0106] In some embodiments, administering of the TNNI3K inhibitor decreases phosphorylation activity. In some embodiments, administering of the TNNI3K inhibitor decreases phosphorylation activity while TNNI3K levels remain stable.

[0107] In some embodiments, administering of the TNNI3K inhibitor reduces cardiac cTnI phosphorylation associated with DMD.

[0108] In some embodiments, administering of the TNNI3K inhibitor reduces fast progressing heart disease.

[0109] In some embodiments, administering of the TNNI3K inhibitor reduces early stage fibrosis. In some embodiments, administering of the TNNI3K inhibitor reduces frequency of CCR2+ cells in the heart.

[0110] In some embodiments, administering of the TNNI3K inhibitor reduces cardiac fibrosis correlated with CCR2+ cells in the heart.

[0111] In one aspect, disclosed herein is a method for treating cardiomyopathy in a subject in need thereof, comprising administering to the subject a cardiac troponin I interacting kinase (TNNI3K) inhibitor.

[0112] In some embodiments, the TNNI3K inhibitor comprises of a small molecule, an antibody, an antisense oligomer conjugate, or an siRNA. In some embodiments, the TNNI3K inhibitor is a small molecule, or a pharmaceutically acceptable salt thereof. “Small molecule” refers to compounds other than proteins or oligonucleotides; and typically have molecular weights of less than about 2000 Daltons, e.g., 900 Daltons.

[0113] In some embodiments, the method of inhibiting TNNI3K comprises contacting the kinase with a compound of Formula (I), (I-A), (I-B), (II), Table 1, 2, 3, 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of treatment of a TNNI3K-mediated disease or disorder comprising administering an effective amount of the compound of Formula (I), (I-A), (I-B), (II), Table 1, 2, 3, 4, or a pharmaceutically acceptable salt thereof, to a patient, in need thereof. For example, TNNI3K activity may be inhibited in mammalian cardiac tissue by administering to a patient in need thereof, an effective amount a compound of Formula (I), (I- A), (I-B), (II), Table 1, 2, 3, 4, or a pharmaceutically acceptable salt thereof.

[0114] In one aspect, disclosed herein is a method for treatment of TNNI3K-mediated diseases or disorders. In some embodiments, the method comprises the inhibition of TNNI3K activity. In some embodiments, the diseases or disorders are selected from heart failure, particularly congestive heart failure, cardiac hypertrophy, and heart failure or congestive heart failure resulting from cardiac hypertrophy. In some embodiments, a method described herein is useful for the treatment of heart failure or congestive heart failure resulting from myocardial ischemia or myocardial infarction.

[0115] In some embodiments, a method described herein is useful for the treatment of cardiomyopathy, wherein the cardiomyopathy is dystrophic cardiomyopathy. In some embodiments, a method described herein is useful for the treatment of myocarditis.

[0116] In some embodiments of the methods provided herein, the cardiomyopathy is associated with Duchenne muscular dystrophy (DMD). In some embodiments, the cardiomyopathy is associated with Becker muscular dystrophy (BMD). In some embodiments, the cardiomyopathy is associated with X-Linked Cardiomyopathy (Carriers).

[0117] In some embodiments of the methods provided herein, the subject has a muscular dystrophy, wherein the muscular dystrophy is selected from Becker muscular dystrophy (BMD), congenital muscular dystrophy, Duchenne muscular dystrophy (DMD), distal muscular dystrophy, Emery–Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb–girdle muscular dystrophy (LGMD), myotonic muscular dystrophy, X-linked DMD / BMD mutations of female carriers, and oculopharyngeal muscular dystrophy.

[0118] In some embodiments of the methods provided herein, the muscular dystrophy is Duchenne muscular dystrophy (DMD). In some embodiments of the methods provided herein, the muscular dystrophy is Becker muscular dystrophy (BMD). In some embodiments of the methods provided herein, the muscular dystrophy is X-linked DMD / BMD mutations of female carriers.

[0119] In some embodiments of the methods provided herein, the subject is a human of at least 1 year of age. In some embodiment, the subject is a human of at least 2 years of age. the subject is a human of at least 3 years of age. In some embodiment, the subject is a human of at least 4 years of age. In some embodiment, the subject is a human of at least 5 years of age. In some embodiment, the subject is a human of at least 6 years of age. In some embodiment, the subject is a human of at least 7 years of age. In some embodiment, the subject is a human of at least 8 years of age. In some embodiment, the subject is a human of at least 9 years of age. In some embodiment, the subject is a human of at least 10 years of age. In some embodiment, the subject is a human of at least 11 years of age. In some embodiment, the subject is a human of at least 12 years of age. In some embodiment, the subject is a human of at least 13 years of age. In some embodiment, the subject is a human of at least 14 years of age. In some embodiment, the subject is a human of at least 15 years of age. In some embodiment, the subject is a human of at least 16 years of age. In some embodiment, the subject is a human of at least 17 years of age. In some embodiment, the subject is a human of at least 18 years of age. In some embodiment, the subject is a human of at least 25 years of age. In some embodiment, the subject is from age 8 to 25. In some embodiment, the subject is from age 8 to 18. In some embodiment, the subject is from age 1 to 8. In some embodiment, the subject is a human of at least 25 years of age. In some embodiment, the subject is a human of at least 30 years of age. In some embodiment, the subject    is a human of at least 35 years of age. In some embodiment, the subject is a human of at least 40 years of age. In some embodiment, the subject is a human of at least 45 years of age. In some embodiment, the subject is a human of at least 50 years of age. In some embodiment, the subject is a human of at least 55 years of age. In some embodiment, the subject is a human of at least 60 years of age.

[0120] In some embodiments of the methods provided herein, the subject is a human of at least 2 years of age with elevated cardiac troponin (cTnI) based on a high sensitivity cardiac troponin assay. In some embodiments of the methods provided herein, the subject has elevated cardiac troponin (cTnI) based on a high sensitivity cardiac troponin assay.

[0121] In some embodiments of the methods provided herein, the subject is a boy of age 1 or above. In some embodiments of the methods provided herein, the subject is a boy of age 2 or above. In some embodiments of the methods provided herein, the subject is a boy of age 3 or above. In some embodiments of the methods provided herein, the subject is a boy of age 4 or above. In some embodiments of the methods provided herein, the subject is a boy of age 5 or above. In some embodiments of the methods provided herein, the subject is a boy of age 6 or above. In some embodiments of the methods provided herein, the subject is a boy of age 7 or above. In some embodiments of the methods provided herein, the subject is a boy of age 8 or above. In some embodiments of the methods provided herein, the subject is a boy of age 9 or above. In some embodiments of the methods provided herein, the subject is a boy of age 10 or above. In some embodiments of the methods provided herein, the subject is a boy of age 11 or above. In some embodiments of the methods provided herein, the subject is a boy of age 12 or above. In some embodiments of the methods provided herein, the subject is a boy of age 13 or above. In some embodiments of the methods provided herein, the subject is a boy of age 14 or above. In some embodiments of the methods provided herein, the subject is a boy of age 15 or above. In some embodiments of the methods provided herein, the subject is a boy of age 16 or above. In some embodiments of the methods provided herein, the subject is a boy of age 17 or above.

[0122] In some embodiments of the methods provided herein, the subject is a boy of age 8 or above. In some embodiments of the methods provided herein, the subject is a boy of age 10 or above.

[0123] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces serum cTnI levels in the subject. In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces serum phospho-cTnI levels in    the subject. In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces both serum cTnI and serum phospho-cTnI levels in the subject. In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces serum cTnI or serum phospho-cTnI levels in the subject.

[0124] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces cTnI Ca++sensitivity in the subject.

[0125] In some embodiments of the methods provided herein, administering of the TNNI3K inhibitor reduces immunogenic cTnI epitopes in the subject. In some embodiments of the methods provided herein, administering the TNNI3K inhibitor reduces immunogenic cTnI phospho-epitopes in the subject.

[0126] In some embodiments, administering the TNNI3K inhibitor reduces cardiac inflammation in the subject. In some embodiments, administering the TNNI3K inhibitor stabilizes or reduces cardiac fibrosis in the subject. In some embodiments, administering of the TNNI3K inhibitor reduces ischemic damage in the subject.

[0127] In some embodiments, administering the TNNI3K inhibitor reduces myocarditis and LV dysfunction in the subject. In some embodiments, administering the TNNI3K inhibitor reduces cardiac immune infiltration from isoproterenol-induced cardiac injury.

[0128] In some embodiments of the methods provided herein, administering the TNNI3K inhibitor reduces loss of cardiac function in the subject.

[0129] In some embodiments of the methods provided herein, the TNNI3K inhibitor is administered orally. In some embodiments of the methods provided herein, the TNNI3K inhibitor is administered parenterally. In some embodiments of the methods provided herein, the TNNI3K inhibitor is administered nasally.

[0130] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (I), or a pharmaceutically acceptable salt thereof,   Formula (I) wherein: R1is (C1-C4)alkyl; R2is hydrogen or halogen; R3is hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, aryl, hydroxyl, -(C1-C4)alkylhydroxyl, (C1-C4)alkoxy, -(C1-C4)alkylene-(C1-C4)alkoxy, (C1- C4)haloalkoxy, (C3-C6)cycloalkyloxy, -S-(C1-C4)alkyl, amino, -NH(C1-C4)alkyl, or -N((C1- C4)alkyl)2; R4is hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1- C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene-(C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3- C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(C3-C8)cycloalkyl, -S(=O)2(C1-C8)alkyl, - S(=O)2(C1-C8)haloalkyl, -S(=O)2(C3-C8)cycloalkyl, phenyl, 5-membered heteroaryl, amino, -NHRa, or -NRaRb; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1-C6)alkoxy, (C1- C4)haloalkoxy, -(C1-C4)alkylhydroxyl, and -N(Ra)(Rb); R5is hydrogen; or R4and R5taken together with intervening atoms to form a 5 or 6 membered ring, which ring may be unsubstituted, or substituted with one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1-C4)alkylhydroxyl, oxo, hydroxyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, and -S-(C1-C8)alkyl; each R6and R7is independently hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, heteroaryl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene-(C1-C4)alkoxyl, (C1-C4)haloalkoxy, (C3-C6)cycloalkyloxy, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(=O)2(C1- C8)alkyl , -NHRc, or -NRcRd; or R6and R7are taken together with the atoms to which they are attached, to form a (C3- C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl, wherein any said (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one to five substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, - C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, SRa, -S(=O)2(C1- C8)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1- C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORe, -(C1-C2)alkylhydroxyl, and -(C1-    C2)alkylene-ORa; or two of the substituents are taken together with the atoms to which they are attached, to form a (C4-C8)cycloalkyl, (C4-C8)heterocycloalkyl, aryl, or heteroaryl; each Reis, independently, (C1-C8)alkyl or a 5-6 membered heterocycloalkyl, wherein said (C1-C8)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, and -N(Ra)(Rb); each Rcand Rdis independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, - CO2H, -CO2Ra, -C(=O)NH2, C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1- C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, - NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1- C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1- C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, - S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, - NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa; each Raand Rbis independently selected from (C1-C4)alkyl, aryl, heterocycloalkyl, or - (C1-C2)alkylene-heterocycloalkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C6)alkoxy, amino, - NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -CO2H, -CO2(C1-C6)alkyl, -C(=O)NH2, -C(=O)NH(C1- C6)alkyl, and C(=O)N((C1-C6)alkyl)2, wherein any heterocycloalkyl is optionally substituted by (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached to form a 5-7 membered heterocyclic ring, wherein said ring is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino, - NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, -(C1-C4)alkylhydroxyl, oxo, (C1-C4)alkoxy, (C1- C4)haloalkoxy, and (C1-C4)alkoxy(C1-C4)alkyl; or a salt thereof.

[0131] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (I-A), or a pharmaceutically acceptable salt thereof,Formula (I-A) wherein: Rcis hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, - C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1-C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, - (C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3- C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, - C(=O)NHRa, -C(=O)NRaRb, SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, - ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa.

[0132] In some embodiments of Formula (I) or (I-A), R1is (C1-C4)alkyl. In some embodiments, R1is methyl.

[0133] In some embodiments of Formula (I) or (I-A), R2is hydrogen or halogen. In some embodiments, R2is hydrogen or fluorine. In some embodiments, R2is hydrogen. In some embodiments, R2is fluorine.

[0134] In some embodiments of Formula (I) or (I-A), R3is hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, aryl, hydroxyl, -(C1-C4)alkylhydroxyl, (C1-C4)alkoxy, -(C1-    C4)alkylene-(C1-C4)alkoxy, (C1-C4)haloalkoxy, (C3-C6)cycloalkyloxy, -S-(C1-C4)alkyl, amino, - NH(C1-C4)alkyl, or -N((C1-C4)alkyl)2. In some embodiments, R3is hydrogen, halogen, (C1- C4)alkyl, (C1-C4)haloalkyl, aryl, (C1-C4)alkoxy, -S-(C1-C4)alkyl, amino, or -N((C1-C4)alkyl)2. In some embodiments, R3is hydrogen, chlorine, or -N(Me)2. In some embodiments, R3is hydrogen.

[0135] In some embodiments of Formula (I) or (I-A), R2and R3are each hydrogen.

[0136] In some embodiments of Formula (I) or (I-A), R4is hydrogen, halogen, (C1-C8)alkyl, (C1- C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene- (C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3-C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, - S(=O)2(C1-C4)alkyl, amino, -NHRa, or -NRaRb.

[0137] In some embodiments of Formula (I) or (I-A), R4is hydrogen, halogen, (C1-C8)alkyl, (C1- C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene- (C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3-C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(C3- C8)cycloalkyl, -S(=O)2(C1-C8)alkyl, -S(=O)2(C1-C8)haloalkyl, -S(=O)2(C3-C8)cycloalkyl, phenyl, 5- membered heteroaryl, amino, -NHRa, or -NRaRb.

[0138] In some embodiments of Formula (I) or (I-A), R4is hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1- C8)alkylene-(C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3-C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1- C8)haloalkyl, -S(=O)2(C1-C8)alkyl, amino, -NH(C1-C4)alkyl, -NH(C1-C4)haloalkyl, -N((C1- C4)alkyl)2, -N((C1-C4)alkyl)((C1-C4)haloalkyl), -N((C1-C4)haloalkyl)2, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, wherein said pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino, , -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, oxo, (C1-C4)alkoxy, and (C1-C4)alkoxy(C1-C4)alkyl.

[0139] In some embodiments of Formula (I) or (I-A), R4is hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1- C8)alkylene-(C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3-C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1- C8)haloalkyl, -S(=O)2(C1-C8)alkyl, amino, -NH(C1-C4)alkyl, -NH(C1-C4)haloalkyl, -N((C1- C4)alkyl)2, -N((C1-C4)alkyl)((C1-C4)haloalkyl), -N((C1-C4)haloalkyl)2, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl. In some embodiments, R4is hydrogen, fluorine, chlorine, hydroxyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, isobutyloxy, 3-methyl-2-butyloxy, 3-pentyloxy, trifluoromethoxy, 2,2,2-    trifluoroethoxy, 1,1,1-trifluoro-2-propyloxy, 3,3,3-trifluoro-1-propyloxy, 1,1,1-trifluoro-2- methyl-2-propyloxy, 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyloxy, cyclopentyloxy, cyclohexyloxy, methylthio-, ethylthio-, isobutylthio-, 2,2,2-trifluoroethylthio-, methylsulfone, ethylsulfone, isopropylsulfone, isobutylsulfone, tert-butylsulfone, amino, dimethylamino, ethylmethylamino, diethylamino, methyl-2,2,2-trifluoroethylamino, 2-methylpyrrolidin-1-yl, (R)-2-trifluoromethylpyrrolidin-1-yl, 2,5-dimethylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3,3-difluoropiperidin-1-yl, or morpholin-4-yl.

[0140] In some embodiments of Formula (I) or (I-A), R4and R5taken together with intervening atoms to form a 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted, or substituted with one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1- C4)alkylhydroxyl, oxo, hydroxyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, and -S-(C1-C8)alkyl. In some embodiments, R4and R5taken together with intervening atoms to form a 5 or 6 membered ring, optionally containing one or two additional heteroatoms selected from N, O and S, which ring may be unsubstituted, or substituted with one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1-C4)alkylhydroxyl, (C1- C4)alkoxy, (C1-C4)haloalkoxy, and -S-(C1-C8)alkyl. In some embodiments, R4and R5taken together represent -CH2CH2-, -C(CH3)2CH2-, -CH=CH-, -NH(C=O)-, or -N=CH-. In a further specific embodiment of this invention, R4and R5taken together represent -CH2CH2-.

[0141] In some embodiments of Formula (I) or (I-A), R4and R5are taken together with intervening atoms to form a 5 membered heterocycloalkyl.

[0142] In some embodiments of Formula (I) or (I-A), Rcis (C1-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1- C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1- C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1- C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, - NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1- C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1- C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, SRa, -S(=O)2(C1-C4)alkyl, -    S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, - NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa.

[0143] In some embodiments of Formula (I) or (I-A), Rcis (C1-C6)alkyl, phenyl, dihydroindenyl, tetrahydronaphthalenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzothiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxolyl, or dihydrobenzodioxinyl, wherein said phenyl, dihydroindenyl, tetrahydronaphthalenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzothiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzodioxolyl, or dihydrobenzodioxinyl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, - CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1- C2)alkylCO2Ra, -(C1-C2)alkylcyano, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, - S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1- C2)alkylene-NRaRb, -(C1-C2)alkylene-triazolyl, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1- C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, - C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, - (C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa.

[0144] In some embodiments of Formula (I) or (I-A), Rcis (C1-C6)alkyl, phenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, chromenyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzothiazolyl, dihydrobenzoisothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or dihydrobenzodioxinyl, wherein said phenyl, oxazolyl, thiazolyl, thiadiazolyl, pyridinyl, indolyl, indazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, benzothiazolyl, dihydrobenzoisothiazolyl,    quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or dihydrobenzodioxinyl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -(C1- C2)alkylCO2H, -(C1-C2)alkylCO2Ra, -(C1-C2)alkylcyano, -SRa, -S(=O)2(C1-C4)alkyl, - S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, - (C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, -(C1-C2)alkylene-triazolyl, -NHC(=O)(C1- C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1- C2)alkylene-ORa, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, - C(=O)NHRa, -C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, - S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa.

[0145] In some embodiments of Formula (I) or (I-A), Rcis phenyl optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, - CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1-C2)alkylCO2Ra, - (C1-C2)alkylcyano, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1-C2)alkylene- NRaRb, -(C1-C2)alkylene-triazolyl, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, and pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or pyridinyl is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1- C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, - C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, - (C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa.

[0146] In some embodiments of Formula (I) or (I-A), Rcis phenyl optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -    C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1-C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, - S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, - (C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1- C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, phenyl, thienyl, pyrazolyl, imidazolyl, and pyridinyl, wherein said phenyl, thienyl, pyrazolyl, imidazolyl, or pyridinyl is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, - S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, - NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene- ORa.

[0147] In some embodiments of Formula (I) or (I-A), Rcis pyridinyl optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, - C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1-C2)alkylCO2Ra, -(C1-C2)alkylcyano, -SRa, -S(=O)2(C1- C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1- C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, -(C1-C2)alkylene-triazolyl, - NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, and -(C1-C2)alkylene-ORa.

[0148] In some embodiments of Formula (I) or (I-A), Rcis pyridinyl optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, or cyano.

[0149] In some embodiments of Formula (I) or (I-A), Rcis methyl, ethyl, oxazol-2-yl, oxazol- 5-yl, 4-methyl-oxazol-2-yl, thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 4-isopropyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 4-carboxymethyl-thiazol-2-yl, 4-(methoxycarbonyl)methyl-thiazol-2-yl, 5-carboxy-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, 3-fluoro-pyridin-2-yl, 5-fluoro- pyridin-2-yl, 5-chloro-pyridin-2-yl, 5-isopropyl-pyridin-2-yl, 5-trifluoromethyl-pyridin-2-yl, 5- cyano-pyridin-2-yl, 5-chloro-3-fluoro-pyridin-2-yl, 3,5-dichloro-pyridin-2-yl, 4,5-dichloro- pyridin-2-yl, 5-chloro-4-methyl-pyridin-2-yl, 5-chloro-6-methyl-pyridin-2-yl, 5-bromo-6- methyl-pyridin-2-yl, 6-bromo-4-methyl-pyridin-2-yl, pyridin-3-yl, 5-methyl-pyridin-3-yl, 6- trifluoromethyl-pyridin-3-yl, 5-methylsulfonamide-pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, 2,3-dihydro-1H-inden-5-yl, 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl, 1H-indol-5-yl, 1H-indol-6- yl, 1-acetyl-2,3-dihydro-1H-indol-6-yl, 2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl, 1H-    indazol-5-yl, 1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, 2- oxo-2,3-dihydro-1H-indol-6-yl, 2-methyl-4-oxo-4H-chromen-7-yl, 4-methyl-2-oxo-2H- chromen-7-yl, 2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 2-oxo-2,3-dihydro-1,3-benzoxazol-6- yl, 2-methyl-1,3-benzothiazol-5-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,1-dioxido- 2,3-dihydro-1,2-benzisothiazol-6-yl, quinolin-2-yl, quinolin-6-yl, isoquinolin-3-yl, 4-methyl-2- oxo-1,2-dihydroquinolin-7-yl, 2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl, 2-oxo-1,2,3,4- tetrahydroquinolin-7-yl, 1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3-fluoro-4- chlorophenyl, 3-bromo-4-chlorophenyl, 3-bromo-5-chlorophenyl, 3,4,5-trifluorophenyl, 3- methylphenyl, 4-methylphenyl, 3-isopropyl phenyl, 4-isopropylphenyl, 4-sec-butylphenyl, 3- tert-butylphenyl, 4-tert-butylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-methylphenyl, 3-bromo-5-methylphenyl, 3- ethynylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-fluoro-4- trifluoromethylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methyl-3-trifluoromethylphenyl, 4- cyclopropylphenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(thien-2-yl)phenyl, 4-(1H-pyrazol-1- yl)phenyl, 4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl, 4-(2-methyl-1H-imidazol-1-yl)phenyl, 4- (oxazol-5-yl)phenyl, 3-(2-methyl-thiazol-4-yl)phenyl, 3-biphenylyl, 3'-aminocarbonyl-3- biphenylyl, 4'-aminocarbonyl-3-biphenylyl, 3'-dimethylamino-3-biphenylyl, 4'-dimethylamino- 3-biphenylyl, 4'-morpholin-4-yl-3-biphenylyl, 3'-acetylamino-3-biphenylyl, 4'-acetylamino-3- biphenylyl, 3'-[(methylsulfonyl)amino]-3-biphenylyl, 4'-[(methylsulfonyl)amino]-3-biphenylyl, 3'-[(methylamino)sulfonyl]-3-biphenylyl, 4'-[(methylamino)sulfonyl]-3-biphenylyl, 5-methyl-3- biphenylyl, 4-chloro-3'-morpholin-4-yl-3-biphenylyl, 4-chloro-3'-aminocarbonyl-3-biphenylyl, 3-(4-methoxy-pyridin-3-yl)phenyl, 3-(5-methoxy-pyridin-3-yl)phenyl, 3-(6-methoxy-pyridin-3- yl)phenyl, 3-(6-oxo-pyridin-3-yl)phenyl, 3-(6-dimethylamino-pyridin-3-yl)phenyl, 5-methyl-3- (pyridin-3-yl)phenyl, 4-chloro-3-(pyridin-3-yl)phenyl, 4-(cyanomethyl)phenyl, 3-(1- pyrrolidinylmethyl)phenyl, 3-[(4-methyl-1-piperazinyl)methyl]phenyl, 4-(1H-1,2,4-triazol-1- ylmethyl)phenyl, 4-(4H-1,2,4-triazol-4-ylmethyl)phenyl, 3-acetylphenyl, 4-acetylphenyl, 4- carboxyphenyl, 4-[(methoxy)carbonyl]phenyl, 4-[(isopropoxy)carbonyl]phenyl, 3- aminocarbonylphenyl, 4-aminocarbonylphenyl, 4-(methylamino)carbonylphenyl, 4- (dimethylaminoethylamino)carbonylphenyl, 4-(hydroxyethylamino)carbonylphenyl, 4- (methoxyethylamino)carbonylphenyl, 4-(methoxypropylamino)carbonylphenyl, 4- (carboxymethylamino)carbonylphenyl, 4-[(1-methyl-piperidin-4-yl)amino]carbonylphenyl, 3-    (phenylamino)carbonylphenyl, 4-(phenylamino)carbonylphenyl, 4-(d imethylamino)carbonylphenyl, 4-(diethylamino)carbonylphenyl, 4-[N-methyl-N-(N',N'- dimethylaminoethyl)amino]carbonylphenyl, 4-(pyrrolidin-1-yl)carbonylphenyl, 4-[(3S)-3- (dimethylamino)pyrrolidin-1-yl]carbonylphenyl, 4-[(3R)-3-(dimethylamino)pyrrolidin-1- yl]carbonylphenyl, 4-(4,4-difluoropiperidin-1-yl)carbonylphenyl, 4-(morpholin-4- yl)carbonylphenyl, 4-(thiomorpholin-4-yl)carbonylphenyl, 4-(piperazin-1-yl)carbonylphenyl, 4- (4-methyl-piperazin-1-yl)carbonylphenyl, 4-(4-methoxyethyl-piperazin-1-yl)carbonylphenyl, 4- (4-methyl-hexahydro-1H-1,4-diazepin-1-yl)carbonylphenyl, 4-cyanophenyl, 3-chloro-4- cyanophenyl, 3-nitrophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3-(pyrrolidin-1- yl)phenyl, 4-(piperidin-1-yl)phenyl, 4-(piperazin-1-yl)phenyl, 3-(morpholin-4-yl)phenyl, 4- (morpholin-4-yl)phenyl, 3-(4-methyl-piperazin-1-yl)phenyl, 3-(acetylamino)phenyl, 4- (acetylamino)phenyl, 3-(propionylamino)phenyl, 4-(2-oxo-pyrrolidin-1-yl)phenyl, 3- [(methylsulfonyl)amino]phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-d ifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-ethoxyphenyl, 3-(2,2,2- trifluoroethoxy)phenyl, 4-isopropoxyphenyl, 3-(carboxymethyloxy)phenyl, 3- [(isopropoxycarbonyl)methyloxy]phenyl, 3-[(dimethylaminocarbonyl)methyloxy]phenyl, 4- (methoxyethyloxy)phenyl, 4-(dimethylaminoethyloxy)phenyl, 4-(diethylaminoethyloxy)phenyl, 4-[(morpholin-4-yl)ethyloxy]phenyl, 3-fluoro-4-methoxyphenyl, 3-chloro-4-hydroxyphenyl, 3- chloro-4-methoxyphenyl, 4-chloro-3-methoxyphenyl, 3-methoxy-5-trifluoromethylphenyl, 4- methoxy-3-trifluoromethylphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,5-dichloro-4- hydroxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-(methylthio)phenyl, 4- (trifluoromethylthio)phenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3- aminosulfonylphenyl, 3-(methylamino)sulfonylphenyl, 4-(methylamino)sulfonylphenyl, 3- (ethylamino)sulfonylphenyl, 3-(isopropylamino)sulfonylphenyl, 3- (dimethylamino)sulfonylphenyl, or 3-(morpholin-4-yl)sulfonylphenyl.

[0150] In some embodiments of Formula (I) or (I-A), Rais independently selected from (C1- C4)alkyl, aryl, heterocycloalkyl, or -(C1-C2)alkylene-heterocycloalkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C6)alkoxy, amino, -NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -CO2H, -CO2(C1-C6)alkyl, -C(=O)NH2, -C(=O)NH(C1-C6)alkyl, and C(=O)N((C1-C6)alkyl)2, wherein any heterocycloalkyl is optionally substituted by (C1-C4)alkyl.

[0151] In some embodiments of Formula (I) or (I-A), Rais independently selected from (C1- C4)alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or    pyrrolidinyl(C1-C2)alkyl, piperidinyl(C1-C2)alkyl, morpholinyl(C1-C2)alkyl, thiomorpholinyl(C1- C2)alkyl, and piperazinyl(C1-C2)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -CO2H, -CO2(C1-C4)alkyl, -C(=O)NH2, -C(=O)NH(C1- C4)alkyl, and -C(=O)N((C1-C4)alkyl)((C1-C4)alkyl); and wherein any pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl is optionally substituted by (C1-C4)alkyl. In some embodiments, Rais methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, dimethylaminoethyl, diethylaminoethyl, hydroxyethyl, methoxyethyl, methoxypropyl, carboxymethyl, (isopropoxycarbonyl)methyl, (dimethylaminocarbonyl)methyl, phenyl, 1- methyl-piperidin-4-yl, or (morpholin-4-yl)ethyl.

[0152] In some embodiments of Formula (I) or (I-A), Rbis (C1-C4)alkyl. In some embodiments, Rbis methyl or ethyl.

[0153] In some embodiments of Formula (I) or (I-A), Raand Rbare taken together with the nitrogen to which they are attached to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, -(C1- C4)alkylhydroxyl, oxo, (C1-C4)alkoxy, (C1-C4)haloalkoxy, and (C1-C4)alkoxy(C1-C4)alkyl.

[0154] In some embodiments of Formula (I) or (I-A), Raand Rbare taken together with the nitrogen to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or hexahydro-1H-1,4-diazepinyl, each is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C4)alkyl, (C1- C4)haloalkyl, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, oxo, (C1-C4)alkoxy, and (C1-C4)alkoxy(C1-C4)alkyl. In some embodiments, Raand Rbare taken together with the nitrogen to which they are attached to form pyrrolidinyl, 2-methylpyrrolidinyl, 2- trifluoromethylpyrrolidinyl, 3-(dimethylamino)pyrrolidinyl, 2-oxo-pyrrolidinyl, 2,5- dimethylpyrrolidinyl, 3,3-difluoropyrrolidinyl, piperidinyl, 3,3-difluoropiperidinyl, 4,4- difluoropiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4- methoxyethylpiperazinyl, or 4-methyl-hexahydro-1H-1,4-diazepinyl.

[0155] Exemplary compounds of Formula (I-A) include the compounds described in the following Table 1:    TABLE 1

[0156] In some embodiments of the methods provided herein, the TNNI3K inhibitor is 3-((6- ((5-chloropyridin-2-yl)amino)pyrimidin-4-yl)amino)-4-(ethylsulfonyl)-N- methylbenzenesulfonamide, having the structure of:or a pharmaceutically acceptable salt thereof.

[0157] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (I-B), or a pharmaceutically acceptable salt thereof,Formula (I-B) wherein: each R8, R9, and R10are each, independently, H, halogen, nitro, amino, -NH(Ci-C4)alkyl, - N((Ci-C4)alkyl)2, hydroxyl, or ORe; and each Reis, independently, (Ci-C8)alkyl or a 5-6 membered heterocycloalkyl, wherein said (Ci-C8)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (Ci-C4)alkoxy, amino, -NH(Ci-C4)alkyl, and -N(Ra)(Rb); or R9and R10are taken together with the intervening atoms to form a five or six membered heterocycle.

[0158] In some embodiments of Formula (I) or (I-B), R1is -CH3.

[0159] In some embodiments of Formula (I) or (I-B), R2is hydrogen or fluorine. In some embodiments, R2is hydrogen. In some embodiments, R2is fluorine.

[0160] In some embodiments of Formula (I) or (I-B), R4is hydrogen, halogen, (Ci-Cs)alkyl, (Ci- Csjhaloalkyl, (Ch-Csjcycloalkyloxy, hydroxyl, -(Ci-Cs)alkylhydroxyl, (Ci-Cs)alkoxy, (Ci-C8)haloalkoxy, -S(Ci-C8)alkyl, -S(Ci-C8)haloalkyl, -S(C3-C8)cycloalkyl, -S(=O)2(Ci-C8)alkyl, - S(=O)2(Ci-C8)haloalkyl, -S(=O)2(C3-C8)cycloalkyl, phenyl, 5-membered heteroaryl, or -NRaRb; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (Ci-Ce)alkyl, (Ci-C4)haloalkyl, (Ci-Ce)alkoxy, (Ci- C4)haloalkoxy, -(Ci-C4)alkylhydroxyl, and -N(Ra)(Rb).

[0161] In some embodiments of Formula (I) or (I-B), R4is hydrogen, halogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl, (Ci-Ce)alkoxy, (Cs-Cejcycloalkyloxy, (Ci-Ce)haloalkoxy, -S(Ci-Ce)alkyl, - S(Ci-C6)haloalkyl, -S(C5-C6)cycloalkyl, -S(=O)2(Ci-C6)alkyl, -S(=O)2(Ci-C6)haloalkyl, - S(=O)2(C5-C6)cycloalkyl, phenyl, 5-membered heteroaryl, or -NRaRb; wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionallyWSGR Ref. No.: 65669-701.601   contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1-C6)alkoxy, and -N(Ra)(Rb).

[0162] In some embodiments of Formula (I) or (I-B), R4is hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, hydroxy, -(C1-C8)alkylhydroxy, (C1-C8)alkoxy, (C3-C8)cycloalkyloxy, (C1- C8)haloalkoxy, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(C3-C8)cycloalkyl, phenyl, 5-membered heteroaryl, or -NRaRb; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1- C6)alkoxy, (C1-C4)haloalkoxy, -(C1-C4)alkylhydroxy, and -N(Ra)(Rb).

[0163] In some embodiments of Formula (I) or (I-B), R4is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, -(C1-C6)alkylhydroxy, (C1-C6)alkoxy, (C3-C6)cycloalkyloxy, (C1- C6)haloalkoxy, -S(C1-C6)alkyl, -S(C1-C6)haloalkyl, -S(C3-C6)cycloalkyl, phenyl, 5-membered heteroaryl, or -NRaRb; wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1- C6)alkoxy, and -N(Ra)(Rb).

[0164] In some embodiments of Formula (I) or (I-B), R4is hydrogen, halogen, (C1-C4)alkoxy, (C5-C6)cycloalkyloxy, (C1-C4)haloalkoxy, -S(C1-C4)alkyl, -S(C1-C4)haloalkyl, -S(C5- C6)cycloalkyl, -S(=O)2(C1-C4)alkyl, -S(=O)2(C1-C4)haloalkyl, -S(=O)2(C5-C6)cycloalkyl, or - NRaRb.

[0165] In some embodiments of Formula (I) or (I-B), R4is H, F, CI, -OCH3,-OCH(CH3)2, - OCF3, -OCH2CF3, -OCH(CH3)CF3, -SCH3, -SCH2CF3, -SO2CH3, -N(CH3)2, -N(CH3)CH2CH3, - N(CH3)CH2CF3, 2-(trifluoromethyl)pyrrolidin-1-yl, 2,5-(dimethyl)pyrrolidin-1-yl, piperidin-1-yl, 4,4-difluoro-piperidin-1-yl, or morpholin-4-yl.

[0166] In some embodiments of Formula (I) or (I-B), Rais independently -CH3, -CH2CH3, or -CH2CF3; and Rbis -CH3; or Raand Rbtaken together with the nitrogen to which they are attached to form pyrrolidin-1-yl, piperidin-1-yl, or morpholin-4-yl, wherein said pyrrolidine-1-yl, piperidin-1-yl, 104    or morpholin-4-yl is optionally substituted with one or two substituents, independently, selected from F, -CH3, and -CF3.

[0167] In some embodiments of Formula (I) or (I-B), each R8, R9, and R10are each, independently, H, halogen, nitro, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, or ORe; and each Reis, independently, (C1-C8)alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydro-4H-1,4-thiazinyl, or 1,4- dioxanyl, wherein said (C1-C8)alkyl is optionally substituted by halogen, hydroxyl, trifluoromethyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydro-4H-1,4-thiazinyl, or 1,4-dioxanyl; or R9and R10are taken together with the intervening atoms to form a five or six membered heterocycle.

[0168] In some embodiments of Formula (I) or (I-B), R9and R10are each ORe; and each Reis, independently, (C1-C8)alkyl, optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1- C4)alkyl, or -N((C1-C4)alkyl)2.

[0169] In some embodiments of Formula (I) or (I-B), R9is H, CI, I, -OCH3, -OCH2CH3, - OCH(CH3)2, -O(CH2)2OCH3, -O(CH2)3-morpholin-4-yl, -NH2, -NHCH3, or -N(CH3)2.

[0170] In some embodiments of Formula (I) or (I-B), R9is H.

[0171] In some embodiments of Formula (I) or (I-B), R10is H, -OH, -OCH3, -OCH2CH3, - OCH(CH3)2, -O-(CH2)2CH2Cl, -O-(CH2)2-O-CH3, -O-(CH2)3-O-CH3, -O(CH2)3-morpholin-4-yl, - NH2, -NHCH3, or -NO2.

[0172] In some embodiments of Formula (I) or (I-B), R9and R10are taken together to form -O- (C1-C2)alkyl-O-.

[0173] In some embodiments of Formula (I) or (I-B), R1is (C1-C4)alkyl; R2is hydrogen or halogen; R4is hydrogen, halogen, (C1-C4)alkoxy, (C5-C6)cycloalkyloxy, (C1-C4)haloalkoxy, -S(C1- C4)alkyl, -S(C1-C4)haloalkyl, -S(C5-C6)cycloalkyl, -S(O)2(C1-C4)alkyl, -S(O)2(C1-C4)haloalkyl, - S(O)2(C5-C6)cycloalkyl, or -NRaRb;    each Rais independently (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, by halogen, hydroxyl, (C1-C4)alkoxy, amino, - NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -CO2H, -CO2(C1-C4)alkyl, -C(=O)NH2, -C(=O)NH(C1- C4)alkyl, or -C(=O)N((C1-C4)alkyl)(( C1-C4)alkyl), wherein any heterocycloalkyl is optionally substituted by (C1-C4)alkyl; Rbis (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached represent a 5- membered or 6-membered heterocyclic ring, wherein said ring is optionally substituted with one or two substituents, independently, by halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino, - NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, -(C1-C4)alkylhydroxyl, oxo, (C1-C4)alkoxy, (C1- C4)haloalkoxy, or (C1-C4)alkoxy(C1-C4)alkyl; R5is hydrogen; each R8, R9, and R10are each, independently, H, halogen, nitro, amino, -NH(C1-C4)alkyl, - N((C1-C4)alkyl)2, hydroxyl, or ORe; and each Reis, independently, (C1-C4)alkyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydro-4H-1,4- thiazinyl, or 1,4-dioxanyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, by halogen, hydroxyl, trifluoromethyl, (C1-C4)alkoxy, amino, - NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydro-4H-1,4-thiazinyl, or 1,4- dioxanyl; or R9and R10taken together represent -O-(C1-C2)alkyl-O-; or a salt thereof.

[0174] In some embodiments of Formula (I) or (I-B), R1is (C1-C3)alkyl; R2is hydrogen; R4is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, -(C1-C6)alkylhydroxy, (C1- C6)alkoxy, (C3-C6)cycloalkyloxy, (C1-C6)haloalkoxy, -S(C1-C6)alkyl, -S(C1-C6)haloalkyl, -S(C3- C6)cycloalkyl, aryl, 5-membered heteroaryl, or -NRaRb; wherein said heteroaryl contains one heteroatom selected from N, O and S, or contains one nitrogen atom and optionally contains 1 additional heteroatom selected from N, O and S, or contains two nitrogen atoms and optionally contains 1 additional heteroatom selected from N, O and S;    wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, by halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, or -N(Ra)(Rb); each Rais independently (C1-C4)alkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, by hydroxyl, trifluoromethyl, (C1-C6)alkoxy, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, and Rbis (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached represent a 5- membered or 6-membered heterocyclic ring, wherein said ring is optionally substituted with one or two substituents, independently, by (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1- C4)alkylhydroxyl, oxo, or (C1-C4)alkoxy(C1-C4)alkyl; R5is hydrogen; R8is hydrogen; R9, and R10are each ORe; and each Reis, independently, (C1-C4)alkyl, optionally substituted with one to three substituents, by halogen.

[0175] Exemplary compounds of Formula (I-B) include the compounds described in the following Tables 2: TABLE 2:

[0176] In some embodiments of the methods provided herein, the TNNI3K inhibitor is 3-((6,7- dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide, having the structure of:or a pharmaceutically acceptable salt thereof.

[0177] Disclosed herein is a method of treating muscular dystrophy in a subject in need thereof, the method comprising administering to the subject a TNNI3K inhibitor comprises a structure of Formula (II), or a pharmaceutically acceptable salt thereof,    wherein: R11is halogen, (C1-C4)alkyl, or -ORf; R12is H, halogen, (C1-C4)alkyl, or -ORf; and Rfis (C1-C4)alkyl which is optionally substituted with one to three halogen.

[0178] In some embodiments of Formula (II), R11is selected from chloro, fluoro, bromo, methyl, ethyl, methoxy, and trifluoromethoxy; and R12is selected from hydrogen, chloro, fluoro, bromo, and methyl.

[0179] In some embodiments of Formula (II), R11is selected from chloro, fluoro, bromo, and methyl. In some embodiments, R11is chloro. In some embodiments, R11is fluoro. In some embodiments, R11is bromo. In some embodiments, R11is methyl. In some embodiments, R11is ethyl. In some embodiments, R11is methoxy. In some embodiments, R11is trifluoromethoxy.

[0180] In some embodiments of Formula (II), R12is selected from chloro, fluoro, bromo, and methyl. In some embodiments, R12is hydrogen. In some embodiments, R12is chloro. In some embodiments, R12is fluoro. In some embodiments, R12is bromo. In some embodiments, R12is methyl.

[0181] Exemplary compounds of Formula (II) include the compounds described in the following Tables 3: TABLE 3:

[0182] In some embodiments of the methods provided herein, the TNNI3K inhibitor is 1-(3,5- dichloro-4-((6-(methylamino)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea, having the structure of:or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments of the methods provided herein, the TNNI3K inhibitor is selected from the compounds of Table 4, or a pharmaceutically acceptable salt thereof, TABLE 4:                     Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[0184] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[0185] In some embodiments, the compounds described herein exist in their isotopically- labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to    those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,l5N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents.

[0186] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0187] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0188] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0189] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts    including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1- napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0190] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-1- carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0191] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a    pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4 alkyl)4 hydroxide, and the like.

[0192] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0193] A method described herein further encompasses administering solvates of herein- disclosed TNNI3K inhibitors. Solvates may involve nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. Pharmaceutical Compositions and Administration

[0194] Provided herein are a pharmaceutical composition comprising a compound of Formula (I), (I-A), (I-B), (II), Table 1, 2, 3, 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0195] In some embodiments, the pharmaceutical composition contains one compound of Formula (I), (I-A), (I-B), (II), Table 1, 2, 3, 4, or a pharmaceutically acceptable salt thereof.

[0196] The compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.

[0197] In some embodiments, compounds and the pharmaceutically-acceptable excipient or excipients will be formulated into a dosage form adapted for administration to the patient by the desired route of administration.

[0198] In some embodiments, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form. In some embodiments, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.

[0199] In some embodiments, a method described herein does not substantially change the weight of the subject. In some embodiments, the administering of a compound described herein to a subject does not substantially change the weight of the subject. In some embodiments, the pharmaceutical compositions are provided in a dosage form that does not substantially change the weight of the subject. In some embodiments, the weight change of the subject is less than ±5%. In some embodiments, the weight change of the subject is less than ±10%. In some embodiments, the weight change of the subject is less than ±20%. In some embodiments, the weight change of the subject is less than ±30%. In some embodiments, the weight change of the subject is 0% to 40%. In some embodiments, the weight change of the subject is 0% to 5%. In some embodiments, the weight change of the subject is 5% to 10%. In some embodiments, the weight change of the subject is 10% to 15%. In some embodiments, the average subject weight change over a dosage schedule is 0% to 5%. In some embodiments, the weight change is determined over a period of time. In some embodiments, the weigh change is determined over a period of time, e.g., 2 years, 1 year, 6 months, 3 months, 2 months, or 1 months. In some embodiments, the weigh change is determined over a period of one year. In some embodiments, the weigh change is determined over a period of 6 months.

[0200] These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, NY, 2008).

[0201] In some embodiments, TNNI3K inhibitors described herein or salts thereof is administered in an amount of about 0.1 mg to 1000 mg to the patient. In some embodiments, in the treatment, prevention, or amelioration of one or more symptoms of the disorders, diseases, or conditions described herein, an appropriate dosage level of compounds of Formula (I), (I-A), (I- B), (II), Table 1, 2, 3, 4, or a pharmaceutically acceptable salt thereof, ranges from about 1 to    about 1000 mg. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated. EXAMPLES

[0202] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); µL, (microliters); M (molar); mM (millimolar), µM (micro molar); eq. (equivalent); mmol (millimoles), Hz (Hertz), MHz (megahertz); hr or hrs (hour or hours); min (minutes); and MS (mass spectrometry).

[0203] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.

[0204] Syntheses of compounds of Formula (I), (I-A), (I-B), (II), Table (I), (II), (III), and (IV) are described in WO2011056740A1, US20120220588A1, US8859571B2, WO2011025798A1, US20120157482A1, WO2011088027A1, US20120329784A1, Molecules.2020 Apr; 25(7): 1697, Eur. J. Med. Chem.2020,197, 112314, J. Med. Chem.2021, 64, 21, 15651–15670, which are incorporated by reference for such disclosure. Biology Examples

[0205] The present invention is explained in more detail in the following Examples, which are not to be construed as limitative, and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims. Example 1: Protocol for determination of cardiac infiltrates (immunophenotyping) example protocol Muscle Digestion, Generation of Single-Cell Suspensions, and Density-Dependent Centrifugation

[0206] Eight-week-old C57BL / 10 (n = 6M), mdx (n = 3M and 3F), and Het (n = 3M and 3F) mice are euthanized via cervical dislocation, and muscle tissue are harvested, rinsed in cold Dulbecco’s phosphate-buffered saline without CaCl2 or MgCl2 (Thermo Fisher; A1285601), and weighed. Tissues are finely minced with a razor blade and incubated in 10 mL / g digestion buffer (Dulbecco’s modified Eagle’s medium; Thermo Fisher; 21013024; 0.02% Collagenase P; Sigma; 11213857001; 0.1% RQ1 DNase) at 37°C for 30 minutes. The digested tissues are triturated using a 5-mL pipet coated in fetal bovine serum (R&D; S11150), and 3 mL of autoMACS Running Buffer (Miltenyi Biotec, Bergisch Gladbach, Germany; 130091221) is added to quench collagenase P enzymatic activity. For the direct primary immune cell isolation method, 70- and 40-μm filtrations are performed to obtain single-cell suspensions and then cells are subsequently fixed in 1% paraformaldehyde (Sigma; P6148) in Dulbecco’s phosphate- buffered saline on ice for 10 minutes. For the density-dependent immune cell isolation method, filtered single-cell suspensions are carefully overlaid on 10 mL of either histopaque (Sigma; 10771) or lympholyte (Cedarlane, Burlington, NC; CL5031) and centrifuged at 400 × g for 30 minutes with no brake. Following separate interface and pellet collection, a wash step in autoMACS Running Buffer is performed before fixation. For the comparison between cell isolation methods, six pairs of mdx quadriceps (n = 3M and 3F) are pooled and separated into three aliquots for equal distribution of cells between the three different isolation techniques. For blood leukocyte isolation, 50 μL of blood obtained via submandibular blood collection is incubated with 2 mL of RBC Lysis Buffer (Thermo Fisher; 00433357) for 5 minutes and then fixed, as described earlier in this paragraph. Staining and analytical flow cytometry are completed within 24 to 96 hours of fixation for all experiments. Cardiac and Skeletal Muscle Single-Cell Suspension Staining and Flow Cytometry

[0207] Following fixation of the single-cell suspensions, volumes of each sample are measured and adjusted to equal volumes with autoMACS Running Buffer. Flow cytometry antibodies used are as follows: CD45 (phycoerythrin-Cy7; Thermo Fisher; 25045182), CD11b (allophycocyanin; Biolegend, San Diego, CA; 101212), F4 / 80 (fluorescein isothiocyanate; Biolegend; 123108), LY6C (eFluo450; Thermo Fisher; 48593282), LY6G (allophycocyanin / FIRE750; Biolegend; 127652),CD3 (PE-CF94), CD19 (BB700). An aliquot (100 μL) of each sample is taken in round-bottom 5-mL flow tubes, and extracellular staining is performed for 45 minutes on ice. Excess antibody is washed using autoMACS Running Buffer, followed by intracellular staining using 40 μL of 0.5% Tween-20 (Sigma; P1379) in Dulbecco’s phosphate-buffered saline as the permeabilizer. UltraComp eBeads (Thermo Fisher; 01222242)    are used as single-color controls for compensation. Samples are washed again with autoMACS Running Buffer, and as an internal control 2000 (2 μL) AccuCount Blank Particles (Spherotech, Lake Forest, IL; ACBP10010) are added to each sample before flow cytometry to enable calculation of total cell counts in each sample. Immune cell populations are gated with the markers to distinguish the following populations: immune (CD45+), myeloid enriched (CD45+ CD11b+), neutrophils (CD45+ CD11b+ LY6G+), macrophages (CD45+ CD11b+ LY6G− F4 / 80Hi / Lo), infiltrating monocytes (CD45+ CD11b+ LY6G− F4 / 80Lo LY6CHi), and patrolling monocytes (CD45+ CD11b+ LY6G− F4 / 80Lo LY6CLo). Samples are acquired using a flow cytometer and analyzed using FlowJo software. Example 2: H&E Scoring example procedure

[0208] Tissue sections (5 μm) are stained with H&E for routine histopathology and then evaluated by a board-certified veterinary pathologist in a blinded manner. Sections are evaluated on six separate criteria: inflammation, myofiber degeneration necrosis, myofiber regeneration, fibrosis, edema, and mineralization. Each criterion is evaluated on a scale of 0 (absent / within normal limits), 1 (<10% of tissue section affected), 2 (10–50% of tissue affected), or 3 (>50% of tissue affected). All slides are examined using an Olympus BX51 light microscope, and photomicrographs are taken using an Olympus DP73 camera. Example 3: Fibrosis scoring example protocol

[0209] Histology: Heart ventricles are embedded in tissue-freezing medium after dissection (O.C.T. Compound, Sakura, 4583) and snap-frozen in liquid nitrogen-cooled isopentane. Frozen heart ventricles are cut into 8 μm sections and stored at −20 °C until use. The sections are stained with Sirius red or Sirius red / picric acid (both from Sigma-Aldrich, St. Louis, MO, USA). Quantification of collagen deposition is determined using the Color Deconvolution plugin (by G. Landini) of ImageJ software. Example 4: Western blot of cardiac lysates (SimpleWes) example protocol

[0210] Total heart protein is isolated using RIPA buffer (Cell Signaling Technology, USA). The automated western blot is performed using Simple Wes (Protein Simple, USA) following the manufacturer’s protocol. Briefly, 2.5 μg of protein from the lysates is added to the standard fluorescent mastermix, then is loaded into corresponding wells of the prefilled Wes assay plate, along with antibody diluent (Protein Simple, USA), primary antibody [eg; anti-p-p38(Cell Signaling Technology, USA)], loading control anti-β-Tublin (Affinity, USA), anti-rabbit secondary antibody (Protein Simple, USA), and Streptavidin-HRP, followed by luminal peroxide mix. The imaging and analysis are done with compass software (Protein Simple).    Example 5: Serum ELISA for cTnI example protocol

[0211] Terminal blood lood (~1 ml) is drawn from the anesthetized mouse. Blood is collected in a non-coated eppendorf tube, is allowed to clot at room temperature for 10 min and stored on ice. Samples are centrifuged at 1700 g for 10 min at 4 °C and stored at −80 °C. Levels of cardiac Troponin I and NT-proBNP are measured using the High Sensitivity Mouse Cardiac Troponin-I ELISA Kit (Life Diagnostics, USA). Example 6: Procedure Summary for Study A

[0212] Study A consists of a 6-month dosing regimen. The dosing regimen was applied to naturally progressing X-linked muscular dystrophy (mdx) mice (Duchenne Muscular Dystrophy model) over the six-month period. Four cohorts of mice were treated starting at an age of 8 weeks, demonstrated below: Cohort 1: 8-week old WT (normal) mice under 6-month treatment, with Control (unmedicated) diet; Cohort 2: 8-week old mdx mice (muscular dystrophy model) under 6-month treatment, with Control (unmedicated) diet; Cohort 3: 8-week-old mdx mice (muscular dystrophy model) under 6-month treatment, with 40 mg / kg wt / wt diet of a compound disclosed herein; Cohort 4: 8-week-old mdx mice (muscular dystrophy model) under 6-month treatment, with 100 mg / kg wt / wt diet of a compound disclosed herein. Mouse Plasma Sample Preparation for Compound 321 Measurement

[0213] Mouse plasma samples were prepared in acetonitrile organic phase tolbutamide internal standards and analyzed by LC-MS / MS on Zorbax SB-C185µ 50*2.1mm columns using Perkin Elmer PE Series 200. Flow rate was set at 1.000mL / min and 0.1% formic acid in water was used as the aqueous phase. Standard curves were similarly prepared and covered 5 to 5000 ng / mL range. Low, Medium, and High Quality Control samples consisting of, respectively, 15, 1880, and 3760 ng / mL analyte were also assessed. Flow Cytometry

[0214] Tissues were homogenized using the mouse Tumor Dissociation Kit with Debris Removal Solution (Miltenyi Biotec) and gentleMACS Octo Dissociators (Miltenyi Biotec). Fluorescently labeled antibodies are in Table 5 below. Cell suspensions were run on a FACSymphony A5 SE flow cytometer (BD Biosciences) and analyzed using FlowJo software (FlowJo LLC).    Table 5: Flow Cytometry ProtocolProtein Assays

[0215] Hemi-hearts were homogenized in RIPA buffer containing protease and phosphatase inhibitors (Roche), using a FastPrep tissue homogenizer (MP Biomedicals). Tissue homogenates were cleared by centrifugation, aliquoted at 40uL, and frozen. Protein concentrations were measured using the Bradford method (Bio-Rad). Capillary-based separation was performed using the Simple Western system (ProteinSimple). Alpha-tubulin was used as loading control. Target proteins were detected using the antibodies listed below in Table 6. Quantification was performed using Compass software for Simple Western (ProteinSimple). Table 6: Protein Assay Protocol   Example 7: Heart Fibrosis Example

[0216] A cardiac fibrosis study was completed using the mdx model of DMD of Study A, as discussed in Example 6.

[0217] Fibrosis was quantified by Sirius Red staining. The quantification consists of tissues processed on a HistoCore PELORIS 3 processing system (Leica Biosystems) for FFPE embedding, and stained with H&E and Sirius Red according to standard protocols. Slides stained with Sirius Red were scanned using a NanoZoomer S210 digital slide scanner (Hamamatsu). To measure Sirius Red positive area, the muscle area was cropped from the slide scan, and fascia were excluded from quantification. Sirius Red positive area was measured using ImageJ software, and expressed as the % total muscle area.

[0218] Two types of mouse tissues were included in the study, as well as two Compound 321 dosages and a control. The two mouse tissues processed for this test were WT (B10) and mdx (B10) (DMD model) mice. The WT mouse tissue was dosed with a control. The mdx mouse tissue was split into three aliquots with the following dosages: (i) control; (ii) 4 mg / kg / d Compound 321; (iii) 10 mg / kg / d Compound 321. Results are provided in the below Table 7, where a number of % Sirius red area measurements were taken and a mean and standard error were calculated per each dosage regimen. The results of the six-month dosing regimen provided that Compound 321 reduces cardiac fibrosis. Table 7: Cardiac Fibrosis Measurements   Example 8: Heart Inflammation Example

[0219] A heart inflammation study was completed using the mdx model of DMD of Study A, as discussed in Example 6.

[0220] Two types of mouse tissues were included in the study, as well as one Compound 321 dosage and a control. The two mouse tissues processed for this test were WT (B10) and mdx (B10) (DMD model) mice. The WT mouse tissue was dosed with a control. The mdx mouse tissue was split into two aliquots with the following dosages: (i) control and (ii) 10 mg / kg / d Compound 321. Results were measured by extracting cells / antigens from tissue digestion through flow cytometry and determining the count of each per mg tissue. The four cell / antigen are: CD45+ Cells (all immune cells); CD11b+ F4 / 80+ Cells (Macrophages); CD3+ Cells (T cells); CD19+ Cells (B cells). Results are provided in the below Table 8, where a number of cells per mg tissue measurements were taken and a mean and standard error were calculated per each dosage regimen. The results of the six-month dosing regimen provided that Compound 321 reduces inflammatory cells in the heart. Table 8: Heart Inflammation Measurements   Example 9: Skeletal Muscle Fibrosis Example

[0221] A skeletal muscle fibrosis study was completed using the mdx model of DMD of Study A, as discussed in Example 6.

[0222] Fibrosis was quantified by Sirius Red staining. The quantification consists of tissues processed on a HistoCore PELORIS 3 processing system (Leica Biosystems) for FFPE embedding, and stained with H&E and Sirius Red according to standard protocols. Slides stained with Sirius Red were scanned using a NanoZoomer S210 digital slide scanner (Hamamatsu). To measure Sirius Red positive area, the muscle area was cropped from the slide scan, and fascia were excluded from quantification. Sirius Red positive area was measured using ImageJ software, and expressed as the % total muscle area.

[0223] Two types of mouse tissues were included in the study, as well as two Compound 321 dosages and a control. The two mouse tissues processed for this test were WT (B10) and mdx (B10) (DMD model) mice. The WT mouse tissue was dosed with a control. The mdx mouse tissue was split into three aliquots with the following dosages: (i) control; (ii) 4 mg / kg / d Compound 321; (iii) 10 mg / kg / d Compound 321. Results are provided in the below Table 9, where a number of % Sirius red area measurements were taken and a mean and standard error were calculated per each dosage regimen. The results of the six-month dosing regimen provided    that Compound 321 does not reduce Quadricep fibrosis, but TNNI3K is not expressed in Quadriceps. Table 9: Skeletal Muscle Fibrosis MeasurementsExample 10: PD Response Example

[0224] A PD (pharmacodynamic) response study was completed using the mdx model of DMD of Study A, as discussed in Example 6.

[0225] Here, mdx (B10) (DMD model) mouse tissue was processed and tested. Three target antigens were identified for testing and measurement. The target protein, as referenced in Table 6, are: phospho-cTnl (kinase phosphorylation target); phospho-p38 (downstream pathway signaling); and TNNI3K (drug target). The mdx mouse tissue was split into three aliquots with the following dosages: (i) control; (ii) 4 mg / kg / d Compound 321; (iii) 10 mg / kg / d Compound 321. Results were measured by Western blotting heart extracts to isolate and identify the target antigens. Hemi-hearts were homogenized in RIPA buffer containing protease and phosphatase inhibitors (Roche), using a FastPrep tissue homogenizer (MP Biomedicals). Tissue homogenates were cleared by centrifugation, aliquoted at 40uL, and frozen. Protein concentrations were    measured using the Bradford method (Bio-Rad). Capillary-based separation was performed using the Simple Western system (ProteinSimple). Alpha-tubulin was used as loading control and target proteins were detected antibodies listed in Table 6. Quantification was performed using Compass software for Simple Western (ProteinSimple).

[0226] Results are provided below in Table 10, where the measurements were analyzed by quantifying the target protein, normalized to alpha-Tubulin, and a mean and standard error were calculated per each dosage regimen. The results of the six-month dosing regimen provided that Compound 321 reduced TNNI3K-target phospho-cTnl phosphorylation and mechanism-related phospho-p38 phosphorylation but Compound 321-target TNNI3K levels were unchanged. The results further indicate a reduced activity of TNNI3K, which is likely caused by the inhibition by Compound 321. Table 10: PD Response Measurements   Example 11: PK-PD Correlation Example

[0227] A PK-PD correlation study was completed using the mdx model of DMD of Study A, as discussed in Example 6.

[0228] Here, mdx (B10) (DMD model) mouse tissue was processed and tested. The mdx mouse tissue was split into three aliquots with the following dosages: (i) control; (ii) 4 mg / kg / d Compound 321; (iii) 10 mg / kg / d Compound 321. Compound 321 plasma levels were collected from each dosage levels, measured in ng / mL. These values were then compared to two outcome measures: % cardiac fibrosis present and heart phospho-cTnI phosphorylation. The % cardiac fibrosis was quantified by Sirius Red staining. The quanitification consists of tissues processed on a HistoCore PELORIS 3 processing system (Leica Biosystems) for FFPE embedding, and stained with H&E and Sirius Red according to standard protocols. Slides stained with Sirius Red    were scanned using a NanoZoomer S210 digital slide scanner (Hamamatsu). To measure Sirius Red positive area, the muscle area was cropped from the slide scan, and fascia were excluded from quantification. Sirius Red positive area was measured using ImageJ software, and expressed as the % total muscle area.

[0229] The heart phospho-cTnl phosphorylation was measured by Western blotting. Hemi- hearts were homogenized in RIPA buffer containing protease and phosphatase inhibitors (Roche), using a FastPrep tissue homogenizer (MP Biomedicals). Tissue homogenates were cleared by centrifugation, aliquoted at 40uL, and frozen. Protein concentrations were measured using the Bradford method (Bio-Rad). Capillary-based separation was performed using the Simple Western system (ProteinSimple). Alpha-tubulin was used as loading control. Target proteins were detected using the antibodies listed below in Table 6. Quantification was performed using Compass software for Simple Western (ProteinSimple).

[0230] The correlation data is provided below in Table 11, where correlation between the Compound 321 plasma levels and outcome measures were provided. Cardiac fibrosis measurements are provided as % of cardiac fibrosis present in a sample and cardiac phospho- cTnI measurements are presented as normalized against Tubulin. The results of the six-month dosing regimen provided that Compound 321 plasma levels correlate with reduction in cardiac fibrosis and cardiac phospho-cTnI phosphorylation. Table 11: PK-PD Response Correlation   Example 12: Safety and Tolerability Example

[0231] A safety and tolerability study was completed by testing four mouse groups with two Compound 321 dosages and a control over a six-month, naturally progressing dose regimen. The two mouse varieties for this test were WT (B10) and mdx (B10) mice. The WT mouse group was treated with a control. The mdx mouse groups were each individually treated with the following dosages: (i) control; (ii) 4 mg / kg / d Compound 321; (iii) 10 mg / kg / d Compound 321. Over the six-month dosing schedule, the average food consumption (in grams) of the mice under study were measured twice-weekly over the 27 weeks of dosing. Further, at the end of the six- month dosing schedule, the mouse body weights (in grams) and heart rates (beats per minute) were measured. Results of the average food consumption observation are provided below in Table 12 and the results of the end of study measurements are provided below in Table 13, with a mean and standard error calculated per each dosage regimen. Table 12: Average Food Consumption Observation Measurements      Table 13: End of Study Measurements   Example 13: Procedure Summary for Study B

[0232] Study B consists of a 5-week dosing regimen. The dosing regimen was applied to isoproterenol induced mdx mice over the five-week period. After the dosing regimen has concluded, tissue sections of the mice were harvested and analyzed.

[0233] Study B further consists of performing a baseline blood collection of C57BL / 10ScSn.DMD (mdx) male mice, aged 4-5 weeks. Treatment was provided to the mice throughout the 5-week dosing regimen, where either a medicated diet or control diet was provided ad libitum throughout the study. After seven days of treatment, mice receive a single dose of isoproterenol (5 mg / kg I.P.). At the end of the 5-week dosing regimen, the heart of the mice were harvested and analyzed. In further examination of the mice, food consumption of the mice was measured five times per week. Isoproterenol treatment accelerates cardiac pathology, allowing for study regarding faster progressing heart disease or early fibrosis stages. Example 14: Isoproterenol-Induced Cardiac Fibrosis Example

[0234] An isoproterenol fibrosis study was completed using the mdx mice of Study B, as discussed in Example 13.

[0235] Fibrosis staining was prepared by arranging prepared tissue slides and allowing the slides to reach room temperature. A hydrophobic barrier was then created around the tissue slices on each slide with a hydrophobic pen. The slides were then rinsed for approximately 30- 60 seconds with PBS (Phosphate-buffered saline). After rinsing, the slides were stained with a Sirius Red-containing dye solution for at least four minutes but no more than eight minutes. Once the dye has been removed, the slides were rinsed with tap water to remove excess dye. After the slides were dried completely, the slides were mounted with a DPX mountant.

[0236] Both mdx (B10) mice and isoproterenol-induced mdx (B10) mice were included in the study, as well as one Compound 321 dosage and a control. The mdx mouse tissue and the iso- induced mdx mouse tissue were split into two aliquots (four total) from the following dosages: (i) control and (ii) 10 mg / kg / d Compound 321. Results are provided below in Table 14, where a number of % Sirius red area measurements were taken and a mean and standard error were calculated per each dosage regimen. The results of the dosing regimen provided that Compound 321 treatment reduces isoproterenol-induced cardiac fibrosis.    Table 14: Isoproterenol-Induced Cardiac Fibrosis MeasurementsExample 15: Isoproterenol-Induced CCR2+ Example

[0237] An isoproterenol-induced CCR2+ study was completed using the mdx mice of Study B, as discussed in Example 13.

[0238] CCR2 staining was prepared by first allowing tissue sections on slides to acclimate to room temperature in a humidified chamber for five minutes. Once acclimated, the tissue sections were outlines with a hydrophobic barrier PAP pen, where fixation was not done with 4% paraformaldehyde (PFA). The tissue sections were then washed three times each with a 1X-PBS solution for five minutes each. After the triple washing was completed, the tissue sections were then washed one time for ten minutes in 1X-PBST (99.8% 1X-PBS; 0.2% Triton X-100). The tissue section slides were then blocked for 30 minutes at room temperature in a 1X-PBST-NGS solution (89.8% 1X-PBST; 10% normal goat serum (NGS); 0.2% Triton X-100). The tissue samples were again washed three times with 1X-PBS for 10 minutes each wash. The tissue samples were then incubated in a primary antibody concentration (Abcam Cat # Ab273050) in 2% NGS with 1X-PBS overnight at 4° C. After overnight incubation, the tissue samples were again washed three times with 1X-PBS for 10 minutes each wash. A secondary antibody incubation in 1X-PBS followed at room temperature for 1-2 hours. After secondary incubation, the tissue samples were again washed three times with 1X-PBS for 10 minutes each wash. The    tissue samples were then mounted with Prolong Diamond Antifade with DAPI and a coverslip. The slides were then left to cure overnight at room temperature and then left to store at -20°C.

[0239] Both mdx (B10) mice and isoproterenol-induced mdx (B10) mice were included in the study, as well as one Compound 321 dosage and a control. The mdx mouse tissue and the iso- induced mdx mouse tissue were split into two aliquots (four total) from the following dosages: (i) control and (ii) 10 mg / kg / d Compound 321. Results are provided below in Table 15, where a number of CCR2+ cell counts were taken against the DAPI count, and a mean and standard error were calculated per each dosage regimen. The results of the dosing regimen provided that Compound 321 treatment reduces frequency of CCR2+ cells in the heart induced by isoproterenol. Table 15: Isoproterenol-Induced CCR2+ MeasurementsExample 16: Isoproterenol-Induced Fibrosis and CCR2+ Correlation Example

[0240] An isoproterenol-induced fibrosis and CCR2+ correlation study was completed using the mdx mice of Study B, as discussed in Example 13, and the methods of Examples 14 and 15.

[0241] Both mdx (B10) mice and isoproterenol-induced mdx (B10) mice were included, as well as one Compound 321 dosage and a control. The mdx mouse tissue and the iso-induced mdx mouse tissue were split into two sections (four total) from the following dosages: (i) control and (ii) 10 mg / kg / d Compound 321.

[0242] The correlation data is provided below in Table 16, where correlation between the cardiac fibrosis percentage in a sample and CCR2+ cell frequency are provided. The results of    the five-week dosing regimen provided that cardiac fibrosis directly correlates with CCR2+ cells in the heart and both are reduced by Compound 321 treatment. Table 16: Isoproterenol-Induced Fibrosis and CCR2+ Correlation

[0243] From the foregoing, it will be appreciated that, although specific embodiments have been described herein for the purpose of illustration, various modifications may be made without deviating from the spirit and scope of what is provided herein. All of the references referred to above are incorporated herein by reference in their entireties.

Claims

CLAIMS What is claimed is:

1. A method for treating muscular dystrophy in a subject in need thereof, comprising administering to the subject a TNNI3K inhibitor having a structure ofpharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the muscular dystrophy is Duchenne’s muscular dystrophy (DMD).

3. A method for treating cardiomyopathy in a subject in need thereof, comprising administering to the subject a cardiac troponin I interacting kinase (TNNI3K) inhibitor.

4. The method of claim 3, wherein the TNNI3K inhibitor comprises a structure of Formula (I), or a pharmaceutically acceptable salt thereof,Formula (I) wherein: R1is (C1-C4)alkyl; R2is hydrogen or halogen; R3is hydrogen, halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C3-C6)cycloalkyl, aryl, hydroxyl, -(C1-C4)alkylhydroxyl, (C1-C4)alkoxy, -(C1-C4)alkylene-(C1-C4)alkoxy, (C1- C4)haloalkoxy, (C3-C6)cycloalkyloxy, -S-(C1-C4)alkyl, amino, -NH(C1-C4)alkyl, or -N((C1- C4)alkyl)2; R4is hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, hydroxyl, -(C1- C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene-(C1-C4)alkoxy, (C1-C8)haloalkoxy, (C3-    C8)cycloalkyloxy, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(C3-C8)cycloalkyl, -S(=O)2(C1-C8)alkyl, - S(=O)2(C1-C8)haloalkyl, -S(=O)2(C3-C8)cycloalkyl, phenyl, 5-membered heteroaryl, amino, -NHRa, or -NRaRb; wherein said phenyl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C1-C4)haloalkyl, (C1-C6)alkoxy, (C1- C4)haloalkoxy, -(C1-C4)alkylhydroxyl, and -N(Ra)(Rb); R5is hydrogen; or R4and R5taken together with intervening atoms to form a 5 or 6 membered ring, which ring may be unsubstituted, or substituted with one to three substituents independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1-C4)alkylhydroxyl, oxo, hydroxyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, and -S-(C1-C8)alkyl; each R6and R7is independently hydrogen, halogen, (C1-C8)alkyl, (C1-C8)haloalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, heteroaryl, hydroxyl, -(C1-C8)alkylhydroxyl, (C1-C8)alkoxy, -(C1-C8)alkylene-(C1-C4)alkoxyl, (C1-C4)haloalkoxy, (C3-C6)cycloalkyloxy, amino, -NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, -S(C1-C8)alkyl, -S(C1-C8)haloalkyl, -S(=O)2(C1- C8)alkyl , -NHRc, or -NRcRd; or R6and R7are taken together with the atoms to which they are attached, to form a (C3- C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl, wherein any said (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one to five substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, - C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, SRa, -S(=O)2(C1- C8)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1- C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORe, -(C1-C2)alkylhydroxyl, and -(C1- C2)alkylene-ORa; or two of the substituents are taken together with the atoms to which they are attached, to form a (C4-C8)cycloalkyl, (C4-C8)heterocycloalkyl, aryl, or heteroaryl; each Reis, independently, (C1-C8)alkyl or a 5-6 membered heterocycloalkyl, wherein said (C1-C8)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, and -N(Ra)(Rb); each Rcand Rdis independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2- C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, - C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, C(=O)NHRa, -C(=O)NRaRb, -(C1- C2)alkylCO2H, -(C1-C2)alkylCO2Ra, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -    S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, - (C1-C2)alkylene-NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, - ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, - C(=O)NRaRb, -SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, - ORa, -(C1-C2)alkyl-hydroxyl, and -(C1-C2)alkylene-ORa; each Raand Rbis independently selected from (C1-C4)alkyl, aryl, heterocycloalkyl, or - (C1-C2)alkylene-heterocycloalkyl, wherein said (C1-C4)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C6)alkoxy, amino, - NH(C1-C6)alkyl, -N((C1-C6)alkyl)2, -CO2H, -CO2(C1-C6)alkyl, -C(=O)NH2, -C(=O)NH(C1- C6)alkyl, and C(=O)N((C1-C6)alkyl)2, wherein any heterocycloalkyl is optionally substituted by (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached to form a 5-7 membered heterocyclic ring, wherein said ring is optionally substituted with one or two substituents, independently, selected from halogen, (C1-C4)alkyl, (C1-C4)haloalkyl, amino, - NH(C1-C4)alkyl, -N((C1-C4)alkyl)2, hydroxyl, -(C1-C4)alkylhydroxyl, oxo, (C1-C4)alkoxy, (C1- C4)haloalkoxy, and (C1-C4)alkoxy(C1-C4)alkyl; or a salt thereof.

5. The method of claim 4, wherein the TNNI3K inhibitor comprises a structure of Formula (I- A), or a pharmaceutically acceptable salt thereof,Formula (I-A) wherein:    Rcis hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)cycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2- C6)alkynyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, - CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -(C1-C2)alkylCO2H, -(C1-C2)alkylCO2Ra, - SRa, -S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, - NRaRb, -(C1-C2)alkylamino, -(C1-C2)alkylene-NHRa, -(C1-C2)alkylene-NRaRb, - NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkylhydroxyl, -(C1-C2)alkylene-ORa, -(C1-C2)alkylcyano, aryl, heteroaryl, and -(C1-C2)alkylheteroaryl, wherein any said aryl or heteroaryl is optionally substituted with one to three substituents, independently, selected from halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C4)haloalkyl, cyano, -C(=O)(C1-C4)alkyl, -CO2H, -CO2Ra, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, SRa, - S(=O)2(C1-C4)alkyl, -S(=O)2NH2, -S(=O)2NHRa, -S(=O)2NRaRb, nitro, amino, -NHRa, -NRaRb, -NHC(=O)(C1-C4)alkyl, -NHS(=O)2(C1-C4)alkyl, oxo, hydroxyl, -ORa, -(C1-C2)alkyl- hydroxyl, and -(C1-C2)alkylene-ORa.

6. The method of claim 4 or 5, wherein the TNNI3K inhibitor is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 4-6, wherein the TNNI3K inhibitor isor a pharmaceutically acceptable salt thereof.

8. The method of claim 4, wherein the TNNI3K inhibitor comprises a structure of Formula (I- B), or a pharmaceutically acceptable salt thereof:    Formula (I-B) wherein: each R8, R9, and R10are each, independently, H, halogen, nitro, amino, -NH(C1-C4)alkyl, - N((C1-C4)alkyl)2, hydroxyl, or ORe; and each Reis, independently, (C1-C8)alkyl or a 5-6 membered heterocycloalkyl, wherein said (C1-C8)alkyl is optionally substituted with one to three substituents, independently, selected from halogen, hydroxyl, (C1-C4)alkoxy, amino, -NH(C1-C4)alkyl, and -N(Ra)(Rb); or R9and R10are taken together with the intervening atoms to form a five or six membered heterocycle.

9. The method of claim 3, wherein the TNNI3K inhibitor comprises a structure of Formula (II), or a pharmaceutically acceptable salt thereof:Formula (II) wherein: R11is halogen, (C1-C4)alkyl, or -ORf; R12is H, halogen, (C1-C4)alkyl, or -ORf; and Rfis (C1-C4)alkyl which is optionally substituted with one to three halogen.

10. The method of any one of claims 1-9, wherein the cardiomyopathy is dystrophic cardiomyopathy.

11. The method of any one of claims 1-10, wherein the cardiomyopathy is associated with Duchenne muscular dystrophy (DMD).

12. The method of any one of claims 1-10, wherein the cardiomyopathy is associated with Becker muscular dystrophy (BMD).

13. The method of any one of claims 1-10, wherein the cardiomyopathy is associated with X- Linked DMD / BMD mutations of female carriers.

14. The method of any one of claims 1-13, wherein the subject has a muscular dystrophy.

15. The method of claim 14, wherein the muscular dystrophy is selected from Becker muscular dystrophy (BMD), congenital muscular dystrophy, Duchenne muscular dystrophy (DMD), distal muscular dystrophy, Emery–Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD), limb–girdle muscular dystrophy (LGMD), myotonic muscular dystrophy, X-linked DMD / BMD mutations of female carriers, and oculopharyngeal muscular dystrophy.

16. The method of claim 15, wherein the muscular dystrophy is Duchenne muscular dystrophy (DMD).

17. The method of claim 15, wherein the muscular dystrophy is Becker muscular dystrophy (BMD).

18. The method of claim 15, wherein the muscular dystrophy is X-Linked DMD / BMD mutations of female carriers.

19. The method of any one of claims 1-18, wherein the subject is a human of at least 2 years of age with elevated cardiac troponin (cTnI) based on a high sensitivity cardiac troponin assay.

20. The method of claim 19, wherein the subject is a boy of 8 years of age.

21. The method of claim 19, wherein the subject is a boy of 10 years of age.

22. The method of any one of claims 1-21, wherein the administering of the TNNI3K inhibitor reduces serum cTnI levels in the subject.

23. The method of any one of claims 1-21, wherein the administering of the TNNI3K inhibitor reduces serum phospho-cTnI levels in the subject.

24. The method of any one of claims 1-23, wherein the administering of the TNNI3K inhibitor reduces cTnI Ca++sensitivity in the subject.

25. The method of any one of claims 1-23, wherein the administering of the TNNI3K inhibitor reduces immunogenic cTnI epitopes in the subject.

26. The method of any one of claims 1-24, wherein the administering of the TNNI3K inhibitor reduces immunogenic cTnI phospho-epitopes in the subject.

27. The method of any one of claims 1-24, wherein the administering of the TNNI3K inhibitor reduces cardiac inflammation in the subject.

28. The method of any one of claims 1-25, wherein the administering of the TNNI3K inhibitor stabilizes or reduces cardiac fibrosis in the subject.

29. The method of any one of claims 1-26, wherein the administering of the TNNI3K inhibitor reduces ischemic damage in the subject.

30. The method of any one of claims 1-26, wherein the administering of the TNNI3K inhibitor reduces non-ischemic damage in the subject.

31. The method of any one of claims 1-27, wherein the administering of the TNNI3K inhibitor reduces dystrophic cardiomyopathy in the subject.

32. The method of any one of claims 1-28, wherein the administering of the TNNI3K inhibitor reduces loss of cardiac function in the subject.

33. The method of any one of claims 1-32, wherein the TNNI3K inhibitor is administered orally.

34. The method of any one of claims 1-33, wherein the administering of the TNNI3K inhibitor does not substantially change the subject’s weight.

35. The method of any one of claims 1-28, wherein the administering of the TNNI3K inhibitor produces an anti-fibrotic effect.

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