Compositions for the treatment of neurodegenerative and mitochondrial diseases and methods of use thereof

Abstract

To provide compounds and compositions capable of modulating PINK1 kinase activity, and methods for producing and using the same.SOLUTION: A compound has a structure in the figure. (In the formula: Z is O, NH, or CH2; R1a, R1b, R1c and R1d are H, halogen, CN, NH2, or the like; and R2 is -(CH2)nCy1, -O(CH2)nCy1, Cy1, or the like, where Cy1 is C4-C9 cycloalkyl, C3-C9 heterocycle, or the like.)SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 62 / 980,143, filed February 21, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] Sequence Listing Reference The Sequence Listing, created on February 22, 2021, and submitted on February 22, 2021 as a text file named "37930_0006P1_ST25.txt" and having a size of 20,293 bytes, is incorporated herein by reference pursuant to 37 CFR §1.52(e)(5). [Background technology]

[0003] background Maintaining mitochondrial function is essential for the health and survival of numerous cell types, including cardiomyocytes, hepatocytes, kidney cells, and neurons. Abnormal mitochondrial quality control has been demonstrated to be a key factor in the development of neurodegenerative diseases, kidney diseases, and cardiomyopathies (Schapira, A.H. Mitochondrial disease. Lancet 379, 1825-1834, (2012) (Non-Patent Document 1); and Chen, Y. and Dorn, G. PINK1-Phosphorylated Mitofusin-2 Is a Parkin Receptor for Culling Damaged Mitochondria. Science 340, 471-475, (2013) (Non-Patent Document 2)). The mitochondrial kinase PTEN-induced kinase 1 (PINK1) plays a key role in the mitochondrial quality control process by responding to damage at the level of individual mitochondria. The PINK1 pathway is also associated with the induction of mitochondrial biogenesis and, importantly, the reduction of mitochondria-induced apoptosis. See, for example, Narendra, D.P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8, e1000298 (2010) (Non-Patent Document 3); Wang, X., (2011). et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147, 893-906, (2011) (Non-Patent Document 4); and Shin, J.H. et al. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 144, 689-702, (2011) (Non-Patent Document 5).

[0004] Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet no disease-modifying therapies are currently approved for treating PD. Both environmental and genetic factors lead to the progression of dopaminergic neuron apoptosis, declining dopamine levels, and ultimately PD. PINK1 kinase activity appears to be essential for mediating its neuroprotective activity. Regulation of mitochondrial movement, distribution, and clearance is a critical part of the neuronal oxidative stress response. Disruption of these regulatory pathways has been shown to contribute to chronic neurodegenerative diseases. See Schapira and Chen, supra.

[0005] Cardiomyopathy refers to diseases of myocardial tissue, and it is estimated that 5-10% of the 5-6 million patients in the United States already diagnosed with heart failure have cardiomyopathy. Based on etiology and pathophysiology, the World Health Organization has created a classification of cardiomyopathy, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, and unclassifiable cardiomyopathy. See, for example, Richardson P, et al., Report of the 1995 World Health Organization / International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathy. Circulation 1996;93:841 (Non-Patent Document 6). PINK1 kinase activity appears to mediate its cardioprotective activity. Regulation of mitochondrial movement, distribution, and clearance is part of the oxidative stress response in cardiac cells. Disruption of these regulatory pathways has been shown to contribute to cardiomyopathy. See Schapira and Chen, supra. See Wang, X., (2011) et al. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147, 893-906, (2011) (Non-Patent Document 4), and Richardson P, et al. Report of the 1995 World Health Organization / International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996; 93: 841 (Non-Patent Document 6). Recently, several cases of adult-onset LS have also been reported. For example, Longo, D, et al. Harrison's Internal Medicine. 18 thed. (online), Ch. 238 (2011) (Non-Patent Document 7), Koh, H. & Chung, J. PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity, Mol Cells 34, 7-13, (2012) (Non-Patent Document 8), Martins-Branco, D. et al. Ubiquitin proteasome system in Parkinson's disease: a keeper or a witness? Exp Neurol 238, 89-99, (2012) (Non-Patent Document 9), and Geisler, S. et al. The PINK1 / Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6, 871-878, (2010) (Non-Patent Document 10).

[0006] In vivo imaging techniques such as MRI reveal bilateral hyperintense lesions in the basal ganglia, thalamus, substantia nigra, brainstem, cerebellar white matter and cortex, cerebral white matter, or spinal cord in patients with LS. For example, see the above Longo and Shin, J. et al., "PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease." Cell 144, 689-702, (2011) (Non-Patent Document 5); Henchcliffe, C. & Beal, M. F., "Mitochondrial biology and oxidative stress in Parkinson's disease pathogenesis." Nat Clin Pract Neurol 4, 600-609 (2008) (Non-Patent Document 11); Pridgeon, J. W., Olzmann, J. A., Chin, L. S. & Li, L., "PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1." PLoS Biol 5, e172 (2007) (Non-Patent Document 12); and Haque, M. E. et al., "Cytoplasmic Pink1 activity protects neurons from dopaminergic See neurotoxin MPTP. Proc Natl Acad Sci USA 105, 1716-1721 (2008) (Non-Patent Document 13). Lesions are usually correlated with gliosis, demyelination, capillary proliferation, and / or necrosis.See Geisler, S. et al., "The PINK1 / Parkin-mediated mitophagy is compromised by PD-associated mutations." Autophagy 6, 871-878, (2010) (Non-Patent Document 10), and Gautier, CA, Kitada, T. & Shen, J. "Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress." Proc Natl Acad Sci USA 105, 11364-11369 (2008) (Non-Patent Document 14). Behavioral symptoms in LS patients can include developmental delay (with a wide variety of clinical symptoms), hypotonia, ataxia, spasticity, dystonia, weakness, optic atrophy, ocular or eyelid movement disorders, hearing impairment, respiratory abnormalities, dysarthria, swallowing difficulties, growth failure, and gastrointestinal disorders. See, for example, Wang and Richardson, supra, as well as Samaranch, L. et al., PINK1-linked parkinsonism is associated with Lewy body pathology. Brain 133, 1128-1142, (2010) (Non-Patent Document 15), and Merrick, K.A. et al., Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. Mol Cell 42, 624-636, (2011) (Non-Patent Document 16). The cause of death in most LS cases is unknown, and the lack of genetic models to study disease progression and cause of death hinders the development of appropriate treatments. The prognosis for LS (and most diseases caused by mitochondrial dysfunction) is very poor, with no cure and often ineffective treatments.

[0007] Parkinson's disease (PD) is one of the most common neurodegenerative disorders, yet no disease-modifying therapies are currently approved for treating PD. Both environmental and genetic factors lead to the progression of dopaminergic neuron apoptosis, declining dopamine levels, and ultimately PD. PINK1 kinase activity appears to mediate its neuroprotective activity. Regulation of mitochondrial movement, distribution, and clearance is a critical part of the neuronal oxidative stress response. Disruption of these regulatory pathways has been shown to contribute to chronic neurodegenerative diseases. See Schapira and Chen, supra.

[0008] Despite the prevalence of disorders associated with the PINK1 pathway, compounds that selectively target this pathway and therefore can treat disorders associated with this pathway have not yet been discovered. Thus, there remains a need for compounds and compositions that can modulate PINK1 kinase activity, as well as methods for making and using them. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Schapira, AHMitochondrial disease. Lancet 379, 1825-1834, (2012) [Non-patent document 2] Chen,Y.and Dorn,G.PINK1-Phosphorylated Mitofusin-2 Is a Parkin Receptor for Culling Damaged Mitochondria.Science 340,471-475,(2013) [Non-patent document 3] Narendra,DPet al.PINK1 is selectively stabilized on impaired mitochondria to activate Parkin.PLoS Biol 8,e1000298(2010) [Non-patent document 4] Wang,X.,(2011).et al.PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility.Cell 147,893-906,(2011) [Non-patent document 5] Shin,JHet al.PARIS(ZNF746)repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease.Cell 144,689-702,(2011) [Non-patent document 6] Richardson P,et al.Report of the 1995 World Health Organization / International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies.Circulation 1996;93:841 [Non-Patent Document 7] Longo,D,et al.Harrison's Internal Medicine.18th ed.(online),Ch.238(2011) [Non-patent document 8] Koh, H. & Chung, J. PINK1 as a molecular checkpoint in the maintenance of mitochondrial function and integrity,Mol Cells 34,7-13,(2012) [Non-Patent Document 9] Martins-Branco, D. et al. Ubiquitin proteasome system in Parkinson's disease: a keeper or a witness? Exp Neurol 238,89-99,(2012) [Non-Patent Document 10] Geisler,S.et al.The PINK1 / Parkin-mediated mitophagy is compromised by PD-associated mutations.Autophagy 6,871-878,(2010) [Non-Patent Document 11] Henchcliffe, C. & Beal, MF Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis.Nat Clin Pract Neurol 4,600-609(2008) [Non-Patent Document 12] Pridgeon,JW,Olzmann,JA,Chin,LS&Li,L.PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1.PLoS Biol 5,e172(2007) [Non-Patent Document 13] Haque,MEet al.Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP.Proc Natl Acad Sci USA 105,1716-1721(2008) [Non-Patent Document 14] Gautier,CA,Kitada,T.&Shen,J.Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress.Proc Natl Acad Sci USA 105,11364-11369(2008) [Non-Patent Document 15] Samaranch,L.et al.PINK1-linked parkinsonism is associated with Lewy body pathology.Brain 133,1128-1142,(2010) [Non-Patent Document 16] Merrick,KAet al.Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation.Mol Cell 42,624-636,(2011) Summary of the Invention

[0010] overview In accordance with the object(s) of the present invention as embodied and outlined herein, the present invention relates, in some embodiments, to adenine compounds useful for the treatment of disorders associated with PINK1 kinase activity, such as, for example, neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathies.

[0011] Thus, the structure represented by the formula: TIFF0007808226000001.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof.

[0012] The structure represented by the formula: TIFF0007808226000002.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3 Also described are compounds, or pharmaceutically acceptable salts thereof, wherein is 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl.

[0013] Without wishing to be bound by theory, an advantage of the compounds described in the present invention is that they have improved efficacy and reduced toxicity. For example, the disclosed compounds have an EC of less than 0.3 μM with less than 10% toxicity. 50 See, for example, Tables 2A and 2B, and Figures 1A-F, Compound No. EP-0038098.

[0014] Methods for making the disclosed compounds are also provided.

[0015] Also provided are pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier.

[0016] Also provided are methods for modulating PINK1 kinase activity in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of at least one disclosed compound.

[0017] Also disclosed are methods of modulating PINK1 kinase activity in at least one cell, comprising contacting the cell with an effective amount of at least one disclosed compound.

[0018] Also provided is a method for treating a disorder in a subject in need thereof, comprising administering to a subject in need thereof an effective amount of at least one disclosed compound, wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy.

[0019] a disclosed compound; (a) at least one agent known for treating a neurodegenerative disorder, a mitochondrial disorder, a fibrosis, or a cardiomyopathy; (b) instructions for administering a compound associated with a neurodegenerative disorder, a mitochondrial disorder, a fibrosis, or a cardiomyopathy; and / or (c) instructions for treating the disorder. and one or more of A kit is also provided, comprising:

[0020] [The present invention 1001] The structure represented by the formula: TIFF0007808226000003.tif42165, During the ceremony, m is 0 or 1, Q 1 and Q 2 are each independently N or CH; Q 3is CH2 or NH, Z is CR 11a R 11b , N.R. 12 , or O, During the ceremony, R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C1-C4 alkyloxy; or R 11a and R 11b each, when present, together constitutes =O, R 12 if present, is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl); R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 is selected from During the ceremony, n, if present, is 0, 1, or 2; R 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl; R 4 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. [The present invention 1002] R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from Cy 1is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 4 is hydrogen. [The present invention 1003] 1001. The compound of the present invention, wherein m is 1. [The present invention 1004] Q 1 1001. The compound of the present invention, wherein is CH. [The present invention 1005] Q 2 The compound of the present invention 1001, wherein is N. [The present invention 1006] Q 3 1001. The compound of the present invention, wherein is NH. [The present invention 1007] Q 1 is CH and Q 2 is N and Q 3 1001. The compound of the present invention, wherein is NH. [The present invention 1008] 1001. The compound of the present invention, wherein Z is CH2. [The present invention 1009] R 1a , R 1b , R 1c , and R 1d 1001. The compound of claim 1001, wherein each independently is hydrogen, halogen, or C1-C4 alkyl. [The present invention 1010] R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1, and Cy 1 1001 compounds of the present invention selected from: [The present invention 1011] R 2 Cy 1 The compound of the present invention 1001, [The present invention 1012] Cy 1 is an unsubstituted C3-C9 heterocycle having at least one O, S, or N atom. [The present invention 1013] Cy 1 is represented by a formula selected from the following: The compound of the present invention 1011 is TIFF0007808226000004.tif29165. [The present invention 1014] Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom. [The present invention 1015] The compound of the present invention 1014, wherein said C3-C9 heterocycle is a monocyclic heterocycle. [The present invention 1016] 1014. The compound of the present invention, wherein said C3-C9 heterocycle is a bicyclic heterocycle. [The present invention 1017] The compound of the present invention 1014, wherein said C3-C9 heterocycle is a spirocyclic heterocycle. [The present invention 1018] The compound of the present invention 1014, wherein said C3-C9 heterocycle is a fused heterocycle. [The present invention 1019] Cy 1 is a C2-C9 heteroaryl having at least one O, S, or N atom. [The present invention 1020] Cy 1is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. [The present invention 1021] R 3 is a 3- to 6-membered cycloalkyl or C1-C6 haloalkyl. [The present invention 1022] R 3 1001. A compound of the present invention, wherein is a 3-membered cycloalkyl or -CF3. [The present invention 1023] R 4 1001. The compound of the present invention, wherein is hydrogen. [The present invention 1024] The structure represented by the formula: Compound 1001 of the present invention having TIFF0007808226000005.tif48165. [The present invention 1025] The structure represented by the formula: Compound 1001 of the present invention having TIFF0007808226000006.tif48165. [The present invention 1026] A structure represented by a formula selected from the following: Compound 1001 of the present invention having TIFF0007808226000007.tif48165. [The present invention 1027] A structure represented by a formula selected from the following: Compound 1001 of the present invention having TIFF0007808226000008.tif48165. [The present invention 1028] below: A compound of the present invention 1001 selected from TIFF0007808226000009.tif183165TIFF0007808226000010.tif183165TIFF0007808226000011.tif229165. [The present invention 1029] below: 1001. A compound of the present invention selected from TIFF0007808226000012.tif188165TIFF0007808226000013.tif185165TIFF0007808226000014.tif185165TIFF0007808226000015.tif137165. [The present invention 1030] below: TIFF0007808226000016.tif175165TIFF0007808226000017.tif173165TIFF0007808226000018. tif173165TIFF0007808226000019.tif175165TIFF0007808226000020.tif183165TIFF00078082 26000021.tif180165TIFF0007808226000022.tif181165TIFF0007808226000023.tif178165TIF F0007808226000024.tif183165TIFF0007808226000025.tif175165TIFF0007808226000026.tif 177165TIFF0007808226000027.tif173165TIFF0007808226000028.tif178165TIFF00078082260 00029.tif177165TIFF0007808226000030.tif184165TIFF0007808226000031.tif176165TIFF00 07808226000032.tif146165TIFF0007808226000033.tif150165TIFF0007808226000034.tif153165TIFF0007808226000035.tif153165TIFF0007808226000036.tif97165. [The present invention 1031] below: TIFF0007808226000037.tif175165TIFF0007808226000038.tif173165TIFF0007808226000039.tif173165TIFF0007808226000040. tif177165TIFF0007808226000041.tif190165TIFF0007808226000042.tif176165TIFF0007808226000043.tif182165TIFF00078082 26000044.tif177165TIFF0007808226000045.tif183165TIFF0007808226000046.tif184165TIFF0007808226000047.tif185165TIF F0007808226000048.tif180165TIFF0007808226000049.tif176165TIFF0007808226000050.tif170165TIFF0007808226000051.tif1 79165TIFF0007808226000052.tif179165TIFF0007808226000053.tif173165TIFF0007808226000054.tif180165TIFF000780822600 0055.tif172165TIFF0007808226000056.tif185165TIFF0007808226000057.tif185165TIFF0007808226000058.tif175165TIFF000 7808226000059.tif185165TIFF0007808226000060.tif185165TIFF0007808226000061.tif144165TIFF0007808226000062.tif150165TIFF0007808226000063.tif149165TIFF0007808226000064.tif148165TIFF0007808226000065.tif154165. [The present invention 1032] below: TIFF0007808226000066.tif48165, compound of the present invention 1001. [The present invention 1033] A pharmaceutical composition comprising a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1032 and a pharmaceutically acceptable carrier. [The present invention 1034] A method for regulating PINK1 kinase activity in a subject in need of such regulation, comprising administering to the subject in need thereof an effective amount of any of the compounds of present inventions 1001 to 1032. [This invention 1035] 1034. The method of claim 1034, wherein said modulation is inhibition. [The present invention 1036] A method for modulating PINK1 kinase activity in at least one cell, the method comprising contacting the cell with an effective amount of any of the compounds of present inventions 1001 to 1032. [This invention 1037] 1036. The method of claim 1036, wherein said cell is a mammalian cell. [The present invention 1038] The method of claim 1037, wherein said cell is isolated from a mammal prior to said contacting step. [This invention 1039] 1036. The method of claim 1036, wherein said cell comprises impaired PINK1 kinase activity. [The present invention 1040] The method of claim 1036, wherein said contacting step is performed in vitro. [The present invention 1041] A method for treating a disorder in a subject in need thereof, comprising administering to said subject in need thereof an effective amount of any of the compounds of the present inventions 1001 to 1032, wherein said disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy. [The present invention 1042] 1042. The method of claim 1041, wherein the subject is a mammal. [This invention 1043] 1042. The method of claim 1041, wherein the subject is a human. [This invention 1044] The method of claim 1041, wherein said subject has been diagnosed with said disorder prior to said administering step. [This invention 1045] The method of claim 1041, wherein said administering is accomplished by oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, topical administration, inhalation administration, buccal administration, intrapleural administration, intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration, and intraarticular administration, or a combination thereof. [The present invention 1046] 1041. The method of claim 1041, wherein said administering comprises administering about 1 to about 2000 micrograms of the expressible nucleic acid sequence. [This invention 1047] 1041. The method of claim 1041, wherein said neurodegenerative disorder is Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis. [This invention 1048] any one of compounds 1001 to 1032 of the present invention; (a) at least one agent known for the treatment of neurodegenerative disorders, mitochondrial disorders, fibrosis, and cardiomyopathies; (b) instructions for administering said compound in connection with said neurodegenerative disorder, mitochondrial disorder, fibrosis, or cardiomyopathy; and / or (c) instructions for treating said disorder; and one or more of Includes a kit. Still other objects and advantages of the present disclosure will become readily apparent to those skilled in the art from the following detailed description, in which only preferred embodiments are shown and described, merely as illustrations of the best mode. As will be realized, the present disclosure is susceptible to other and different embodiments, and its several details are susceptible to modification in various obvious respects, without departing from the present disclosure. Accordingly, the description is to be regarded as illustrative in nature, and not as limiting. [Brief explanation of the drawings]

[0021] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and, together with the description, serve to explain the principles of the invention.

[0022] [Figure 1A] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0037821, EP-0038098, and EP-0038099 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6-hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 1B] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0037821, EP-0038098, and EP-0038099 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6-hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 1C] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0037821, EP-0038098, and EP-0038099 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6-hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 1D] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0037821, EP-0038098, and EP-0038099 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6-hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 1E] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0037821, EP-0038098, and EP-0038099 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6-hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 1F] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0037821, EP-0038098, and EP-0038099 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6-hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 2A] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, and EP-0038503 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 2B] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, and EP-0038503 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 2C] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, and EP-0038503 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 2D] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, and EP-0038503 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 2E]Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, and EP-0038503 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 2F] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, and EP-0038503 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 3A] Representative data are shown showing the efficacy and toxicity of compounds nos. EP-0035985, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 3B] Representative data are shown showing the efficacy and toxicity of compounds nos. EP-0035985, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 3C] Representative data are shown showing the efficacy and toxicity of compounds nos. EP-0035985, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 3D]Representative data are shown showing the efficacy and toxicity of compounds nos. EP-0035985, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 3E] Representative data are shown showing the efficacy and toxicity of compounds nos. EP-0035985, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 3F] Representative data are shown showing the efficacy and toxicity of compounds nos. EP-0035985, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 4A] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, EP-0038503, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 4B] Representative data are shown showing the efficacy and toxicity of compound numbers EP-0035985, EP-0038461, EP-0038463, EP-0038503, EP-0038504, EP-0038508, and EP-0038521 in the presence of 1 μM FCCP / oligomycin or in the absence of toxin (no FO) over a 6.5 hour period. H2O2 treatment was run as a control for cell death as measured by DAPI staining. [Figure 5A]Representative data are shown showing that compounds Nos. EP-0038504 and EP-0038461 exhibit low mitochondrial toxicity. [Figure 5B] Representative data are shown showing that compounds Nos. EP-0038504 and EP-0038461 exhibit low mitochondrial toxicity. [Figure 5C] Representative data are shown showing that compounds Nos. EP-0038504 and EP-0038461 exhibit low mitochondrial toxicity. [Figure 6A] Representative data are shown showing that compound numbers EP-0038508 and EP-0038463 exhibit low mitochondrial toxicity. [Figure 6B] Representative data are shown showing that compound numbers EP-0038508 and EP-0038463 exhibit low mitochondrial toxicity. [Figure 6C] Representative data are shown showing that compound numbers EP-0038508 and EP-0038463 exhibit low mitochondrial toxicity. [Figure 7A] Representative data are shown showing that compound numbers EP-0038503 and EP-00338521 exhibit low mitochondrial toxicity. [Figure 7B] Representative data are shown showing that compound numbers EP-0038503 and EP-00338521 exhibit low mitochondrial toxicity. [Figure 7C] Representative data are shown showing that compound numbers EP-0038503 and EP-00338521 exhibit low mitochondrial toxicity. [Figure 8A] Representative data are shown showing that compound numbers EP-0035985 and EP-0038098 can reduce pathological α-synuclein levels in primary neurons. (Note: MTK458=35985, MTK898=38098) [Figure 8B]Representative data are shown showing that compound numbers EP-0035985 and EP-0038098 can reduce pathological α-synuclein levels in primary neurons. (Note: MTK458=35985, MTK898=38098) [Figure 8C] Representative data are shown showing that compound numbers EP-0035985 and EP-0038098 can reduce pathological α-synuclein levels in primary neurons. (Note: MTK458=35985, MTK898=38098) [Figure 9A] Representative in vivo data for EP-0040180 in the α-synuclein (PFF) model are shown. Specifically, Figure 9A shows that oral administration of EP-0040180 at 50, 25, 12.5, and 6.25 mg / kg twice daily significantly reduced PFF-induced pathological (pS129) α-synuclein(250-12) (Figure 9A) and pathological (pS129) α-synuclein (monomer) (Figure 9B) in the striatum. [Figure 9B] Representative in vivo data for EP-0040180 in the α-synuclein (PFF) model are shown. Specifically, Figure 9A shows that oral administration of EP-0040180 at 50, 25, 12.5, and 6.25 mg / kg twice daily significantly reduced PFF-induced pathological (pS129) α-synuclein(250-12) (Figure 9A) and pathological (pS129) α-synuclein (monomer) (Figure 9B) in the striatum. [Figure 10A] Representative data are shown showing that increasing doses of EP-0040503 decrease pS129 α-synuclein (FIG. 10A) in primary neuronal cultures. [Figure 10B] Representative data are shown showing that increasing doses of EP-0040503 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 10C]Representative data are shown showing that increasing doses of EP-0040503 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 11A] Representative data are shown showing that increasing doses of EP-0040850 decrease pS129 α-synuclein in primary neuronal cultures. [Figure 11B] Representative data are shown showing that increasing doses of EP-0040850 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 11C] Representative data are shown showing that increasing doses of EP-0040850 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 12] Representative data are shown showing that treatment with the toxin resulted in an increase in cleaved caspase-3 levels, whereas EP-0040850 did not. [Figure 13A] Representative data are shown showing that increasing doses of EP-0040857 reduce pS129 α-synuclein in primary neuronal cultures. [Figure 13B] Representative data are shown showing that increasing doses of EP-0040857 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 13C] Representative data are shown showing that increasing doses of EP-0040857 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 14A] Representative data are shown showing that increasing doses of EP-0040270 decrease pS129 α-synuclein in primary neuronal cultures. [Figure 14B] Representative data are shown showing that increasing doses of EP-0040270 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 14C] Representative data are shown showing that increasing doses of EP-0040270 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 15] Representative data are shown showing that treatment with toxin and high doses of EP-0040270 increases cleaved caspase-3 levels. [Figure 16A] Representative data are shown showing that increasing doses of EP-0040587 reduce pS129 α-synuclein in primary neuronal cultures. [Figure 16B] Representative data are shown showing that increasing doses of EP-0040587 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 16C] Representative data are shown showing that increasing doses of EP-0040587 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 17A] Representative data are shown showing that increasing doses of EP-0040180 reduce pS129 α-synuclein in primary neuronal cultures. [Figure 17B] Representative data are shown showing that increasing doses of EP-0040180 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 17C] Representative data are shown showing that increasing doses of EP-0040180 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 18] Representative data are shown, demonstrating that treatment with toxin and EP-0040180 does not significantly alter cleaved caspase-3 levels. [Figure 19]Figure 19A shows representative data showing the effect of EP-0040180 on pS129 signaling. Figure 19B shows representative data showing the effect of EP-0040180 on pS129 signaling. [Figure 20A] Representative data are shown showing that increasing doses of EP-0041161 decrease pS129 α-synuclein in primary neuronal cultures. [Figure 20B] Representative data are shown showing that increasing doses of EP-0041161 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 20C] Representative data are shown showing that increasing doses of EP-0041161 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 21] Representative data are shown showing that treatment with toxin alters cleaved caspase-3 levels, but treatment with EP-0041161 does not alter those levels. [Figure 22] Figure 22A shows representative data showing the effect of EP-0041161 on pS129 signaling. Figure 22B shows representative data showing the effect of EP-0041161 on pS129 signaling. [Figure 23A] Representative data are shown showing that increasing doses of EP-0041088 decrease pS129 α-synuclein in primary neuronal cultures. [Figure 23B] Representative data are shown showing that increasing doses of EP-0041088 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 23C] Representative data are shown showing that increasing doses of EP-0041088 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 24]Figure 24A shows representative data showing the effect of EP-0041088 on pS129 signaling. Figure 24B shows representative data showing the effect of EP-0041088 on pS129 signaling. [Figure 25A] Representative data are shown showing that increasing doses of EP-0040874 reduce pS129 α-synuclein in primary neuronal cultures. [Figure 25B] Representative data are shown showing that increasing doses of EP-0040874 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 25C] Representative data are shown showing that increasing doses of EP-0040874 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 26A] Representative data are shown showing that increasing doses of EP-0041668 decrease pS129 α-synuclein in primary neuronal cultures. [Figure 26B] Representative data are shown showing that increasing doses of EP-0041668 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 26C] Representative data are shown showing that increasing doses of EP-0041668 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 27A] Representative data are shown showing that increasing doses of EP-0041670 decrease pS129 α-synuclein in primary neuronal cultures. [Figure 27B] Representative data are shown showing that increasing doses of EP-0041670 decrease pS129 α-synuclein(250-12) in primary neuronal cultures. [Figure 27C]Representative data are shown showing that increasing doses of EP-0041670 decrease pS129 α-synuclein (monomer) in primary neuronal cultures. [Figure 28] Representative data are shown showing that PINK1 activators 35985 and 40180 induce mitophagy in a dose-dependent manner. [Figure 29] Representative data are shown showing that PINK1 activators 35985 and 40180 promote the recruitment of Parkin to mitochondria. [Figure 30A] Representative data are shown showing that cisplatin induces PINK1 and its direct target pUb. Specifically, Figures 30A and 30B show that cisplatin causes mitochondrial damage in vivo, as indicated by increased pS65-Ub (Figure 30A) and PINK1 induction (Figure 30B). [Figure 30B] Representative data are shown showing that cisplatin induces PINK1 and its direct target pUb. Specifically, Figures 30A and 30B show that cisplatin causes mitochondrial damage in vivo, as indicated by increased pS65-Ub (Figure 30A) and PINK1 induction (Figure 30B). [Figure 30C] Representative data are shown showing that cisplatin induces PINK1 and its direct target pUb. Specifically, Figure 30C shows the correlation between pUb and PINK1. [Figure 31] Representative data are shown showing that cisplatin causes a decrease in the mtDNA / nucDNA ratio. [Figure 32] Figure 32A shows representative data demonstrating that cisplatin-induced kidney damage is increased in PINK1 knockout mice, and Figure 32B shows representative data demonstrating that cisplatin-induced kidney damage is increased in PINK1 knockout mice. [Figure 33] Representative data are shown showing that cisplatin does not induce changes in pS65 ubiquitin in PINK1 knockout mice. [Figure 34] Representative data are shown showing that cisplatin treatment increases mitochondrial stress gene expression in PINK1 knockout mice. [Figure 35] Representative data showing a comparison of mouse plasma pharmacokinetics of 35985 and 40180 are shown. [Figure 36] Representative data are shown showing that 40180 reduces KIM-1 in cisplatin-treated mice. [Figure 37] Representative data are shown showing that 40180 reduces the expression of mitochondrial stress-related genes. DETAILED DESCRIPTION OF THE INVENTION

[0023] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

[0024] Detailed Description The present invention may be understood more readily by reference to the following detailed description and examples included therein.

[0025] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that the present invention is not limited to particular synthetic methods or to particular reagents unless otherwise specified, as synthetic methods and reagents may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described.

[0026] Although embodiments of the present invention may be described and claimed in particular legal classifications, such as system classes, this is done merely for convenience, and one of ordinary skill in the art will understand that each embodiment of the present invention may be described and claimed in any legal classification. Unless otherwise expressly stated, in no way is it intended that any method or embodiment described herein be construed as requiring that its steps be performed in a particular order. Thus, unless the claims or description specifically state that the steps of a method claim are to be limited to a particular order, no order is intended to be implied in any way. This also applies to any possible unstated basis for interpretation, including logical matters regarding the arrangement of steps or operational flow, simple interpretations resulting from grammatical construction or punctuation, or the number or type of embodiments described herein.

[0027] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in the reference that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the publication dates provided herein may be different from the actual publication dates, which may need to be independently confirmed.

[0028] A.Definition Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, whether individually or as part of a larger group, unless otherwise limited in specific instances.

[0029] As used herein, the terms "a" or "an" mean "at least one" or "one or more," unless the context clearly indicates otherwise. The term "and / or," as used in this specification and claims, should be understood to mean "either or both" of the elements connected by the term, i.e., elements that are sometimes present conjunctively and sometimes present separately. Unless otherwise specified, elements other than the elements specifically identified by the "and / or" phrase may optionally be present, whether related or unrelated to the elements specifically identified. Thus, as a non-limiting example, a statement about "A and / or B," when used in conjunction with open-ended language such as "comprising," may, in various embodiments, refer to A without B (optionally including elements other than B); in other embodiments, refer to B without A (optionally including elements other than A); in yet further embodiments, refer to both A and B (optionally including other elements); and so on.

[0030] As used in this specification and the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one, but also more than one, of several elements or a list of elements, and optionally including additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of several elements or a list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by the terms of exclusivity "either," "one of," "only one of," or "exactly one of," and "consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0031] As used herein, "comprising" (and any form of comprising, such as "comprise," "comprises," and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0032] As used herein, the term "about" means that a numerical value is approximate, and small variations do not materially affect the practice of the disclosed embodiments. As used herein, the term "about," when referring to measurable values ​​such as amounts and temporal durations, is intended to encompass variations of ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate for performing the disclosed methods. When a numerical limitation is used, unless the context dictates otherwise, "about" means that the numerical value may vary by ±10%, ±5%, ±4%, ±3%, ±2%, or ±1% and still be within the scope of the disclosed embodiments.

[0033] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0034] In this specification and in the concluding claims, references to parts by weight of a particular element or component in a composition refer to the weight relationship of that element or component to any other element or component expressed in parts by weight in the composition or article. That is, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, regardless of whether additional components are included in the compound.

[0035] Weight percentages (wt %) of ingredients are based on the total weight of the formulation or composition in which the ingredient is included, unless otherwise stated.

[0036] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that both the occurrence and non-occurrence of the event or circumstance are included in the description.

[0037] As used herein, the term "diagnosed" means having undergone a physical examination by a skilled artisan, e.g., a physician, and known to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. In some embodiments of the disclosed methods, the subject has been diagnosed prior to the administering step as being in need of treatment for a disorder associated with PINK1 kinase activity, such as a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy. As used herein, phrases such as "identified as being in need of treatment for a disorder" refer to selection of a subject based on need for treatment for a disorder. It is contemplated that the identification, in some embodiments, may be performed by a person different from the person making the diagnosis. It is also contemplated that in further embodiments, the administration may be performed by a person who subsequently administers.

[0038] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, intranasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration, including injection, such as intravenous, intraarterial, intramuscular, and subcutaneous administration. Administration may be continuous or intermittent. In various embodiments, the preparation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparation can be administered prophylactically, i.e., administered for the prevention of a disease or condition. As used herein, the terms "parenteral administration" and "administered parenterally" refer to forms of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. As used herein, the terms "systemic administration," "systemically administered," "peripheral administration," and "peripherally administered" refer to administration of a compound, drug, or other substance other than by direct administration to the central nervous system, e.g., subcutaneous administration, so that the compound, drug, or other substance enters the patient's system and is therefore subject to metabolism and other similar processes. In some embodiments, the compound is administered intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardially, intradermally, intraperitoneally, transtracheally, subcutaneously, subcuticularly, intraarticularly, subcapsularly, intrathecally, intraspinally, and intrasternally, or by injection or infusion.

[0039] As used herein, the term "contacting" refers to bringing together a disclosed compound and a cell, target receptor, or other biological entity in a manner that allows the compound to affect the activity of the target (e.g., receptor, cell, etc.), whether directly, i.e., by interacting with the target itself, or indirectly, i.e., by interacting with another molecule, cofactor, factor, or protein on which the activity of the target depends.

[0040] As used herein, "IC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process, or a component of a process, by 50%, including a protein, subunit, organelle, ribonucleoprotein, etc. In some embodiments, the IC 50 may refer to the concentration of a substance required for 50% inhibition in vivo, as further defined elsewhere herein.

[0041] As used herein, "EC 50 " is intended to refer to the concentration of a substance (e.g., a compound or drug) that produces a half-maximal response (i.e., 50% of the maximal response) of a biological process or component of a process, including proteins, subunits, organelles, ribonucleoproteins, etc. In some embodiments, the EC 50 may refer to the concentration of a substance required to achieve 50% of the maximal response in vivo, as further defined elsewhere herein.

[0042] The compounds of the present disclosure can be used at hydroxyl or amino functional groups to form prodrugs, using groups such as alkoxy, amino acids, etc. as prodrug-forming moieties. For example, hydroxymethyl positions can form mono-, di-, or triphosphates, and these phosphates can again form prodrugs. The preparation of such prodrug derivatives has been described in various publications (e.g., Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO2000 / 041531, p. 30). The nitrogen functional group that is converted in the preparation of these derivatives is one (or more) of the nitrogen atoms of the compounds of the present disclosure.

[0043] "Derivatives" of the compounds disclosed herein include pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, solvates, and combinations thereof. A "combination" referred to in this context refers to a derivative that falls within at least two of the following groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, and solvates. Examples of radiolabeled forms include compounds labeled with tritium, phosphorus-32, iodine-129, carbon-11, fluorine-18, and the like.

[0044] The term "leaving group" refers to an atom (or group of atoms) with electron-withdrawing ability that can be displaced as a stable species, taking into account the bonding electrons. Examples of suitable leaving groups include sulfonate esters, e.g., triflates, mesylates, tosylates, brosylates, and halides.

[0045] As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad embodiment, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. It is not intended that the disclosure be limited by the permissible substituents of organic compounds in any way. Additionally, the terms "substituted" or "substituted with" include the implicit proviso that such substitution is in accordance with the permissible valences of the atom and substituent substituted and that the substitution results in a stable compound, e.g., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, and the like. It is also contemplated that in certain embodiments, unless expressly stated otherwise, individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0046] In the definition of various terms, "A 1 ","A 2 ","A 3 " and "A 4 " is used herein as a generic symbol to represent various specific substituents. These symbols are not limited to those disclosed herein and can be any substituent, and although in one instance they may be defined as a particular substituent, in another instance they may be defined as some other substituent.

[0047] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0048] As used herein, the term "aliphatic" or "aliphatic group" refers to a hydrocarbon moiety that may be straight-chained (i.e., unbranched), branched, or cyclic (including fused, bridged, and spiro-fused polycyclics) and may be fully saturated or contain one or more units of unsaturation that are not aromatic. Unless otherwise specified, aliphatic groups have 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, straight-chain or branched alkyl, alkenyl, and alkynyl groups, as well as hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0049] The term "alkyl," as used herein, unless otherwise specified, refers to a monovalent saturated straight-chain or branched hydrocarbon radical having 1 to 6 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, tert-pentyl, neopentyl, sec-pentyl, 3-pentyl, sec-isopentyl, hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, 2,3-dimethylbutane, and the like. Alkyl groups can be substituted or unsubstituted. For example, alkyl groups can be substituted with one or more groups described herein, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol. A "lower alkyl" group is an alkyl group having 1 to 6 (e.g., 1 to 4) carbon atoms. The term alkyl group can also be C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, etc., which are alkyls from C1 to C24 and below.

[0050] Throughout this specification, "alkyl" is used generally to refer to both unsubstituted and substituted alkyl groups, although substituted alkyl groups are also specifically referred to herein by identifying the particular substituent(s) on the alkyl group. For example, the term "halogenated alkyl" or "haloalkyl" specifically refers to an alkyl group substituted with one or more halides, such as fluorine, chlorine, bromine, or iodine. Alternatively, the term "monohaloalkyl" specifically refers to an alkyl group substituted with a single halide, such as fluorine, chlorine, bromine, or iodine. The term "polyhaloalkyl" specifically refers to an alkyl group independently substituted with two or more halides; i.e., each halide substituent need not be the same halide as another halide substituent, and multiple instances of halide substituents need not be on the same carbon. The term "alkoxyalkyl" specifically refers to an alkyl group substituted with one or more alkoxy groups, as described below. The term "aminoalkyl" specifically refers to an alkyl group substituted with one or more amino groups. The term "hydroxyalkyl" specifically refers to an alkyl group substituted with one or more hydroxy groups. When "alkyl" is used in one instance and a specific term such as "hydroxyalkyl" is used in another instance, this is not intended to imply that the term "alkyl" does not also refer to the specific term such as "hydroxyalkyl."

[0051] This convention is also used for other groups described herein. That is, while a term such as "cycloalkyl" refers to both unsubstituted and substituted cycloalkyl moieties, these substituted moieties may additionally be specifically identified herein; for example, a particular substituted cycloalkyl may be referred to as, for example, an "alkylcycloalkyl." Similarly, a substituted alkoxy may be specifically referred to as, for example, a "halogenated alkoxy," a particular substituted alkenyl may be, for example, an "alkenylalcohol," and so on. Again, the convention of using a general term such as "cycloalkyl" and a specific term such as "alkylcycloalkyl" is not intended to imply that the general term does not also include the specific term.

[0052] The term "alkenyl," as used herein, refers to a hydrocarbon group having 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. 1 A 2 )C=C(A 3 A 4 Asymmetric structures, such as alkene, ...

[0053] The term "alkynyl," as used herein, refers to a hydrocarbon group having 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond. Alkynyl groups can be unsubstituted or substituted with one or more groups described herein, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

[0054] As used herein, the term "heteroalkyl" refers to an alkyl group having at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, and S, where the nitrogen, phosphorus, and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyl can be substituted as defined above for alkyl groups.

[0055] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0056] "Alkoxy" is an alkyl group attached to another moiety via an oxygen linker (-O(alkyl)). Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy.

[0057] A "haloalkoxy" is a haloalkyl group attached to another moiety through an oxygen atom, such as, but not limited to, -OCHCF2 or -OCF3.

[0058] The term "9- to 10-membered carbocyclyl" refers to a saturated or partially unsaturated 9- or 10-membered monocyclic, bicyclic (e.g., bridged or spiro bicyclic), polycyclic (e.g., tricyclic), or fused hydrocarbon ring system. The term "9- to 10-membered carbocyclyl" also includes saturated or partially unsaturated hydrocarbon rings (e.g., dihydroindenyl and tetrahydronaphthalenyl) fused with one or more aromatic or partially saturated hydrocarbon rings. Bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo[4.3.1]decanyl, etc. Spiro bicyclic cycloalkyl groups include, for example, spiro[3.6]decanyl, spiro[4.5]decanyl, spiro[4.4]nonyl, etc. Fused cycloalkyl rings include, for example, decahydronaphthalenyl, dihydroindenyl, decahydroazulenyl, octahydroazulenyl, tetrahydronaphthalenyl, etc. It is understood that, where specified, optional substituents on a carbocyclyl (e.g., in the case of an optionally substituted cycloalkyl) may be present at any substitutable position, including, for example, the position at which the carbocyclyl group is attached.

[0059] The term "cycloalkyl" as used herein refers to a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, and the like. The term "heterocycloalkyl" is a type of cycloalkyl group defined above and is included in the meaning of the term "cycloalkyl," in which at least one of the ring carbon atoms is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl and heterocycloalkyl groups can be substituted or unsubstituted. Cycloalkyl and heterocycloalkyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. In various aspects, cycloalkyl and heterocycloalkyl groups can be monocyclic, bicyclic (e.g., bridged, such as bicyclo[4.3.1]decanyl, or spiro, e.g., spiro[3.6]decanyl, spiro[4.5]decanyl, spiro[4.4]nonyl, etc.), polycyclic (e.g., tricyclic), or saturated or partially unsaturated fused hydrocarbon ring systems (e.g., decahydronaphthalenyl, dihydroindenyl, decahydroazulenyl, octahydroazulenyl, tetrahydronaphthalenyl).

[0060] The term "cycloalkenyl," as used herein, refers to a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bond, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term "heterocycloalkenyl" is a species of cycloalkenyl group, as defined above, and is included in the meaning of the term "cycloalkenyl," in which at least one of the ring carbon atoms is replaced with a heteroatom, such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups can be substituted or unsubstituted. The cycloalkenyl and heterocycloalkenyl groups can be substituted with one or more groups described herein, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol.

[0061] The term "cycloalkynyl," as used herein, refers to a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bond. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term "heterocycloalkynyl" is a type of cycloalkenyl group, as defined above, and is included within the meaning of the term "cycloalkynyl," in which at least one of the ring carbon atoms is replaced with a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkynyl and heterocycloalkynyl groups can be substituted or unsubstituted. Cycloalkynyl and heterocycloalkynyl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0062] As used herein, the terms "heterocycle" and "heterocyclyl" can be used interchangeably and refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term includes, but is not limited to, "heterocycloalkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle." Heterocycles can be saturated or partially saturated monocyclic, bicyclic (e.g., spiro or bridged), polycyclic, or fused systems. Heterocycles include pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole (including 1,2,3-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole), triazole (including 1,2,3-triazole and 1,3,4-triazole), tetrazole (including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole), pyridazine, pyrazine, triazine (including 1,2,4-triazine and 1,3,5-triazine). Included are tetrazines (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be C2-C18 and smaller heterocyclyls, including C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like. For example, C2 heterocyclyl includes groups having two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.Alternatively, for example, C5 heterocyclyl includes groups having 5 carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, etc. It is understood that a heterocyclyl group can be attached either through a heteroatom within the ring, if chemically possible, or through one of the carbons comprising the heterocyclyl ring.

[0063] As used herein, the term "bicyclic heterocycle" or "bicyclic heterocyclyl" refers to a ring system in which at least one ring member is other than carbon. Bicyclic heterocyclyl includes ring systems in which an aromatic ring is fused to another aromatic ring or an aromatic ring is fused to a non-aromatic ring. Bicyclic heterocyclyl includes ring systems in which a benzene ring is fused to a 5- or 6-membered ring having 1, 2, or 3 ring heteroatoms, or a pyridine ring is fused to a 5- or 6-membered ring having 1, 2, or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl, 1H-pyrrolo[3,2-b]pyridin-3-yl, and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0064] The term "heterocycloalkyl," as used herein, refers to an aliphatic, partially unsaturated, or fully saturated 3- to 14-membered ring system, including monocyclic rings having 3 to 8 atoms, as well as bicyclic and tricyclic ring systems. Heterocycloalkyl ring systems contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0065] The term "9-membered fused heterocyclyl" refers to a 9-membered saturated or partially unsaturated fused monocyclic heterocyclic ring containing at least one oxygen heteroatom and, optionally, two to four additional heteroatoms independently selected from N, O, and S. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein. A heterocyclyl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of fused saturated or partially unsaturated heterocyclic radicals containing at least one oxygen atom include, but are not limited to, dihydrobenzofuranyl, dihydrofuropyridinyl, octahydrobenzofuranyl, and the like. When optionally substituted is specified, the substituent on the heterocyclyl (e.g., in the case of an optionally substituted heterocyclyl) may be present at any substitutable position, including, for example, the position at which the heterocyclyl group is attached.

[0066] As used herein, the term "aromatic group" refers to a ring structure having a cyclic cloud of delocalized π electrons above and below the plane of the molecule, where the π cloud has (4n+2) π electrons. Further discussion of aromaticity can be found in Morrison and Boyd, Organic Chemistry (5th Ed., 1987) (Chapter 13, entitled "Aromaticity," pp. 477-497), which is incorporated herein by reference. The term "aromatic group" includes both aryl and heteroaryl groups.

[0067] The term "aryl," as used herein, refers to a group that includes any carbon-based aromatic group, including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. Aryl groups can be substituted or unsubstituted. Aryl groups can be substituted with one or more groups described herein, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol. The term "biaryl" is a specific type of aryl group and is included in the definition of "aryl." In addition, aryl groups can contain multiple ring structures, either single ring structures, fused ring structures, or linked through one or more bridging groups, such as carbon-carbon bonds. For example, biaryl can be two aryl groups linked together through a fused ring structure, as in naphthalene, or linked through one or more carbon-carbon bonds, as in biphenyl.

[0068] As used herein, the term "heteroaryl" refers to an aromatic group containing at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, with N-oxides, sulfur oxides, and dioxides being acceptable heteroatom substitutions. Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can be substituted with one or more groups, including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. Heteroaryl groups can be monocyclic or can be fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0069] The term "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic radical having 1 to 4 heteroatoms selected from N, O, and S. Non-limiting examples include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. When specified, optional substituents on a heteroaryl group may be located at any substitutable position, including, for example, the position at which the heteroaryl is attached.

[0070] The term "aldehyde" as used herein is represented by the formula -C(O)H. Throughout this specification, "C(O)" is a shorthand notation for a carbonyl group, i.e., C=O.

[0071] As used herein, the term "amine" or "amino" refers to a group of the formula -NA 1 A 2 In the formula, A 1 and A 2 can independently be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A particular example of amino is —NH.

[0072] The term "alkylamino" as used herein is represented by the formula -NH(-alkyl), where alkyl is as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, (sec-butyl)amino, (tert-butyl)amino, pentylamino, isopentylamino, (tert-pentyl)amino, hexylamino, and the like.

[0073] The term "dialkylamino" as used herein is represented by the formula -N(-alkyl), where alkyl is as defined herein. Representative examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, dipentylamino, diisopentylamino, di(tert-pentyl)amino, dihexylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-ethyl-N-propylamino, and the like.

[0074] The term "carboxylic acid" as used herein is represented by the formula -C(O)OH.

[0075] As used herein, the term "ester" refers to an ester of the formula -OC(O)A 1 or -C(O)OA 1 In the formula, A 1 may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. As used herein, the term "polyester" refers to a group of polyesters of the formula -(A 1 O(O)CA 2 -C(O)O) a -or-(A 1 O(O)CA 2 -OC(O)) a -, wherein A 1 and A 2 can independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, and "a" is an integer from 1 to 500. "Polyester" is a term used to describe a group produced by the reaction between a compound having at least two carboxylic acid groups and a compound having at least two hydroxyl groups.

[0076] As used herein, the term "ether" refers to a group of the formula A1 Office Automation 2 In the formula, A 1 and A 2 may independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. As used herein, the term "polyether" refers to a group of the formula -(A 1 Office Automation 2 O) a -, wherein A 1 and A 2 may independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, and "a" is an integer from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0077] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at each position. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. Additionally, in certain embodiments, unless expressly stated otherwise, it is contemplated that individual substituents may be further optionally substituted (i.e., further substituted or unsubstituted).

[0078] In some embodiments, the structure of the compound can be represented by the following formula: TIFF0007808226000067.tif22165This is understood to be equivalent to the following expression: TIFF0007808226000068.tif32165 where n is typically an integer, i.e., R n is a group consisting of five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) In each of these cases, the five R n Each R may be hydrogen or a recited substituent. By "independent substituents" it is meant that each R substituent may be independently defined. For example, in one instance, R n(a) is a halogen, R n(b) is not necessarily a halogen in that case.

[0079] In some still further embodiments, the structure of the compound can be represented by the following formula: TIFF0007808226000069.tif27165 formula, R y For example, A 1 , A 2 , and A 3 and these formulae are understood to be equivalent to the following group of formulae: TIFF0007808226000070.tif43165TIFF0007808226000071.tif43165TIFF0007808226000072.tif93165

[0080] Again, "independent substituents" means that each R substituent can be defined independently. For example, in one instance, R y1 A 1 If R y2 In that case, A is not necessarily 1 isn't it.

[0081] In some further embodiments, the structure of the compound can be represented by the following formula: TIFF0007808226000073.tif32165 In the formula, for example, Q includes three substituents independently selected from hydrogen and A, which is understood to be equivalent to the formula: TIFF0007808226000074.tif32165

[0082] Again, by "independent substituents" it is understood that the Q substituents are each independently defined as hydrogen or A, and that the formula is equivalent to the group of formulas below: TIFF0007808226000075.tif64165

[0083] In some embodiments, the disclosed compounds exist as geometric isomers. "Geometric isomer" refers to an isomer that differs in the orientation of substituent atoms relative to the cycloalkyl ring, i.e., cis isomer or trans isomer. When the disclosed compounds are named or displayed without indicating a specific cis or trans geometric isomer, it is understood that the name or structure encompasses one geometric isomer, without including other geometric isomers, mixtures of geometric isomers, or mixtures enriched in one geometric isomer relative to its corresponding geometric isomer. When a specific geometric isomer, i.e., cis or trans, is designated, the designated isomer is at least about 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight relative to the other geometric isomer.

[0084] The compounds described herein may exist in the form of pharmaceutically acceptable salts. When used in medicine, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts." As mentioned above, the compounds of the present invention can be administered, inter alia, as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. Salts can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compounds in their free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. Salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977). Examples of pharmaceutically acceptable esters of the compounds of the present invention include C1-C8 alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as aryl alkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of the compounds of the present invention can be prepared according to methods well known in the art. Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary C1-C8 alkylamines, and secondary C1-C8 dialkylamines.In the case of secondary amines, the amine may be in the form of a 5- or 6-membered heterocycloalkyl group having at least one nitrogen atom. Amides derived from ammonia, primary C1-C3 alkylamines, and secondary C1-C2 dialkylamines are commonly used. The amides of the compounds of the present invention can be prepared according to methods well known to those skilled in the art.

[0085] Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts.Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid).Examples of pharmaceutically acceptable base addition salts include, for example, salts of sodium, potassium, calcium, ammonium, organic amino, or magnesium.

[0086] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, partial glyceride mixtures of salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0087] As used herein, the phrase "pharmaceutically acceptable" means compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and animals. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state regulatory agency or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0088] Disease, disorder, and condition are used interchangeably herein.

[0089] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment is administered after one or more symptoms have occurred, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of symptom history and / or exposure to a particular organism or other susceptibility factor), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, e.g., to delay their recurrence.

[0090] As used herein, the terms "prevent" or "preventing" refer to making it impossible, avoiding, forestalling, halting, stopping, or impeding something from happening, especially by prior action. It will be appreciated that when mitigating, inhibiting, or preventing is used herein, unless otherwise indicated, the use of the other two terms is also expressly disclosed. The term "preventing" refers to preventing the occurrence of a disease, disorder, or condition and / or inhibiting, i.e., arresting, the occurrence of a disease, disorder, or condition in a human or animal that may be predisposed to, but has not yet been diagnosed with, the disease, disorder, and / or condition.

[0091] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to achieve a desired result (e.g., an amount that elicits a biological or medical response in a subject; e.g., a dosage of 0.01 to 100 mg / kg body weight / day) or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic outcome or to have an effect on an undesired symptom. In some embodiments, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic outcome or to have an effect on an undesired symptom, but generally insufficient to cause adverse side effects. The specific therapeutically effective amount level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the particular composition used; the patient's age, weight, general health, sex, and diet; the time of administration; the route of administration; the rate of excretion of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used, as well as factors well known in the pharmaceutical arts. For example, it is well within the skill of the art to start administering a compound at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Thus, a single-dose composition can contain the amount that makes up the daily dose, or a fraction thereof. The dosage can be adjusted by an individual physician in the event of any contraindications. The dosage can be varied and administered in one or more doses per day for one or several days. Guidance can be found in the literature regarding the appropriate dosage of a given class of pharmaceutical product. In further various embodiments, the preparation can be administered in a "prophylactically effective amount," i.e., an amount effective for preventing a disease or condition.

[0092] As used herein, the term "salt" refers to an acid or base salt of a compound used in the method of the present disclosure. Specific examples of acceptable salts include salts of mineral acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), salts of organic acids (such as acetic acid, propionic acid, glutamic acid, and citric acid), and salts of quaternary ammonium salts (such as methyl iodide and ethyl iodide).

[0093] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). In some embodiments, the subject is a human in need of treatment. In some embodiments, a "patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a compound or pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovine, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and non-mammalian animals. In some embodiments, the patient is a human.

[0094] The term "associated" or "associated with," in the context of a substance or the activity or function of a substance associated with a disease (e.g., a protein-associated disease, a symptom associated with cardiomyopathy, a neurodegenerative disease, or a symptom associated with Parkinson's disease), means that the disease (e.g., cardiomyopathy, neurodegenerative disease, or Parkinson's disease) is caused (in whole or in part) by the substance or the activity or function of the substance, or that the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of the substance. For example, symptoms of a disease or condition associated with reduced PINK1 activity levels can be symptoms attributable (in whole or in part) to reduced PINK1 activity levels (e.g., functional mutations or gene deletions or modulation of the PINK1 signaling pathway). As used herein, something described as associated with a disease can be a therapeutic target for the disease if it is a causative agent. For example, a PINK1-associated disease can be treated with an agent (e.g., a compound described herein) effective in increasing the activity level of PINK1.

[0095] "Control" or "control experiment" is used according to its plain and ordinary meaning to refer to an experiment in which the experimental subject or agent is treated as in a parallel experiment, except for the omission of an experimental procedure, agent, or variable. In some instances, a control is used as a standard of comparison in evaluating the effectiveness of an experiment.

[0096] "Contacting" is used according to its plain and ordinary meaning to refer to a process that allows at least two distinct species (e.g., chemical compounds, including biomolecules, or cells) to come into sufficient proximity to react, interact, or come into physical contact. However, it should be understood that the resulting reaction product may be produced directly from the reaction between the added reagents, or may be produced from intermediates derived from one or more of the added reagents that may be produced in the reaction mixture. The term "contacting" may include causing two species to react, interact, or come into physical contact, and the two species may be a compound described herein and a protein or enzyme (e.g., PINK1). In some embodiments, contacting includes allowing a compound described herein to interact with a protein or enzyme involved in a signaling pathway.

[0097] As defined herein, the terms "inhibition," "inhibit," "inhibiting," and the like, with respect to the interaction of a protein and an inhibitor (e.g., an antagonist), refer to negatively affecting (e.g., decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or disease symptoms. In embodiments, inhibition refers to a decrease in the activity of a signaling pathway or signal pathway. Thus, inhibition includes, at least in part, partially or totally blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signal transduction or enzymatic activity or the amount of a protein.

[0098] The symbol TIFF0007808226000076.tif4128 represents the point of attachment of a chemical moiety to the rest of a molecule or chemical formula.

[0099] As defined herein, the terms "activation," "activate," "activating," and the like, with respect to the interaction of a protein and an activator (e.g., an agonist), refer to positively affecting (e.g., increasing) the activity or function of a protein (e.g., PINK1) relative to the activity or function of the protein in the absence of the activator (e.g., a compound described herein). In embodiments, activation refers to an increase in the activity of a signal transduction pathway or signal pathway (e.g., the PINK1 pathway). Thus, activation can include, at least in part, partially or fully increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating signal transduction or enzyme activity or protein amount decreased in disease (e.g., decreased PINK1 activity or protein levels associated with neurodegenerative diseases such as cardiomyopathy or Parkinson's disease). Activation may include, at least in part, partially or fully increasing stimulation, increasing or enabling activation, or activating, sensitizing, or upregulating the amount of signaling or enzymatic activity or protein (e.g., PINK1) that can modulate the level of another protein or increase cell viability (e.g., increased PINK1 activity can increase cell viability in cells that may or may not have decreased PINK1 activity compared to non-disease controls).

[0100] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule. In embodiments, the modulator is a PINK1 modulator. In embodiments, the modulator is a compound that is a PINK1 modulator and reduces the severity of one or more symptoms of a PINK1-associated disease (e.g., reduces PINK1 activity or protein levels associated with a neurodegenerative disease such as cardiomyopathy or Parkinson's disease). In embodiments, the modulator is a compound that reduces the severity of one or more symptoms of a cardiomyopathy or neurodegenerative disease that is not caused by or characterized by PINK1 (e.g., loss of PINK1 function), but in which modulation of PINK1 activity (e.g., increasing PINK1 levels or PINK1 activity levels) may be effective.

[0101] "Disease" or "condition" refers to a state or condition of a patient or subject that can be treated with a compound, pharmaceutical composition, or method provided herein. In embodiments, the disease is a disease associated with (e.g., characterized by) reduced levels of PINK1. In embodiments, the disease is a disease characterized by loss of dopamine-producing cells (e.g., Parkinson's disease). In embodiments, the disease is a disease characterized by neurodegeneration. In embodiments, the disease is a disease characterized by neuronal cell death. In embodiments, the disease is a disease characterized by reduced levels of PINK1 activity. In embodiments, the disease is Parkinson's disease. In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is a cardiomyopathy.

[0102] As used herein, the term "cardiomyopathy" refers to a pathological condition that adversely affects cardiac tissue and results in measurable deterioration of myocardial function (e.g., systolic function, diastolic function). Dilated cardiomyopathy is characterized by ventricular chamber enlargement accompanied by systolic dysfunction without hypertrophy. Hypertrophic cardiomyopathy is a genetic disease transmitted as an autosomal dominant trait. Hypertrophic cardiomyopathy is morphologically characterized by a hypertrophied left ventricle without dilation. Restrictive cardiomyopathy is characterized by a lack of dilation or hypertrophy, but by reduced ventricular volume leading to impaired ventricular filling. Arrhythmogenic right ventricular cardiomyopathy is a genetic heart disease characterized by myocardial electrical instability. Unclassified cardiomyopathy is a category of cardiomyopathy that does not match the features of any of the other types. Unclassified cardiomyopathy may have features of multiple types, or may have features of, for example, fibroelastosis, noncompaction, or systolic dysfunction, with minimal dilation.

[0103] As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of a subject's nervous system is impaired. Examples of neurodegenerative diseases that can be treated using the compounds or methods described herein include Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, epilepsy, Friedreich's ataxia, frontotemporal dementia, and Gerstmann-Strauss syndrome. Isler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, Leigh's disease (Leigh syndrome), dementia with Lewy bodies, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, Shy-Drager syndrome, subacute combined spinal cord disease secondary to pernicious anemia Degeneration, schizophrenia, spinocerebellar ataxia (various forms with different features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord deafness, drug-induced parkinsonism, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, idiopathic Parkinson's disease, autosomal dominant Parkinson's disease, familial Parkinson's disease type 1 (PARK1), autosomal dominant Parkinson's disease with Lewy bodies type 3 (PARK3), autosomal dominant Parkinson's disease with Lewy bodies type 4 (PARK4), Parkinson's disease type 5 (PARK5) ), autosomal recessive early-onset Parkinson's disease type 6 (PARK6), autosomal recessive juvenile Parkinson's disease type 2 (PARK2), autosomal recessive early-onset Parkinson's disease type 7 (PARK7), Parkinson's disease type 8 (PARK8), Parkinson's disease type 9 (PARK9), Parkinson's disease type 10 (PARK10), Parkinson's disease type 11 (PARK11), Parkinson's disease type 12 (PARK12), Parkinson's disease type 13 (PARK13), or mitochondrial Parkinson's disease. In some embodiments, the autonomic neuropathy is not a neurodegenerative disease.

[0104] The term "signal pathway," as used herein, refers to a series of interactions between cellular and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that communicate a change in one component to one or more other components, which can then communicate the change to further components, which are optionally propagated to other signal pathway components.

[0105] The term "preparation" is intended to include formulations of an active compound with an encapsulating material as a carrier, such as a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier and thereby associated with the carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0106] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration, or implantation of a sustained-release device, such as a mini-osmotic pump, into a subject. Administration can be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "co-administered" is meant that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies (e.g., a cardiomyopathy therapy, such as an angiotensin-converting enzyme inhibitor (e.g., enalipril, lisinopril), an angiotensin receptor blocker (e.g., losartan, valsartan), a beta-blocker (e.g., lopressor, toprol-XL), digoxin, or a diuretic (e.g., Lasix; or a Parkinson's disease therapy, such as levodopa, a dopamine agonist (e.g., bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), an MAO-B inhibitor (e.g., selegiline or rasagiline), amantadine, an anticholinergic, an antipsychotic (e.g., clozapine), a cholinesterase inhibitor, modafinil, or a nonsteroidal anti-inflammatory drug).

[0107] The compounds of the present disclosure can be administered to a patient singly or simultaneously. Simultaneous administration is intended to include simultaneous or sequential administration of compounds individually or in combination (two or more compounds or agents). Thus, preparations can be combined with other active agents, if desired (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols, and can be delivered transdermally or topically. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid preparations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. The compositions of the present disclosure may further comprise ingredients for sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-like polymers, gelling polysaccharides, and micronized drug carrier substrates. These ingredients are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes. The compositions of the present disclosure can also be delivered to the body as microspheres for sustained release. For example, microspheres can be administered by intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).In some embodiments, formulations of the disclosed compositions can be delivered using liposomes that fuse with cell membranes or are endocytosed, i.e., by using receptor ligands attached to the liposomes that bind to cell surface membrane protein receptors and induce endocytosis. The use of liposomes can focus delivery of the disclosed compositions to target cells in vivo, particularly if the liposome surface carries receptor ligands specific to the target cells or is otherwise preferentially directed to a particular organ. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989.) The disclosed compositions can also be delivered as nanoparticles.

[0108] Pharmaceutical compositions provided by the present disclosure include compositions containing an active ingredient (e.g., a compound described herein, including any embodiment or example) in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in a method of treating a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule (e.g., PINK1) and / or reducing, eliminating, or slowing the progression of a symptom of the disease (e.g., a cardiomyopathy or neurodegenerative symptom, e.g., Parkinson's disease symptom). Determination of a therapeutically effective amount of a compound of the present disclosure is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0109] The dosage and frequency (single or multiple doses) administered to a mammal can vary depending on a variety of factors, such as whether the mammal is suffering from another disease and the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and extent of the symptoms of the disease being treated (e.g., neurodegenerative conditions such as cardiomyopathy or Parkinson's disease, and the severity of such conditions), the type of concomitant treatment, complications resulting from the disease being treated, or other health-related problems. Other therapeutic regimens or therapeutic agents can be used in conjunction with the methods and compounds of Applicant's disclosure. Adjustment and manipulation of established dosages (e.g., frequency and duration) is well within the capabilities of one of ordinary skill in the art.

[0110] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration will be the concentration of active compound(s) that can achieve the methods described herein, as measured using methods described herein or known in the art.

[0111] As is well known in the art, the therapeutically effective amount for use in humans can also be determined from animal models. For example, the dose for use in humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage for humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward as described above. Based on the above and other methods, adjusting the dosage to achieve maximum efficacy in humans is well within the capabilities of those skilled in the art.

[0112] Dosages can vary depending on the requirements of the patient and the compound used. The dose administered to a patient, in the context of this disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determination of the dosage appropriate to a particular situation is within the skill of the physician. Generally, treatment is initiated with small dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.

[0113] Dosage amount and interval can be adjusted individually to provide levels of the administered compound that are effective for the particular clinical indication being treated, thereby providing a treatment regimen commensurate with the severity of the individual condition.

[0114] Using the teachings provided herein, one can design an effective prophylactic or therapeutic regimen that does not result in substantial toxicity, yet is effective in treating the clinical symptoms observed in a particular patient. This design must involve careful selection of an active compound by considering factors such as the potency of the compound, its relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred method of administration, and the toxicity profile of the selected agent.

[0115] The compounds described herein may be used in combination with each other, with other active agents known to be useful in treating disease-related neurodegeneration (e.g., Parkinson's disease medications such as levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, antipsychotics (e.g., clozapine), cholinesterase inhibitors, modafinil, or nonsteroidal anti-inflammatory drugs), or with adjunct agents that may not be effective alone but may contribute to the efficacy of the active agent.

[0116] The compounds described herein may be used in combination with each other and with active agents known to be useful in the treatment of cardiomyopathy, such as angiotensin converting enzyme inhibitors (e.g., enalipril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), beta blockers (e.g., lopressor, toprol-XL), digoxin, or diuretics (e.g., Lasix), diseases associated with neurodegeneration (e.g., Parkinson's disease medications, e.g., levodopa, dopamine agonists ( For example, it may be used in combination with bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, antipsychotics (e.g., clozapine), cholinesterase inhibitors, modafinil, or nonsteroidal anti-inflammatory drugs), or in combination with adjuncts that may not be effective alone but may contribute to the efficacy of the active agent.

[0117] In embodiments, simultaneous administration includes administering one active agent within about 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Simultaneous administration includes administering two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In embodiments, the active agents and / or adjunct agents can be linked or conjugated to each other. In embodiments, the compounds described herein can be combined with a neurodegenerative treatment, such as surgery. In embodiments, the compounds described herein can be combined with a cardiomyopathy treatment, such as surgery.

[0118] "PINK1" is used according to its common and ordinary meaning and refers to proteins of identical or similar names, as well as functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of PINK1 (e.g., "PTEN-induced putative kinase 1"; Entrez Gene 65018, OMIM 608309, UniProtKB Q9BXM7, and / or RefSeq(protein)NP_115785.1). The term includes PINK1 and variants thereof that maintain PINK1 activity (e.g., within at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the activity of PINK1).

[0119] The term "neo-substrate" refers to a composition that is structurally similar to a composition that is a substrate for a protein or enzyme when the protein or enzyme performs its normal function, but that is distinctly different in structure from the protein's or enzyme's normal substrate. In some embodiments, the composition comprises a neo-substrate. In embodiments, the neo-substrate is a better substrate (e.g., better (e.g., faster) reaction kinetics, stronger binding, higher turnover, more productive reaction, equilibrium favoring product formation) than the protein's or enzyme's normal substrate. In embodiments, the neo-substrate is a derivative of adenine, adenosine, AMP, ADP, or ATP. In embodiments, the neo-substrate is a substrate for PINK1. In embodiments, the neo-substrate is an N6-substituted adenine, adenosine, AMP, ADP, or ATP.

[0120] The term "derivative" as applied to a phosphate-containing, monophosphate, diphosphate, or triphosphate group or moiety refers to a chemical modification of such a group, which modification may include the addition, removal, or substitution of one or more atoms of the phosphate-containing, monophosphate, diphosphate, or triphosphate group or moiety. In embodiments, such derivatives are prodrugs of phosphate-containing, monophosphate, diphosphate, or triphosphate groups or moieties that are converted from the derivative to the phosphate-containing, monophosphate, diphosphate, or triphosphate group or moiety after administration to a subject, patient, cell, biological sample, or contact with a subject, patient, cell, biological sample, or protein (e.g., enzyme). In one embodiment, the triphosphate derivative is gamma-thiotriphosphate. In one embodiment, the derivative is a phosphoramidate. In embodiments, phosphate-containing derivatives of monophosphate, diphosphate, or triphosphate groups or moieties are disclosed in Murakami et al. J. Med Chem., 2011, 54, 5902; Sofia et al., J. Med Chem. 2010, 53, 7202; Lam et al. ACC, 2010, 54, 3187; Chang et al., ACS Med Chem Lett., 2011, 2, 130; Furman et al., Antiviral Res., 2011, 91, 120; Vernachio et al., ACC, 2011, 55, 1843; Zhou et al., AAC, 2011, 44, 76; Reddy et al., BMCL, 2010, 20, 7376; Lam et al. al., J. Virol., 2011, 85, 12334; Sofia et al., J. Med. Chem., 2012, 55, 2481; Hecker et al., J. Med. Chem., 2008, 51, 2328; or Rautio et al., Nature Rev. Drug. Discov. 2008, 7, 255, all of which are incorporated herein by reference in their entirety for all purposes.

[0121] The term "mitochondrial dysfunction" is used according to its ordinary meaning and refers to abnormal mitochondrial activity or function, including, for example, abnormal respiratory chain activity, reactive oxygen species levels, calcium homeostasis, mitochondrial-mediated programmed cell death, mitochondrial fusion, mitochondrial fission, mitophagy, lipid concentrations in the mitochondrial membrane, and / or mitochondrial permeability transition.

[0122] As used herein, the term "mitochondrial disease" refers to a disease, disorder, or condition in which the function of mitochondria in a subject is impaired or dysfunctional. Examples of mitochondrial diseases that can be treated using the compounds or methods described herein include Alzheimer's disease, amyotrophic lateral sclerosis, Asperger's syndrome, autistic disorder, bipolar disorder, cancer, cardiomyopathy, Charcot-Marie-Tooth disease (CMT, including various subtypes such as type 2b and type 2b CMT), childhood disintegrative disorder (CDD), diabetes, diabetic nephropathy, epilepsy, Friedreich's ataxia (FA), hereditary motor and sensory neuropathy (HMSN), Huntington's disease, Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON, also known as Leber's disease, Leber's syndrome, and Leber's syndrome), and others. Leber's optic atrophy (LOA) or Leber's optic neuropathy (LON), Leigh's disease or syndrome, macular degeneration, MELAS (mitochondrial myopathy, lactacidosis, and stroke), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), motor neuron disease, myoclonic epilepsy with ragged-red fibers (MERRF), NARP (neuropathy, ataxia, retinitis pigmentosa, and ptosis), Parkinson's disease, peroneal muscular atrophy (PMA), pervasive developmental disorder not otherwise specified (PDD-NOS), renal tubular acidosis, Rett's syndrome, schizophrenia, and various types of stroke.

[0123] The term "oxidative stress" is used according to its ordinary meaning to refer to abnormal levels of reactive oxygen species.

[0124] As used herein, the term "animal" includes, but is not limited to, human and non-human vertebrates, such as wild animals, domestic animals, and farm animals.

[0125] As used herein, the term "antagonize" or "antagonizing" means to reduce or completely eliminate the effect, such as activity, of GPR109a.

[0126] As used herein, the phrase "anti-receptor effective amount" of a compound can be measured by the anti-receptor efficacy of the compound. In some embodiments, the anti-receptor effective amount inhibits receptor activity by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%. In some embodiments, an "anti-receptor effective amount" is also a "therapeutically effective amount," whereby the compound reduces or eliminates at least one effect of GPR109a. In some embodiments, the effect is a B-arrestin effect. In some embodiments, the effect is a G protein-mediated effect.

[0127] As used herein, the term "carrier" refers to a diluent, adjuvant, or excipient with which a compound is administered. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical carriers can also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliary substances, stabilizers, thickeners, lubricants, and coloring agents can be used.

[0128] As used herein, "comprising" (and any form of comprising, such as "comprise," "comprises," and "comprised"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0129] As used herein, the term "contacting" refers to bringing two elements together in an in vitro system or an in vivo system. For example, "contacting" a compound disclosed herein with an individual, patient, or cell includes administering the compound to an individual or patient, such as a human, as well as introducing the compound into a sample containing, for example, a cell preparation or purified preparation containing a compound or pharmaceutical composition disclosed herein.

[0130] As used herein, the phrase "inhibiting an activity," such as an enzyme activity or receptor activity, means reducing any measurable amount of activity of PINK1.

[0131] As used herein, the phrase "in need thereof" means that the animal or mammal has been identified as being in need of a particular method or treatment. In some embodiments, identification can be by any diagnostic means. The animal or mammal can be in need of any of the methods and treatments described herein. In some embodiments, the animal or mammal is in or will be transferred to an environment where a particular disease, disorder, or condition is prevalent.

[0132] As used herein, the phrase "an integer between X and Y" means any integer, inclusive. For example, the phrase "an integer between 1 and 5" means 1, 2, 3, 4, or 5.

[0133] As used herein, the term "isolated" means that the compounds described herein have been separated, for example by conventional techniques, from other components of either (a) a natural source such as a plant or cell, or (b) a synthetic organic chemical reaction mixture.

[0134] As used herein, the term "mammal" means a rodent (i.e., a mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0135] As used herein, the term "prodrug" refers to a derivative of a known direct-acting drug that has enhanced delivery properties and therapeutic value compared to the original drug and is converted to an active drug by an enzymatic or chemical process. The compounds described herein also include derivatives known as prodrugs, which can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound. Examples of prodrugs include the compounds of the present disclosure described herein that contain one or more molecular moieties attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, which, upon administration to a patient, are cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present disclosure. The preparation and use of prodrugs are described in T. Higuchi et al., "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.

[0136] As used herein, the term "purified" means that the isolate, when isolated, contains at least 90%, at least 95%, at least 98%, or at least 99%, by weight of the isolate, of a compound described herein.

[0137] As used herein, the phrase "solubilizing agent" means an agent that results in the formation of a micellar or true solution of a drug.

[0138] As used herein, the term "solution / suspension" refers to a liquid composition in which a first portion of the active agent is present in solution and a second portion of the active agent is present in particulate form suspended in a liquid matrix.

[0139] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it was formed or detected.

[0140] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response sought in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician. The therapeutic effect depends on the disorder being treated or the biological effect desired. Thus, the therapeutic effect can be a reduction in the severity of symptoms associated with the disorder and / or inhibition (partial or complete) of the progression of the disorder, or an improvement in treatment, cure, prevention, or elimination of the disorder or side effects. The amount necessary to elicit a therapeutic response can be determined based on the age, health, size, and sex of the subject. The optimal amount can also be determined based on monitoring the subject's response to treatment.

[0141] It will also be understood that certain features described herein, which are for clarity described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features, which are for brevity described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0142] It should be noted that any embodiment of the present invention may optionally exclude one or more embodiments for purposes of claiming inventive subject matter.

[0143] In some embodiments, the compound or salt thereof is substantially isolated. Partial isolation can include, for example, a composition enriched in the compound of the present disclosure. Substantial isolation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present disclosure or its salt. Methods for isolating compounds and salts thereof are routine in the art.

[0144] B. Compound In various embodiments, the present invention relates to compounds useful for treating disorders associated with PINK1 kinase activity, such as, for example, neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathies.

[0145] In various embodiments, the compounds are useful for treating disorders associated with PINK1 kinase activity in a mammal. In a further embodiment, the compounds are useful for treating PINK1 kinase activity in a human.

[0146] It is contemplated that each of the disclosed derivatives may be optionally further substituted.It is also contemplated that any one or more derivatives may be optionally omitted from the present invention.It is understood that the disclosed compounds can be provided by the disclosed methods.It is also understood that the disclosed compounds can be used in the disclosed methods.

[0147] 1. Structure In some embodiments, a structure represented by the following formula: TIFF0007808226000077.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11aand R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. 2 is -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 4 is hydrogen.

[0148] In some embodiments, a structure represented by the following formula: TIFF0007808226000078.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3is a 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, a structure represented by a formula selected from the following: A compound having TIFF0007808226000079.tif42165 is provided.

[0150] In some embodiments, a structure represented by a formula selected from the following: A compound having TIFF0007808226000080.tif42165 is provided.

[0151] In some embodiments, the following structure: TIFF0007808226000081.tif48165, or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, a structure represented by the following formula: TIFF0007808226000082.tif48165, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, a structure represented by the following formula: TIFF0007808226000083.tif48165, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, a structure represented by a formula selected from the following: TIFF0007808226000084.tif48165, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, a structure represented by a formula selected from the following: TIFF0007808226000085.tif48165, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, the compound is selected from the following: TIFF0007808226000086.tif183165TIFF0007808226000087.tif223165.

[0157] In some embodiments, the compound is selected from the following: TIFF0007808226000088.tif188165TIFF0007808226000089.tif235165.

[0158] In some embodiments, the compound is selected from the following: TIFF0007808226000090.tif175165TIFF0007808226000091.tif212165.

[0159] In some embodiments, the compound is selected from the following: TIFF0007808226000092.tif175165TIFF0007808226000093.tif173165TIFF0007808226000094.tif93165.

[0160] In some embodiments, Q 1 is CH and Q 2 is N and Q 3 is NH.

[0161] Thus, in some embodiments, m is 0 or 1. In further embodiments, m is 0. In yet further embodiments, m is 1.

[0162] In some embodiments, n, if present, is 0, 1, or 2. In further embodiments, n, if present, is 0 or 1. In still further embodiments, n, if present, is 1 or 2. In still further embodiments, n, if present, is 0 or 2. In still further embodiments, n, if present, is 0. In still further embodiments, n, if present, is 0. In still further embodiments, n, if present, is 1. In still further embodiments, n, if present, is 2.

[0163] Specific examples of compounds are provided in the Examples section and are included herein. Pharmaceutically acceptable salts as well as neutral forms of these compounds are also included.

[0164] aQ 1 Group and Q 2 base In some embodiments, Q 1 and Q 2 are each independently N or CH. In a further embodiment, Q 1 and Q 2 In still further embodiments, Q 1 and Q 2 Each is N. In yet a further embodiment, Q 1 is N and Q 2 In yet a further embodiment, Q 1 is CH and Q 2 is N.

[0165] In some embodiments, Q 1 is CH or N. In a further embodiment, Q 1 is N. In yet a further embodiment, Q 1 is CH.

[0166] In some embodiments, Q 2 is CH or N. In a further embodiment, Q 2 In yet a further embodiment, Q 2 is NH.

[0167] bQ 3 base In some embodiments, Q 3 is CH or NH. In a further embodiment, Q 2 is CH2. In still further embodiments, Q 2 is NH.

[0168] cZ group In some embodiments, Z is CR 11a R 11b , N.R. 12 or O. In a further embodiment, Z is CR 11a R 11b or NR 12 In still further embodiments, Z is NR 12 Or O.

[0169] In some embodiments, Z is CR 11a R 11b or O. In a further embodiment, Z is CR 11a R 11b In yet a further embodiment, Z is CH. In yet a further embodiment, Z is O.

[0170] In some embodiments, Z is NR 12 is.

[0171] dR 1A Group, R 1B Group, R 1C groups, and R 1D Group(R 1 basis) In some embodiments, R 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino. 1a , R 1b , R 1c , and R 1d are each independently hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, -CH2F, -CH2CH2F, -CH(CH3)CH2F, -CH2CH2CH2F, -CH2Cl, -CH2CH2Cl, -CH(CH3)CH2Cl, -CH2CH2CH2Cl, -CH2CN, -CH2CH2CN, -CH(CH3)CH2CN, -CH2CH2CH2CN, -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -CH2CH2CH2OH, methoxy, ethoxy In still further embodiments, R is selected from the group consisting of hydroxyl, n-propoxy, isopropoxy, -OCF, -OCHF, -OCHF, -OCHCHF, -OCH(CH)CHF, -OCHCHCHF, -OCCl, -OCHCl, -OCHCl, -OCHCHCl, -OCH(CH)CHCl, -OCHCHCHCl, -NHCH, -NHCHCH, -NHCH(CH)CH, -NHCHCHCH, -N(CH), -N(CH)CHCH, -N(CH)CH(CH)CH, and -N(CH)CHCHCH. 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, F, -Cl, -CN, -NH, -OH, -NO, methyl, ethyl, ethenyl, -CHF, -CHCHF, -CHCl, -CHCHCl, -CHCN, -CHCHCN, -CHOH, -CHCHOH, methoxy, ethoxy, -OCF, -OCHF, -OCHF, -OCHCHF, -OCCl, -OCHCl, -OCHCl, -OCHCHCl, -NHCH, -NHCHCH, -N(CH), and -N(CH)CHCH. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH, —OH, —NO, methyl, —CHF, —CHCl, —CHCN, —CHOH, methoxy, —OCF, —OCHF, —OCHF, —OCCl, —OCHCl, —OCHCl, —NHCH, and —N(CH).

[0172] In a further embodiment, R 1a , R 1b , R 1c , and R 1d are each hydrogen.

[0173] In various embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C hydroxyalkyl, C-C haloalkoxy, and C-C alkoxy. 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, F, -Cl, -CN, -NH, -OH, -NO, -CHOH, -CHCHOH, -CH(CH)CHOH, -CHCHCHOH, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF, -OCHF, -OCHF, -OCHCHF, -OCH(CH)CHF, -OCHCHCHF, -OCCl, -OCHCl, -OCHCl, -OCHCHCl, -OCH(CH)CHCl, and -OCHCHCHCl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, -Cl, -CN, -NH, -OH, -NO, -CHOH, -CHCHOH, methoxy, ethoxy, -OCF, -OCHF, -OCHF, -OCHCHF, -OCCl, -OCHCl, -OCHCl, and -OCHCHCl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH 2 , —OH, —NO 2 , —CH 2 OH, methoxy, —OCF 3 , —OCHF 2 , —OCH 2 F, —OCCl 3 , —OCHCl 2 , and —OCH 2 Cl.

[0174] In various embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkylamino, and (C-C)(C-C) dialkylamino. 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, F, -Cl, -CN, -NH, -OH, -NO, -NHCH, -NHCHCH, -NHCH(CH)CH, -NHCHCHCH, -N(CH), -N(CH)CHCH, -N(CH)CH(CH)CH, and -N(CH)CHCHCH. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH, —OH, —NO, —NHCH, —NHCHCH, —N(CH), and —N(CH)CHCH. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH 2 , —OH, —NO 2 , —NHCH 3 , and —N(CH 3 ) 2 .

[0175] In various embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C haloalkyl, and C-C cyanoalkyl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, -Cl, -CN, -NH, -OH, -NO, -CHF, -CHCHF, -CH(CH)CHF, -CHCHCHF, -CHCl, -CHCHCl, -CH(CH)CHCl, -CHCHCHCl, -CHCN, -CHCHCN, -CH(CH)CHCN, and -CHCHCHCN. 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, F, —Cl, —CN, —NH, —OH, —NO, —CHF, —CHCHF, —CHCl, —CHCHCl, —CHCN, and —CHCHCN. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH 2 , —OH, —NO 2 , —CH 2 F, —CH 2 Cl, and —CH 2 CN.

[0176] In various embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, and C-C alkenyl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH, —OH, —NO, methyl, ethyl, n-propyl, isopropyl, ethenyl, and propenyl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH, —OH, —NO, methyl, ethyl, and ethenyl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, F, —Cl, —CN, —NH 2 , —OH, —NO 2 , and methyl.

[0177] In various embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen and C1-C4 alkyl. 1a , R 1b , R 1c, and R 1d are each independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, methyl, and ethyl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen and methyl.

[0178] In various embodiments, R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen and halogen. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, —F, —Cl, and —Br. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, -F, and -Cl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen and —Cl. 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen and —F.

[0179] In some embodiments, R 1a , R 1b , R 1c , and R 1d are each independently hydrogen, halogen, or C1-C4 alkyl. 1a , R 1b , R 1c , and R1d are each independently hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, or isopropyl. 1a , R 1b , R 1c , and R 1d are each independently hydrogen, -F, -Cl, methyl, and ethyl. In still further embodiments, R 1a , R 1b , R 1c , and R 1d are each independently hydrogen, —F, and methyl.

[0180] eR 2 base In some embodiments, R 2 is -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 In a further embodiment, R 2 is -(CH2) n Cy 1 and -CH(OH)Cy 1 In still further embodiments, R 2 is -(CH2) n Cy 1 In yet a further embodiment, R 2 is -CH(OH)Cy 1 is.

[0181] In some embodiments, R 2 is -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 In a further embodiment, R 2 -OCy 1 , -NR 13 Cy 1, -OCH2Cy 1 , -NR 13 CH2Cy 1 , and Cy 1 In still further embodiments, R 2 -OCy 1 , -NR 13 Cy 1 , and Cy 1 is selected from.

[0182] In some embodiments, R 2 is -O(CH2) n Cy 1 and -NR 13 (CH2) n Cy 1 In a further embodiment, R 2 -OCy 1 , -NR 13 Cy 1 , -OCH2Cy 1 , and -NR 13 CH2Cy 1 In still further embodiments, R 2 -OCy 1 and -NR 13 Cy 1 is selected from.

[0183] In some embodiments, R 2 Cy 1 is.

[0184] fR 3 base In some embodiments, R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl. 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl. 3is a 3-6 membered cycloalkyl, -CF, -CHF, -CHF, -CHCF, -CHCHF, -CHCHF, -CCl, -CHCl, -CHCl, -CHCCl, -CHCHCl, -CHCHCl, -OCF, -OCHF, -OCHF, -OCHCF, -OCHCHF, -OCHCHF, -OCCl, -OCHCl, -OCHCl, -OCHCCl, -OCHCHCl, -OCHCHCl, -CH(OH)CF, -CH(OH)CHF, -CH(OH)CHF, -CH(OH)CCl, -CH(OH)CHCl, or -CH(OH)CHCl. 3 is a 3- to 6-membered cycloalkyl, —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, —CH2Cl, —OCF3, —OCHF2, —OCH2F, —OCCl3, —OCHCl2, or —OCH2Cl.

[0185] In some embodiments, R 3 is C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl. 3 is C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 halohydroxyalkyl. 3 is -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CCl3, -CH2CHCl2, -CH2CH2Cl, -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCH2CH2F, -OCCl3, -OCHCl2, -OCH2Cl, -OCH2CCl3, -OCH2CHCl2, -OCH2CH2Cl, -CH(OH)CF3, -CH(OH)CHF2, -CH(OH)CH2F, -CH(OH)CCl3, -CH(OH)CHCl2, or -CH(OH)CH2Cl. 3is —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, —CH2Cl, —OCF3, —OCHF2, —OCH2F, —OCCl3, —OCHCl2, or —OCH2Cl.

[0186] In some embodiments, R 3 is C1-C6 haloalkyl. In a further embodiment, R 3 is C1-C4 haloalkyl. In still further embodiments, R 3 is —CF, —CHF, —CHF, —CHCF, —CHCHF, —CHCHF, —CCl, —CHCl, —CHCl, —CHCCl, —CHCHCl, or —CHCHCl. 3 is —CF3, —CHF2, —CH2F, —CCl3, —CHCl2, or —CH2Cl.

[0187] In some embodiments, R 3 is a 3- to 6-membered cycloalkyl. In a further embodiment, R 3 is a 3- to 5-membered cycloalkyl. In still further embodiments, R 3 is a 3-4 membered cycloalkyl. In still further embodiments, R 3 is a 3-membered cycloalkyl. In yet a further embodiment, R 3 is a four-membered cycloalkyl.

[0188] In some embodiments, R 3 is hydrogen.

[0189] In some embodiments, R 3 is hydrogen, halogen, (C1-C4) alkyl, or 3- to 6-membered cycloalkyl. 3 is hydrogen.

[0190] In a further embodiment, R 3is hydrogen, -F, -Cl, methyl, ethyl, n-propyl, isopropyl, or 3- to 6-membered cycloalkyl. 3 is hydrogen, -F, -Cl, methyl, ethyl, or 3- to 6-membered cycloalkyl. 3 is hydrogen, —F, —Cl, methyl, or 3- to 6-membered cycloalkyl.

[0191] In a further embodiment, R 3 is hydrogen or (C-C) alkyl. In still further embodiments, R 3 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. 3 is hydrogen, methyl, or ethyl. In yet a further embodiment, R 3 is hydrogen or ethyl. In still further embodiments, R 3 is hydrogen or methyl.

[0192] In a further embodiment, R 3 is (C1-C4) alkyl. In still further embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. 3 is methyl or ethyl. In yet a further embodiment, R 3 is ethyl. In still further embodiments, R 3 is methyl.

[0193] In a further embodiment, R 3 is (C1-C4) alkyl. In still further embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, a methyl halide, an ethyl halide, a propyl halide, CF, CCl, or CBr. 3 is methyl or ethyl. In yet a further embodiment, R 3 is ethyl. In still further embodiments, R 3is methyl. In still further embodiments, R 3 is CF3, CCl3, or CBr3.

[0194] In a further embodiment, R 3 is hydrogen or halogen. In still further embodiments, R 3 is hydrogen, -F, -Cl, or -Br. In still further embodiments, R 3 is hydrogen, -F, or -Cl. In yet a further embodiment, R 3 is hydrogen or -F. In still further embodiments, R 3 is hydrogen or -Cl.

[0195] In a further embodiment, R 3 is halogen. In still further embodiments, R 3 is -F, -Cl, or -Br. In still further embodiments, R 3 is -F or -Cl. In yet a further embodiment, R 3 is -F. In still further embodiments, R 3 is -Cl.

[0196] In a further embodiment, R 3 is hydrogen or 3-6 membered cycloalkyl. 3 is hydrogen, cyclopropyl, cyclobutyl, or cyclopentyl. 3 is hydrogen, cyclopropyl, or cyclobutyl. In yet a further embodiment, R 3 is hydrogen or cyclopropyl. In some embodiments, R 3 is not methyl, ethyl, or butyl. In some embodiments, R 3 is not an acyclic alkyl chain containing from about 1 to about 5 substituted or unsubstituted carbons.

[0197] In a further embodiment, R 3 is a 3- to 6-membered cycloalkyl. In still further embodiments, R3 is a 3- to 5-membered cycloalkyl. In still further embodiments, R 3 is a 3-4 membered cycloalkyl. In yet a further embodiment, R 3 is cyclohexyl. In still further embodiments, R 3 is cyclopentyl. In yet a further embodiment, R 3 is cyclobutyl. In yet a further embodiment, R 3 is cyclopropyl.

[0198] In a further embodiment, R 3 is a 3-6 membered cycloalkyl or C-C haloalkyl. 3 is cyclopropyl, cyclobutyl, cyclopentyl, CF, -CHF, -CHF, -CHCF, -CHCHF, -CHCHF, -CCl, -CHCl, -CHCl, -CHCCl, -CHCHCl, or -CHCHCl. 3 is cyclopropyl, cyclobutyl, CF, -CHF, -CHF, -CHCF, -CHCHF, -CHCHF, -CCl, -CHCl, -CHCl, or -CHCCl. 3 is cyclopropyl, CF3, -CHF2, -CH2F, -CCl3, or -CHCl2.

[0199] In a further embodiment, R 3 is a 3-membered cycloalkyl or -CF. In still further embodiments, R 3 is a 3-membered cycloalkyl. In still further embodiments, R 3 is -CF3.

[0200] gR 4 base In some embodiments, R 4 is selected from hydrogen and C1-C4 alkyl. In a further embodiment, R 4is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. 4 is selected from hydrogen, methyl, and ethyl. In yet a further embodiment, R 4 is selected from hydrogen and ethyl. In yet a further embodiment, R 4 is selected from hydrogen and methyl.

[0201] In some embodiments, R 4 is hydrogen.

[0202] In some embodiments, R 4 is C1-C4 alkyl. In a further embodiment, R 4 is selected from methyl, ethyl, n-propyl, and isopropyl. 4 is selected from methyl and ethyl. In yet a further embodiment, R 4 is ethyl. In yet a further embodiment, R 4 is methyl.

[0203] hR 11A Groups and R 11B Group(R 11 basis) In some embodiments, R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C1-C4 alkoxy; or R 11a and R 11b each, when present, together constitute =O.

[0204] In some embodiments, R 11a and R 11b Each, if present, is independently selected from hydrogen, halogen, —OH, and C1-C4 alkoxy. 11a and R 11bEach, if present, is independently selected from hydrogen, —F, —Cl, —Br, —OH, methoxy, ethoxy, n-propoxy, and isopropoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, —F, —Cl, —OH, methoxy, and ethoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, —F, —OH, and methoxy.

[0205] In some embodiments, R 11a and R 11b Each, if present, is independently selected from hydrogen, —OH, and C1-C4 alkoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, —OH, methoxy, ethoxy, n-propoxy, and isopropoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, —OH, methoxy, and ethoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, —OH, and methoxy.

[0206] In some embodiments, R 11a and R 11b Each, if present, is independently selected from hydrogen and C1-C4 alkoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, methoxy, ethoxy, n-propoxy, and isopropoxy. 11a and R 11b Each, if present, is independently selected from hydrogen, methoxy, and ethoxy. 11a and R 11bEach, if present, is independently selected from hydrogen and methoxy.

[0207] In some embodiments, R 11a and R 11b Each, if present, is independently selected from hydrogen and —OH. 11a and R 11b Each, if present, is —OH. In still further embodiments, R 11a and R 11b Each, if present, is hydrogen.

[0208] In some embodiments, R 11a and R 11b Each, if present, is independently selected from hydrogen and halogen. 11a and R 11b Each, if present, is independently selected from hydrogen, —F, —Cl, and —Br. 11a and R 11b Each, if present, is independently selected from hydrogen, —F, and —Cl. 11a and R 11b Each, if present, is independently selected from hydrogen and —F.

[0209] In some embodiments, R 11a and R 11b each, when present, together constitute =O.

[0210] iR 12 base In some embodiments, R 12 When present, R is hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl). 12is, if present, hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2(cyclopropyl), -CH2CH2(cyclopropyl), -CH2CH2CH2(cyclopropyl), -CH(CH3)CH2(cyclopropyl), -CH2(cyclobutyl), -CH2CH2(cyclobutyl), -CH2CH2CH2(cyclobutyl), -CH(CH3)CH2(cyclobutyl), -CH2(cyclopentyl), -CH2CH2(cyclopentyl), -CH2CH2CH2(cyclopentyl), or -CH(CH3)CH2(cyclopentyl). In still further embodiments, R 12 When present, R is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, -CH(cyclopropyl), -CHCH(cyclopropyl), -CH(cyclobutyl), -CHCH(cyclobutyl), -CH(cyclopentyl), or -CHCH(cyclopentyl). 12 If present, is hydrogen, methyl, cyclopropyl, -CH2(cyclopropyl), -CH2(cyclobutyl), or -CH2(cyclopentyl).

[0211] In some embodiments, R 12 When present, R is hydrogen or C-C alkyl. 12 When present, R is hydrogen, methyl, ethyl, n-propyl, or isopropyl. 12 When present, R is hydrogen, methyl, or ethyl. 12 When present, is hydrogen or methyl.

[0212] In some embodiments, R 12 When present, R is C-C alkyl. 12 When present, R is methyl, ethyl, n-propyl, or isopropyl. 12When present, R is methyl or ethyl. 12 When present, is methyl.

[0213] In some embodiments, R 12 When present, R is C-C cycloalkyl or -(C-C alkyl)(C-C cycloalkyl). 12 is, if present, cyclopropyl, cyclobutyl, cyclopentyl, -CH2(cyclopropyl), -CH2CH2(cyclopropyl), -CH2CH2CH2(cyclopropyl), -CH(CH3)CH2(cyclopropyl), -CH2(cyclobutyl), -CH2CH2(cyclobutyl), -CH2CH2CH2(cyclobutyl), -CH(CH3)CH2(cyclobutyl), -CH2(cyclopentyl), -CH2CH2(cyclopentyl), -CH2CH2CH2(cyclopentyl), or -CH(CH3)CH2(cyclopentyl). In still further embodiments, R 12 When present, R is -CH(cyclopropyl), -CHCH(cyclopropyl), -CH(cyclobutyl), -CHCH(cyclobutyl), -CH(cyclopentyl), or -CHCH(cyclopentyl). 12 When present, is -CH2(cyclopropyl), -CH2(cyclobutyl), or -CH2(cyclopentyl).

[0214] In some embodiments, R 12 is hydrogen, if present.

[0215] jR 13 base In some embodiments, R 13 When present, R is selected from hydrogen and C1-C4 alkyl. 13 When present, R is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. 13When present, R is selected from hydrogen, methyl, and ethyl. 13 When present, R is selected from hydrogen and ethyl. 13 When present, is selected from hydrogen and methyl.

[0216] In some embodiments, R 13 When present, R is C-C alkyl. 13 When present, R is selected from methyl, ethyl, n-propyl, and isopropyl. 13 When present, R is selected from methyl and ethyl. 13 When present, R is ethyl. 13 When present, is methyl.

[0217] In some embodiments, R 13 is hydrogen, if present.

[0218] kR 14 base In some embodiments, R 14 When present, R is selected from -OH, -NH, -O(C-C alkyl), -NH(C-C alkyl), and -N(C-C alkyl)(C-C alkyl). 14 When present, R is selected from -OH, -NH, -OCH, -OCHCH, -OCH(CH), -OCHCHCH, -NHCH, -NHCHCH, -NHCH(CH), -NHCHCHCH, -N(CH), -N(CH)CHCH, -N(CH)CHCH, -N(CH)CH(CH), and -N(CH)CHCHCH. 14 When present, R is selected from -OH, -NH, -OCH, -OCHCH, -NHCH, -NHCHCH, -N(CH), and -N(CH)CHCH.14 When present, is selected from -OH, -NH2, -OCH3, -NHCH3, and -N(CH3)2.

[0219] In some embodiments, R 14 When present, R is selected from -OH and -O(C1-C4 alkyl). 14 When present, R is selected from -OH, -OCH, -OCHCH, -OCH(CH), and -OCHCHCH. 14 When present, R is selected from -OH, -OCH, and -OCHCH. 14 When present, is selected from —OH and —OCH 3 .

[0220] In some embodiments, R 14 When present, R is selected from -NH, -NH(C-C alkyl), and -N(C-C alkyl)(C-C alkyl). 14 When present, R is selected from -NH, -NHCH, -NHCHCH, -NHCH(CH), -NHCHCHCH, -N(CH), -N(CH)CHCH, -N(CH)CH(CH), and -N(CH)CHCHCH. 14 When present, R is selected from -NH, -NHCH, -NHCHCH, -N(CH), and -N(CH)CHCH. 14 When present, is selected from -NH2, -NHCH3, and -N(CH3)2.

[0221] In some embodiments, R 14 When present, R is selected from -OH and -NH. 14 When present, R is —OH. 14 is —NH2, if present.

[0222] l.CY 1 base In some embodiments, Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is selected from the group consisting of halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino.

[0223] In some embodiments, Cy 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. Examples of C4-C9 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and spiro[2.4]heptane. In a further embodiment, Cy 1is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 In still further embodiments, Cy is a C4-C9 cycloalkyl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkylamino, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C4-C9 cycloalkyl.

[0224] In some embodiments, Cy1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. Examples of C3-C9 heterocycles include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thiane, 1,3-dithiane, 1,4-dithiane, thiomorpholine, dioxane, morpholine, and hexahydro-1H-furo[3,4-c]pyrrole. In a further embodiment, Cy is a C3-C9 heterocycle having at least one O, S, or N atom substituted with 0, 1, 2, or 3 groups independently selected from , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. Examples of C3-C9 heterocycles include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thiane, 1,3-dithiane, 1,4-dithiane, thiomorpholine, dioxane, morpholine, and hexahydro-1H-furo[3,4-c]pyrrole. 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 In yet further embodiments, Cy is a C3-C9 heterocycle substituted with 0, 1, or 2 groups independently selected from C1-C4 alkylamino, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C3-C9 heterocycle.

[0225] In some embodiments, Cy 1 has at least one O, S, or N atom and is selected from the group consisting of halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. Examples of C2-C9 heteroaryl include furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyrinyl, and the like. In a further embodiment, Cy is 2,3-diamino-2,3-diamino-1 ... 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 In still further embodiments, Cy is a C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from C1-C4 alkylamino, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is halogen, -CN, -NH2, -OH, -NO2, =O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, -(C1-C4)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C2-C9 heteroaryl.

[0226] In some embodiments, Cy 1is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. Examples of C3-C9 heterocycles include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, tetrahydropyran, thiane, 1,3-dithiane, 1,4-dithiane, thiomorpholine, dioxane, morpholine, and hexahydro-1H-furo[3,4-c]pyrrole. In a further embodiment, Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with zero or one group selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1is a C3-C9 heterocycle having at least one O, S, or N atom and monosubstituted with a group selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C3-C9 heterocycle having at least one O, S, or N atom.

[0227] In some embodiments, Cy 1 is a C3-C9 heterocycle having at least one O atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one O atom and substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1is a C3-C9 heterocycle having at least one O atom and substituted with zero or one group selected from halogen, -CN, -NH2, -OH, -NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one O atom and monosubstituted with a group selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C3-C9 heterocycle having at least one O atom.

[0228] In some embodiments, Cy 1 is a C3-C9 heterocycle having at least one S atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1is a C3-C9 heterocycle having at least one S atom and substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one S atom and substituted with zero or one group selected from halogen, -CN, -NH2, -OH, -NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one S atom and monosubstituted with a group selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C3-C9 heterocycle having at least one S atom.

[0229] In some embodiments, Cy 1is a C3-C9 heterocycle having at least one N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one N atom and substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one N atom and substituted with zero or one group selected from halogen, -CN, -NH2, -OH, -NO2, =O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is a C3-C9 heterocycle having at least one N atom and monosubstituted with a group selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. 1 is an unsubstituted C3-C9 heterocycle having at least one N atom.

[0230] In some embodiments, Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom. In a further embodiment, the C3-C9 heterocycle is a monocyclic heterocycle. In a still further embodiment, the C3-C9 heterocycle is a bicyclic heterocycle. In a still further embodiment, the C3-C9 heterocycle is a spirocyclic heterocycle. In a still further embodiment, the C3-C9 heterocycle is a fused heterocycle.

[0231] In some embodiments, Cy 1 is a C2-C9 heteroaryl having at least one O, S, or N atom.

[0232] In some embodiments, Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino.

[0233] In some embodiments, Cy 1 is a structure represented by a formula selected from the following: TIFF0007808226000095.tif29165

[0234] In some embodiments, Cy 1 is a structure represented by the following formula: TIFF0007808226000096.tif27165

[0235] In some embodiments, Cy 1 is a structure represented by the following formula: TIFF0007808226000097.tif22165

[0236] 2. Examples of Compounds In some embodiments, the compound can exist as one or more of the following structures, or a pharmaceutically acceptable salt thereof: TIFF0007808226000098.tif176165TIFF0007808226000099.tif212165.

[0237] In some embodiments, the compound can exist as one or more of the following structures, or a pharmaceutically acceptable salt thereof: TIFF0007808226000100.tif175165TIFF0007808226000101.tif173165TIFF0007808226000102.tif93165.

[0238] In some embodiments, the compound can exist as one or more of the following structures, or a pharmaceutically acceptable salt thereof: TIFF0007808226000103.tif173165TIFF0007808226000104.tif175165TIFF00078082260 00105.tif183165TIFF0007808226000106.tif180165TIFF0007808226000107.tif134165.

[0239] In some embodiments, the compound can exist as one or more of the following structures, or a pharmaceutically acceptable salt thereof: TIFF0007808226000108.tif172165TIFF0007808226000109.tif178165TIFF0007808226000110.tif190165 TIFF0007808226000111.tif178165TIFF0007808226000112.tif175165TIFF0007808226000113.tif181165.

[0240] In some embodiments, the compound can exist as one or more of the following structures, or a pharmaceutically acceptable salt thereof: TIFF0007808226000114.tif178165TIFF0007808226000115.tif183165TIFF0007808226000116.tif177165TIFF000 7808226000117.tif175165TIFF0007808226000118.tif175165TIFF0007808226000119.tif174165TIFF00078082260 00120.tif176165TIFF0007808226000121.tif185165TIFF0007808226000122.tif180165TIFF0007808226000123.ti f185165TIFF0007808226000124.tif150165TIFF0007808226000125.tif153165TIFF0007808226000126.tif201165.

[0241] In some embodiments, the compound can exist as one or more of the following structures, or a pharmaceutically acceptable salt thereof: TIFF0007808226000127.tif184165TIFF0007808226000128.tif184165TIFF00078082260001 29.tif185165TIFF0007808226000130.tif178165TIFF0007808226000131.tif178165TIFF000 7808226000132.tif170165TIFF0007808226000133.tif179165TIFF0007808226000134.tif17 4165TIFF0007808226000135.tif173165TIFF0007808226000136.tif185165TIFF00078082260 00137.tif172165TIFF0007808226000138.tif185165TIFF0007808226000139.tif185165TIFF 0007808226000140.tif175165TIFF0007808226000141.tif185165TIFF0007808226000142.ti f185165TIFF0007808226000143.tif148165TIFF0007808226000144.tif150165TIFF00078082 26000145.tif150165TIFF0007808226000146.tif147165TIFF0007808226000147.tif107165.

[0242] 3. Examples of predicted compounds The following exemplary compounds are predicted and can be prepared using the synthetic methods described herein above, and, if necessary, other general methods that would be known to one of ordinary skill in the art. It is predicted that the predicted compounds are active as modulators of RNA polymerase-I signaling, and that such activity can be determined using the assay methods described herein below.

[0243] In one aspect, the compound is selected from the following: TIFF0007808226000148.tif183165TIFF0007808226000149.tif223165.

[0244] In one aspect, the compound is selected from the following: TIFF0007808226000150.tif188165TIFF0007808226000151.tif223165.

[0245] In one aspect, the compound is selected from the following: TIFF0007808226000152.tif226165.

[0246] In one aspect, the compound is selected from the following: TIFF0007808226000153.tif186165TIFF0007808226000154.tif99165.

[0247] It is contemplated that one or more compounds can optionally be omitted from the disclosed invention.

[0248] It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.

[0249] It is understood that pharmaceutically acceptable derivatives of the disclosed compounds can also be used in connection with the disclosed methods, compositions, kits, and uses. Pharmaceutically acceptable derivatives of the compounds can include any suitable derivatives, such as pharmaceutically acceptable salts, isomers, radiolabeled analogs, tautomers, etc., as discussed below.

[0250] C. Pharmaceutical Compositions Also provided herein is a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Thus, in various embodiments, a pharmaceutical composition is disclosed comprising a therapeutically effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier. In a further embodiment, a pharmaceutical composition can be provided comprising a therapeutically effective amount of at least one disclosed compound. In yet a further embodiment, a pharmaceutical composition can be provided comprising a prophylactically effective amount of at least one disclosed compound. In yet a further embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, wherein the compound is present in an effective amount.

[0251] Thus, in various embodiments, a structure represented by the formula: TIFF0007808226000155.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0252] In various embodiments, the structure is represented by the formula: TIFF0007808226000156.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3 is 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0253] Pharmaceutically acceptable salts of compounds retain the biological effectiveness and properties of the compounds and are conventional acid or base addition salts formed from suitable non-toxic organic or inorganic acids or bases. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, and fumaric acid. Examples of base addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of pharmaceutical compounds to form salts is a known technique for improving the physical and chemical stability, hygroscopicity, flowability, and solubility of the compounds. See, for example, H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995), pp. 196 and 1456-1457.

[0254] The pharmaceutical composition contains a compound in a pharmaceutically acceptable carrier. Pharmaceutically acceptable carrier refers to sterile aqueous or non-aqueous solutions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil, etc.), and injectable organic esters such as ethyl oleate. The compound can be formulated with a pharmaceutically acceptable carrier or diluent, as well as any other known adjuvants and excipients, according to conventional techniques, such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. The phrase "pharmaceutically acceptable carrier" is art-recognized and includes a pharmaceutically acceptable material, composition, or vehicle suitable for administration of a compound of the present invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting the subject agent from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.Some examples of materials which can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, and other non-toxic, compatible substances used in pharmaceutical formulations. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin, which is incorporated herein by reference in its entirety.

[0255] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0256] Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0257] Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about 99 percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent. Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0258] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as a pastille (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or as a mouthwash, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compounds of the present disclosure may also be administered as a bolus, electuary, or paste.

[0259] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be incorporated into one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; humectants, such as glycerol; disintegrants, such as agar-agar; The pharmaceutical compositions may be mixed with any of the following: calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0260] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0261] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, using, for example, hydroxypropylmethylcellulose (used in various proportions to provide the desired release profile), other polymer matrices, liposomes, cataionic vesicles, and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or other sterile injectable medium immediately before use. These compositions can also optionally contain opacifying agents and can be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0262] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan fatty acid esters, etc., and mixtures thereof.

[0263] In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents, and preservatives. Suspensions can contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0264] Pharmaceutical compositions of the present invention for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but become liquid at body temperature, thereby melting in the rectum or vaginal cavity and releasing the active compound. Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing carriers known in the art to be suitable. Dosage forms for topical or transdermal administration of compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0265] Ointments, pastes, creams, and gels can contain, in addition to the active compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can further contain conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0266] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention into the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the active compound in a polymer matrix or gel.

[0267] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0268] Pharmaceutical compositions of the present invention suitable for parenteral administration contain one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted immediately before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0269] These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0270] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.Therefore, the absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0271] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0272] The preparations of the present invention can be administered orally, parenterally, topically, or rectally.Needless to say, they are administered in a form suitable for each administration route.For example, they are administered in the form of tablets or capsules, administered by injection, inhalation, eye lotion, ointment, suppository, etc., administered by injection, infusion, or inhalation, administered topically by lotion or ointment, or administered rectally by suppository.Oral and / or intravenous administration is preferred.

[0273] In a further embodiment, the pharmaceutical composition is administered to a mammal. In yet a further embodiment, the mammal is a human. In yet a further embodiment, the human is a patient.

[0274] In a further embodiment, the pharmaceutical composition is administered after identifying a mammal in need of treatment for a disorder associated with PINK1 kinase activity, hi yet a further embodiment, the mammal has been diagnosed with a need for treatment for a disorder associated with PINK1 kinase activity prior to the administering step.

[0275] In various embodiments, the disclosed pharmaceutical compositions comprise a disclosed compound (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. Compositions of the invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

[0276] The choice of carrier will be determined, in part, by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical compositions of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are exemplary only and are in no way limiting.

[0277] Formulations suitable for oral administration can consist of (a) liquids, such as those in which an effective amount of the compound is dissolved in a diluent, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and pastilles, each containing a predetermined amount of the active ingredient as a solid or granules; (c) powders; (d) suspensions in a suitable liquid; and (e) suitable emulsifying agents. Liquid formulations can contain diluents, such as water, cyclodextrin, dimethyl sulfoxide, and alcohols, including ethanol, benzyl alcohol, propylene glycol, glycerin, and polyethylene alcohols, including polyethylene glycol, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be, for example, the ordinary hard- or soft-shelled gelatin type, containing surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings, and pharmacologically compatible carriers. Lozenge forms may contain the active ingredient in a flavoring agent, usually sucrose and acacia or tragacanth. Pastilles may contain the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acadia. Emulsions and gels may contain additional active ingredients in an inert base, such as gelatin and glycerin or sucrose and acadia. Emulsions and gels may contain, in addition to the active ingredient, carriers known in the art.

[0278] The compounds of the present disclosure, alone or in combination with other suitable components, can be made into aerosol formulations for administration via inhalation. Such aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, and nitrogen. They can also be formulated as pharmaceuticals for non-pressurized preparations, for example, in a nebulizer or atomizer.

[0279] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions and aqueous and non-aqueous sterile suspensions; injection solutions may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; suspensions may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The compounds may be administered in a pharmaceutically acceptable diluent in a pharmaceutical carrier, e.g., a sterile liquid or mixture of liquids including water, saline, aqueous dextrose, and related sugar solutions, alcohols, e.g., ethanol, isopropanol, or hexadecyl alcohol, glycols, e.g., propylene glycol or polyethylene glycols such as poly(ethylene glycol) 400, glycerol ketals, e.g., 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides, with or without pharmaceutically acceptable surfactants, e.g., soaps or detergents, suspending agents, e.g., pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents, and other pharmaceutical adjuvants.

[0280] The oil that can be used in parenteral preparations includes petroleum, animal oil, vegetable oil, or synthetic oil.Specific examples of oil include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum, and mineral oil.The fatty acid that is suitable for use in parenteral preparations includes oleic acid, stearic acid, and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable surfactants include (a) cationic surfactants, such as dimethyldialkylammonium halides and alkylpyridinium halides; (b) anionic surfactants, such as alkyl, aryl, and olefin sulfonates, alkyl olefin, ether, and monoglyceride sulfates, and sulfosuccinates; (c) nonionic surfactants, such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers; (d) amphoteric surfactants, such as alkyl β-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and (e) mixtures thereof.

[0281] Parenteral formulations typically contain about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. To minimize or eliminate irritation at the injection site, such compositions can contain one or more non-ionic surfactants with a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and polymeric adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol.

[0282] Pharmaceutically acceptable excipients are also well known to those skilled in the art. The choice of excipient will be determined in part by the specific compound and the specific method used to administer the composition. Thus, there are a wide variety of suitable formulations for the pharmaceutical compositions of the present invention. The following methods and excipients are merely exemplary and in no way limiting. Pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredient and do not cause adverse side effects. Suitable carriers and excipients include solvents, such as water, alcohol, and propylene glycol, solid absorbents and diluents, surfactants, suspending agents, tablet binders, lubricants, flavoring agents, and coloring agents.

[0283] The formulations can be provided in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a lyophilized condition, requiring only the addition of a sterile liquid vehicle for injection, e.g., water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those skilled in the art. Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, PA, Banker and Chalmers, Eds., pp. 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4 th ed., 622-630 (1986).

[0284] Formulations suitable for topical administration include lozenges comprising the active ingredient in a flavoring agent, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier; and creams, emulsions, and gels containing, in addition to the active ingredient, such carriers as are known in the art.

[0285] Additionally, formulations suitable for rectal administration can be provided as suppositories by mixing with a variety of bases, for example, emulsifying bases or water-soluble bases, etc. Formulations suitable for vaginal administration can be provided as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, which contain, in addition to the active ingredient, carriers known in the art to be appropriate.

[0286] Those skilled in the art will recognize that suitable methods of exogenously administering the compounds of the present disclosure to animals are available, and that while more than one route may be available for administering a particular compound, one particular route may provide a more immediate and effective response than another route.

[0287] For these uses, the method of the present invention comprises administering to an animal, particularly a mammal, more particularly a human, a therapeutically effective amount of a compound effective for treating (e.g., preventing or treating) a disorder associated with PINK1 kinase activity. The method also comprises administering a therapeutically effective amount of a compound for treating a patient predisposed to suffering from a disorder associated with PINK1 kinase activity. In the context of the present invention, the dose administered to an animal, particularly a human, should be sufficient to produce a therapeutic response in the animal over a reasonable time frame. Those skilled in the art will recognize that the dosage depends on various factors, including the condition of the animal, the animal's weight, and the severity and stage of the disorder.

[0288] The total amount of a compound of the present disclosure administered in a typical treatment is preferably about 1 mg / kg to about 100 mg / kg body weight in mice, about 10 mg / kg to about 50 mg / kg body weight, and about 20 mg / kg to about 40 mg / kg body weight in humans, per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses about once to about three times daily for about 24 months, or twice daily for about 12 months.

[0289] The size of the dose will also be determined by the route, timing, and frequency of administration, as well as the existence, nature, and extent of any adverse side effects that may accompany the administration of the compound, and the desired physiological effect. As will be appreciated by those skilled in the art, various conditions or pathologies, particularly chronic conditions or pathologies, may require long-term treatment involving multiple administrations.

[0290] In certain embodiments, the compositions described herein are formulated for administration to a patient in need of such a composition. The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0291] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease being treated, etc. The amount of a compound described herein in the composition will also depend on the particular compound in the composition.

[0292] The compounds described herein may be administered alone or simultaneously with additional therapeutic agents. Thus, preparations may also be combined with other active substances (e.g., to reduce metabolic degradation) if desired. Additional therapeutic agents include, but are not limited to, other active agents known to be useful in treating disease-related neurodegeneration (e.g., Parkinson's medications, such as levodopa), dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, antipsychotics (e.g., clozapine), cholinesterase inhibitors, modafinil, or nonsteroidal anti-inflammatory drugs), angiotensin-converting enzyme inhibitors (e.g., enalipril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), beta-blockers (e.g., lopressor, toprol-XL), digoxin, or diuretics.

[0293] In some embodiments, the compounds described herein may be delivered in vesicles, particularly liposomes (see Langer, Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see ibid. generally).

[0294] Suitable compositions include, but are not limited to, oral non-absorbable compositions, including, but not limited to, saline, water, cyclodextrin solutions, and buffer solutions of pH 3-9.

[0295] The compounds described herein, or pharmaceutically acceptable salts thereof, may be used in any of the following solutions: purified water, propylene glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid / sodium citrate (pH 3), citric acid / sodium citrate (pH 5), tris(hydroxymethyl)aminomethane HCl (pH 7.0), 0.9% saline, 1.2% saline, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, and glutamic acid. It can be formulated with a variety of excipients, including, but not limited to, tocopherol, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, tosylate, and any combination thereof. In some embodiments, the excipient is selected from propylene glycol, purified water, and glycerin.

[0296] In some embodiments, the formulation may be lyophilized to a solid and reconstituted, for example with water, prior to use.

[0297] When administered to a mammal (eg, an animal for veterinary use or a human for clinical use), the compound may be administered in isolated form.

[0298] When administered to humans, the compound can be sterile. Water is a suitable carrier when the compound of Formula I is administered intravenously. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The compositions of the present invention can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

[0299] The compositions described herein can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, liquid-containing capsule, powder, sustained-release formulation, suppository, aerosol, spray, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A.R. Gennaro (Editor), Mack Publishing Co.

[0300] In some embodiments, the compound is formulated into a pharmaceutical composition suitable for human administration according to conventional procedures. Typically, the compound is a solution in a sterile isotonic aqueous buffer solution. If necessary, the composition can also contain a solubilizing agent. A composition for intravenous administration can optionally contain a local anesthetic, such as lidocaine, to alleviate pain at the injection site. Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in an airtightly sealed container, such as an ampoule or sachet, indicating the quantity of active agent. When the compound is administered by infusion, it can be dispensed, for example, using an infusion bottle containing pharmaceutical-grade sterile water or saline. When the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed before administration.

[0301] The pharmaceutical composition may be in unit dosage form. In such form, the composition may be divided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, for example, individual tablets, capsules, and powders in vials or ampoules. The unit dosage form may be a capsule, cachet, or tablet itself, or the appropriate number of any of these packaged forms.

[0302] In some embodiments, the compositions of the present disclosure are in liquid form, and the active agent is present dissolved, suspended, as an emulsion, or as a solution / suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

[0303] In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, the ophthalmic composition is a solid article that can be inserted into a suitable position in the eye, for example, between the eyelid and the eyelid or into the conjunctival sac, to release an active agent, as described in, for example, U.S. Patent No. 3,863,633, U.S. Patent No. 3,867,519, U.S. Patent No. 3,868,445, U.S. Patent No. 3,960,150, U.S. Patent No. 3,963,025, U.S. Patent No. 4,186,184, U.S. Patent No. 4,303,637, U.S. Patent No. 5,443,505, and U.S. Patent No. 5,869,079. Release from such an article usually occurs to the cornea, either through the tear fluid that bathes the surface of the cornea, or directly onto the cornea itself, with which the solid article is generally in close contact. Solid articles suitable for implantation into the eye in this manner are generally primarily composed of polymers and may be biodegradable or non-biodegradable. Biodegradable polymers that can be used in accordance with the present disclosure to prepare intraocular implants having one or more of the compounds described herein include, but are not limited to, poly(glycolide), poly(lactide), poly(epsilon-caprolactone), poly-(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polyesters such as polymers and copolymers of aliphatic polycarbonates and polyether lactones. Suitable non-bioerodible polymers include silicone elastomers.

[0304] Compositions described herein can contain antiseptic.Suitable antiseptics include but are not limited to mercury-containing substances such as phenylmercury salts (for example, phenylmercury acetate, phenylmercury borate, and phenylmercury nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride; imidazolidinyl urea; parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, and their salts; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; EDTA disodium; and sorbic acid and its salts.

[0305] In some embodiments, a compound or pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is a neo-substrate for PINK1. In some embodiments, the neo-substrate is not kinetin. In some embodiments, the neo-substrate is not kinetin riboside. In some embodiments, the neo-substrate is not kinetin riboside 5' monophosphate. In some embodiments, the neo-substrate is not kinetin riboside 5' diphosphate. In some embodiments, the neo-substrate is not kinetin riboside 5' triphosphate. In some embodiments, the neo-substrate is not a derivative (e.g., a prodrug) of kinetin, kinetin riboside, kinetin riboside 5' monophosphate, kinetin riboside 5' diphosphate, or kinetin riboside 5' triphosphate. In some embodiments, the neo-substrate is not N6-(delta 2-isopentenyl)-adenine. In some embodiments, the neo-substrate is not N6-(delta 2-isopentenyl)-adenosine, N6-(delta 2-isopentenyl)-adenosine 5' monophosphate, N6-(delta 2-isopentenyl)-adenosine 5' diphosphate, N6-(delta 2-isopentenyl)-adenosine 5' triphosphate, or a derivative (e.g., prodrug) thereof. In some embodiments, the neo-substrate is not a cytokinin. In some embodiments, the neo-substrate is not a cytokinin riboside, cytokinin riboside 5' monophosphate, cytokinin riboside 5' diphosphate, cytokinin riboside 5' triphosphate, or a derivative (e.g., prodrug) thereof.

[0306] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be used in the disclosed methods.

[0307] D. Methods for Making Compounds In various embodiments, the present invention relates to methods of making compounds useful in the treatment of disorders associated with PINK1 kinase activity. Accordingly, in some embodiments, methods of making the disclosed compounds are disclosed.

[0308] Compounds according to the present disclosure can be prepared by several methods, for example, as outlined below. Those skilled in the art will understand the preparation of known compounds found in the literature using appropriate use of protecting groups [see Greene and Wuts, Protective Groups in Organic Synthesis] and standard methods of organic synthesis. It may occasionally be necessary to rearrange the recommended order of synthetic steps, as will be apparent to the judgment of a chemist skilled in the art of organic synthesis. The following examples are provided so that the invention may be more fully understood and are illustrative only and should not be construed as limiting.

[0309] In some embodiments, the disclosed compounds include the products of the synthetic methods described herein. In further embodiments, the disclosed compounds include compounds produced by the synthetic methods described herein. In still further embodiments, the invention includes a pharmaceutical composition comprising a therapeutically effective amount of a product of the disclosed methods and a pharmaceutically acceptable carrier. In still further embodiments, the invention includes a method of producing a medicament, the method comprising combining at least one compound of any of the disclosed compounds or at least one product of the disclosed methods with a pharmaceutically acceptable carrier or diluent.

[0310] 1. Route I In some embodiments, the compounds can be prepared as shown below. TIFF0007808226000157.tif90165

[0311] The compounds are represented in generic form, with substituents as described in the compound descriptions elsewhere herein. More specific examples are described below. TIFF0007808226000158.tif90165

[0312] In some embodiments, compounds of type 1.14 and similar compounds can be prepared according to Reaction Scheme 1B above. Thus, compounds of type 1.11 can be prepared by Grignard reaction of an appropriate aryl bromine, such as 1.8 shown above. Suitable aryl bromines are commercially available or prepared by methods known to those skilled in the art. The Grignard reaction is carried out in the presence of a suitable metal source, such as magnesium metal, in a suitable solvent, such as tetrahydrofuran (THF), followed by reaction with an appropriate carbonyl analog, such as 1.10 shown above. Suitable carbonyl analogs are commercially available or prepared by methods known to those skilled in the art. Compounds of type 1.12 can be prepared by reduction of an appropriate ketone, such as 1.11 shown above. The reduction is carried out in the presence of a suitable reducing agent, such as hydrogen gas, and a suitable catalyst, such as palladium on carbon. Compounds of type 1.13 can be prepared by cyclization of an appropriate aryl carboxylic acid analog, such as 1.12 shown above. The cyclization is carried out in the presence of a strong acid (such as trifluorosulfonic acid) and heat. Compounds of type 1.14 can be prepared by reduction of an appropriate ketone, such as 1.13 shown above. The reduction is carried out in the presence of a suitable activating agent, such as paratoluenesulfonic acid, and a suitable reducing agent, such as sodium borohydride. As one skilled in the art would appreciate, the above reaction provides an example of a generalized approach in which compounds structurally similar to the specific reactants above (compounds similar to compounds of types 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6) can be substituted during the reaction to provide compounds similar to formula 1.7.

[0313] 2. Route II In some embodiments, the compounds can be prepared as shown below. TIFF0007808226000159.tif54165

[0314] The compounds are represented in generic form, with substituents as described in the compound descriptions elsewhere herein. More specific examples are described below. TIFF0007808226000160.tif90165

[0315] In some embodiments, compounds of type 2.7 and similar compounds can be prepared according to Reaction Scheme 2B above. Thus, compounds of type 2.5 can be prepared by the reaction of an appropriate aryl ketone, such as 1.8 shown above, with an appropriate ketone, such as tetrahydro-4H-pyran-4-one shown above. Suitable aryl ketones and ketones are commercially available or prepared by methods known to those skilled in the art. The reaction is carried out in the presence of a suitable amine, such as diisopropylamine (DIPA), and a suitable base, such as n-butyllithium, in a suitable solvent, such as THF, at a suitable temperature, such as -78°C. Compounds of type 2.6 can be prepared by the reduction of an appropriate alcohol, such as 2.5 shown above. The reduction is carried out in the presence of a suitable activating agent, such as toluenesulfonic acid, in a suitable solvent, such as toluene, followed by reaction with a suitable reducing agent, such as hydrogen gas, and a suitable catalyst, such as platinum oxide. Compounds of type 2.7 can be prepared by reductive amination of an appropriate ketone, such as 2.6 shown above. The reductive amination is carried out in the presence of a suitable agent, such as hydroxylamine. As one skilled in the art would appreciate, the above reaction provides an example of a generalized approach where compounds structurally similar to the specific reactants above (e.g., compounds similar to compounds of type 2.1 and 2.2) can be substituted during the reaction to provide compounds similar to formula 2.3.

[0316] 3. Route III In some embodiments, the compounds can be prepared as shown below. TIFF0007808226000161.tif48165

[0317] The compounds are represented in generic form, with substituents as described in the compound descriptions elsewhere herein. More specific examples are described below. TIFF0007808226000162.tif64165

[0318] In some embodiments, compounds of type 3.4 and similar compounds can be prepared according to Reaction Scheme 3B above. Thus, compounds of type 3.3 can be prepared by epoxidation of an appropriate alkene, such as 3.1 shown above. Epoxidation is carried out in the presence of a suitable oxidizing agent, such as metachloroperoxybenzoic acid (mCPBA), in a suitable solvent, such as dichloromethane (DCM), followed by ring-opening in the presence of a suitable amine, such as 3.2 shown above. Suitable amines are commercially available or can be prepared by methods known to those skilled in the art. Ring-opening is carried out in the presence of a suitable base, such as triethylamine (TEA), in a suitable solvent, such as chloroform (CHCl). Compounds of type 3.4 can be prepared by rearrangement of an appropriate alcohol, such as 3.3 shown above. The rearrangement is carried out in the presence of a suitable activating agent, such as methanesulfonic anhydride, a suitable base, such as TEA, in a suitable solvent, such as DCM, followed by reaction with a suitable imine, such as benzophenone imine. As can be appreciated by those skilled in the art, the above reaction provides an example of a generalized approach where compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1, 3.2, and 3.3) can be substituted during the reaction to provide compounds similar to formula 3.4.

[0319] 4. Route IV In some embodiments, the compounds can be prepared as shown below. TIFF0007808226000163.tif90165

[0320] The compounds are represented in generic form, with substituents as described in the compound descriptions elsewhere herein. More specific examples are described below. TIFF0007808226000164.tif95165

[0321] In some embodiments, compounds of type 4.10 and similar compounds can be prepared according to Reaction Scheme 4B above. Thus, compounds of type 4.7 can be prepared by halogenation of a suitable ketone, such as 4.6 shown above. Suitable ketones are commercially available or prepared by methods known to those skilled in the art. The halogenation is carried out in the presence of a suitable halide source, such as bromine, in a suitable solvent, such as DCM. Compounds of type 4.9 can be prepared by displacement of a suitable halide, such as 4.7 shown above. The displacement reaction is carried out in the presence of a suitable nucleophile, such as 4.8 shown above, and a suitable base, such as potassium carbonate, in a suitable solvent, such as acetonitrile. Suitable nucleophiles are commercially available or prepared by methods known to those skilled in the art. Compounds of type 4.10 can be prepared by reductive amination of a suitable ketone, such as 4.9 shown above. The reductive amination is carried out in the presence of a suitable amine, such as hydroxylamine, and a suitable base, such as pyridine, in a suitable solvent, such as ethanol, followed by reaction with a suitable reducing agent, such as hydrogen gas, a suitable catalyst, such as palladium on carbon, and a suitable acid, such as acetic acid, in a suitable solvent, such as ethanol. As one skilled in the art would appreciate, the above reaction provides an example of a generalized approach in which compounds structurally similar to the specific reactants above (compounds similar to compounds of type 4.1, 4.2, 4.3, and 4.4) can be substituted during the reaction to provide compounds similar to formula 4.5.

[0322] 5. Route V In some embodiments, adenine analogs can be prepared as shown below. TIFF0007808226000165.tif54165

[0323] The compounds are represented in general form, where X is a halogen, and other substituents are as described in the compound descriptions elsewhere herein. More specific examples are described below. TIFF0007808226000166.tif59165

[0324] In some embodiments, compounds of type 5.3 and similar compounds can be prepared according to Reaction Scheme 5B above. Thus, compounds of type 5.3 can be prepared by arylation of an appropriate amine, such as 5.1 shown above. The arylation is carried out in the presence of a suitable halide, such as 5.2 shown above, and a suitable base, such as diisopropylethylamine (DIPEA), in a suitable solvent, such as ethanol (EtOH). Suitable halides are commercially available or prepared by methods known to those skilled in the art. As will be appreciated by those skilled in the art, the above reaction provides an example of a generalized approach in which compounds structurally similar to the specific reactants above (compounds similar to compounds of types 5.1 and 5.2) can be substituted during the reaction to provide adenine analogs similar to formula 5.3.

[0325] The compounds and compositions described herein are generally useful for modulating the activity of PINK1. In some embodiments, the compounds and compositions described herein inhibit PINK1 activity.

[0326] E. Methods of Using the Compounds The compounds and pharmaceutical compositions of the present invention are useful for treating or controlling disorders associated with PINK1 kinase activity. To treat or control a disorder, the compounds and pharmaceutical compositions containing the compounds are administered to a subject in need thereof, e.g., a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex; that is, it is intended to encompass adult and newborn subjects, as well as fetuses, both male and female. The subject is preferably a mammal, such as a human. The subject may have been diagnosed as needing treatment for a disorder associated with PINK1 kinase activity prior to administration of the compound or composition.

[0327] The compound or composition can be administered to a subject by any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injections such as intravenous, intraarterial, intramuscular, and subcutaneous administration. Administration can be continuous or intermittent. The preparation can be administered therapeutically, i.e., administered to treat an existing disease or condition. The preparation can also be administered prophylactically, i.e., administered to prevent a disease or condition.

[0328] The therapeutically effective amount or dosage of a compound can vary within wide limits. Such dosage will be adjusted to the individual requirements of each particular case, including the specific compound(s) administered, the route of administration, the condition being treated, and the patient being treated. Generally, for oral or parenteral administration to an adult weighing at least about 70 kg, a daily dosage of about 10 mg to about 10,000 mg, preferably about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose, in divided doses, or, in the case of parenteral administration, as a continuous infusion. A single-dose composition can contain the amount of compound or composition that constitutes a daily dose, or a fraction thereof. The dosage can be adjusted by the individual physician in the event of any contraindications. The dosage is variable and can be administered in one or more doses daily for one or several days.

[0329] 1. Treatment The compounds disclosed herein are useful for treating or controlling disorders associated with PINK1 kinase activity. Accordingly, methods are provided that include administering to a subject a therapeutically effective amount of a composition comprising the disclosed compound.

[0330] Thus, in some embodiments, the present disclosure provides a method of treating or preventing a neurodegenerative disease (e.g., Parkinson's disease, Leigh's syndrome) in a subject, comprising administering to the subject one or more compounds or pharmaceutically acceptable salts thereof of any one of the compounds described herein, or a pharmaceutical composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, treating the neurodegenerative disease comprises ameliorating symptoms by stimulating PINK1 or mutant PINK1.

[0331] In some embodiments, the present disclosure provides a method for treating or preventing a mitochondrial disease in a subject, comprising administering to the subject one or more compounds or pharmaceutically acceptable salts thereof of any one of the compounds described herein, or a pharmaceutical composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, treating the mitochondrial disease comprises stimulating PINK1 or mutant PINK1 to improve symptoms.

[0332] In some embodiments, the present disclosure provides a method of treating or preventing fibrosis in a subject, comprising administering to the subject one or more compounds or pharmaceutically acceptable salts thereof of any one of the compounds described herein, or a pharmaceutical composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, treating fibrosis comprises stimulating PINK1 or mutant PINK1 to improve symptoms.

[0333] In some embodiments, the present disclosure provides a method for treating or preventing cardiomyopathy in a subject, comprising administering to the subject one or more compounds or pharmaceutically acceptable salts thereof of any one of the compounds described herein, or a pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof described herein. In some embodiments, treating cardiomyopathy comprises stimulating PINK1 or mutant PINK1 to improve symptoms.

[0334] In some embodiments, methods are provided for treating one or more of the following mitochondrial diseases in a subject: LHON, MELAS, and Charcot-Marie-Tooth disease. In some embodiments, the method comprises administering to the subject one or more compounds described herein or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, the method comprises administering to the subject a compound that functions as a PINK1 substrate, or a pharmaceutically acceptable salt thereof, together with one or more compounds described herein or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, the cholesterol therapeutic agent is niacin or acifuran. In some embodiments, the subject is in need thereof.

[0335] a. Treatment of disorders associated with PINK1 activity In some embodiments, the compounds and compositions described herein are useful for treating disorders associated with PINK1 function. Accordingly, provided herein are methods for treating disorders associated with PINK1 function, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof. Disorders treatable by the compounds and compositions of the present invention include, for example, neurodegenerative diseases, mitochondrial diseases, fibrosis, or cardiomyopathies.

[0336] Thus, in various embodiments, there is provided a method of treating a disorder in a subject in need thereof, comprising administering to the subject in need thereof a compound having a structure represented by the following formula: TIFF0007808226000167.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or a cardiomyopathy.

[0337] In various embodiments, there is provided a method of treating a disorder in a subject in need thereof, comprising: To a subject in need thereof, a structure represented by the following formula: TIFF0007808226000168.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3 is a 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof. wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or a cardiomyopathy.

[0338] Examples of neurodegenerative diseases that can be treated using the compounds or compositions described herein include Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, epilepsy, Friedreich's ataxia, frontotemporal dementia, Gerstmann-Schött syndrome, and others. Loisler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, Leigh's disease (Leigh syndrome), dementia with Lewy bodies, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilder's disease, Shy-Drager syndrome, subacute association of the spinal cord secondary to pernicious anemia Neurodegeneration, schizophrenia, spinocerebellar ataxia (various types with different features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, spinal cord deafness, drug-induced parkinsonism, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy, idiopathic Parkinson's disease, autosomal dominant Parkinson's disease, familial Parkinson's disease type 1 (PARK1), autosomal dominant Parkinson's disease with Lewy bodies type 3 (PARK3), autosomal dominant Parkinson's disease with Lewy bodies type 4 (PARK4), Parkinson's disease type 5 (PARK 5), autosomal recessive early-onset Parkinson's disease type 6 (PARK6), autosomal recessive juvenile Parkinson's disease type 2 (PARK2), autosomal recessive early-onset Parkinson's disease type 7 (PARK7), Parkinson's disease type 8 (PARK8), Parkinson's disease type 9 (PARK9), Parkinson's disease type 10 (PARK10), Parkinson's disease type 11 (PARK11), Parkinson's disease type 12 (PARK12), Parkinson's disease type 13 (PARK13), or mitochondrial Parkinson's disease. In some embodiments, the autonomic neuropathy is not a neurodegenerative disease.

[0339] Examples of mitochondrial diseases that can be treated using the compounds or compositions described herein include Alzheimer's disease, amyotrophic lateral sclerosis, Asperger's disorder, autistic disorder, bipolar disorder, cancer, cardiomyopathy, Charcot-Marie-Tooth disease (CMT, including various subtypes such as type 2b and type 2b CMT), childhood disintegrative disorder (CDD), diabetes, diabetic nephropathy, epilepsy, Friedreich's ataxia (FA), hereditary motor and sensory neuropathy (HMSN), Huntington's disease, Kearns-Sayre syndrome (KSS), Leber's hereditary optic neuropathy (LHON, also known as Leber's disease, Leber's syndrome, Leber's syndrome), and mitochondrial neuropathy (MRSA). These include Bell's optic atrophy (LOA) or Leber's optic neuropathy (LON), Leigh's disease or syndrome, macular degeneration, MELAS (mitochondrial myopathy, lactacidosis, and stroke), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), motor neuron disease, myoclonic epilepsy with ragged-red fibers (MERRF), NARP (neuropathy, ataxia, retinitis pigmentosa, and ptosis), Parkinson's disease, peroneal muscular atrophy (PMA), pervasive developmental disorder not otherwise specified (PDD-NOS), renal tubular acidosis, Rett's syndrome, schizophrenia, and various types of stroke.

[0340] Cardiomyopathy refers to a pathological condition that adversely affects cardiac tissue and results in a measurable deterioration of myocardial function (e.g., systolic function, diastolic function). Dilated cardiomyopathy is characterized by ventricular chamber enlargement accompanied by systolic dysfunction without hypertrophy. Hypertrophic cardiomyopathy is a genetic disorder transmitted as an autosomal dominant trait. Hypertrophic cardiomyopathy is morphologically characterized by a hypertrophied left ventricle without dilation. Restrictive cardiomyopathy is characterized by a lack of dilation or hypertrophy, but by reduced ventricular volume leading to impaired ventricular filling. Arrhythmogenic right ventricular cardiomyopathy is a genetic heart disease characterized by myocardial electrical instability. Unclassified cardiomyopathy is a category of cardiomyopathy that does not match the features of any of the other types. Unclassified cardiomyopathy may have features of multiple types or, for example, features of fibroelastosis, noncompaction, or systolic dysfunction, with minimal dilation.

[0341] In certain embodiments, the compounds and compositions described herein may be used to treat Parkinson's disease by reducing the production of Lewy bodies, reducing the accumulation of alpha-synuclein, reducing cell death, reducing the loss of dopamine-producing cells, reducing the loss of cells in the substantia nigra, reducing the loss of dopamine production, reducing the symptoms of Parkinson's disease, reducing loss of motor function, reducing tremors or slowing the increase in tremors (tremor), reducing stiffness or increase in stiffness, reducing slowness of movement (bradykinesia) or slowing of movement, alleviating sensory symptoms, reducing insomnia, reducing sleepiness, improving mental health, improving mental function, slowing the decline in mental function, alleviating dementia, delaying the onset of dementia, improving cognitive skills, reducing the loss of cognitive skills, improving memory, reducing memory deterioration, or prolonging survival. In certain embodiments, the compounds and compositions described herein may be used to treat cardiomyopathy by improving cardiac function, improving exercise tolerance, preventing heart failure, increasing blood oxygen content, or improving respiratory function.

[0342] In certain embodiments, the disease treated by the disclosed compounds or compositions is a disease characterized by a decreased level of PINK1. In certain embodiments, the disease is a disease characterized by a loss of dopamine-producing cells (e.g., Parkinson's disease). In certain embodiments, the disease is a disease characterized by neurodegeneration. In certain embodiments, the disease is a disease characterized by neuronal cell death. In certain embodiments, the disease is a disease characterized by a decreased level of PINK1 activity. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disease is a neurodegenerative disease. In certain embodiments, the disease is a cardiomyopathy.

[0343] In further embodiments, the neurodegenerative disease is Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis.

[0344] In a further embodiment, the subject has been diagnosed with a need for treatment for a disorder associated with PINK1 kinase activity prior to the administering step.

[0345] In a further embodiment, the subject is a mammal. In yet a further embodiment, the mammal is a human.

[0346] In a further embodiment, the method further comprises identifying a subject in need of treatment for a disorder associated with PINK1 kinase activity.

[0347] In further embodiments, administration is accomplished by oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, inhalation, buccal, intrapleural, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intranasal, intrathecal, and intraarticular administration, or a combination thereof.

[0348] 2. Methods for modulating PINK1 kinase activity in mammals In some embodiments, a method of modulating PINK1 kinase activity in a mammal is disclosed, the method comprising administering to the mammal a therapeutically effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0349] Thus, in various embodiments, there is provided a method of modulating PINK1 kinase activity in a subject in need thereof, comprising administering to said subject: To a subject in need thereof, a structure represented by the following formula: TIFF0007808226000169.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. A method is disclosed that includes administering an effective amount of

[0350] In various embodiments, a method of modulating PINK1 kinase activity in a subject in need thereof comprises administering to the subject: To a subject in need thereof, a structure represented by the following formula: TIFF0007808226000170.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3 is a 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof. A method is disclosed that includes administering an effective amount of

[0351] As used herein, "modulation" can refer to either inhibition or enhancement of a particular activity. For example, modulation of PINK1 activity can refer to the inhibition and / or activation of PINK1-dependent activity, such as a decrease in Parkin recruitment. In some embodiments, modulation refers to the inhibition or activation of Parkin recruitment. In some embodiments, compounds described herein activate PINK1 activity by about 1% to about 50%. PINK1 activity can be measured by any method, including, but not limited to, those described herein.

[0352] The compounds described herein are novel substrates of PINK1. The ability of a compound to stimulate or inhibit PINK1 activity can be measured using any assay known in the art that is used to detect Parkin recruitment or PINK1 phosphorylation, or the absence of such signaling / activity. "PINK1 activity" refers to the ability of PINK1 to phosphorylate any substrate. Such activity can be measured, for example, by expressing mutant PINK1 in a cell(s), administering a compound disclosed herein, and measuring the extent to which cells expressing mutant PINK1 are able to phosphorylate an enzymatically active substrate compared to cells expressing wild-type PINK1.

[0353] PINK1 activity is measured by the time required to recruit 50% of the substrate ("R 50 "). In some embodiments, the compound reduces R by about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%. ... 50 In some embodiments, the compound reduces R 50In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 In some embodiments, the compound reduces R 50 Reduces by approximately 10% to 20%.

[0354] A plasmid expressing PINK1 may be transfected into isolated cells, expressed in isolated cells, expressed in membranes derived from cells, expressed in tissues, or expressed in animals. For example, the above-mentioned PINK1 activity can be tested using nerve cells, immune system cells, transformed cells, or membranes. Modulation is tested using one of the in vitro or in vivo assays described herein. Compounds can also be tested using other commonly known assays. Signal transduction can also be examined in vitro using chimeric molecules, such as the extracellular domain of a receptor covalently linked to a heterologous signaling domain, or the transmembrane and / or cytoplasmic domain of a receptor, in solution or solid-phase reactions. Furthermore, the ligand-binding domain of a protein of interest can be used in in vivo solution or solid-phase reactions to assay for ligand binding.

[0355] In some embodiments, the effect of a compound on PINK1 regulation is measured using cells expressing mutant and wild-type PINK1. PINK1 is publicly known. In some embodiments, enzyme rescue is measured. An enzyme rescue experiment is an experiment in which cells expressing mutant PINK1 with reduced or absent enzymatic activity are contacted with a compound of the invention, allowing the mutant PINK1 enzymatic activity to be reactivated. The PINK1 molecule is known. In some embodiments, a compound of the invention can enzymatically rescue human PINK1 (Accession No. NM_032409.3, incorporated by reference in its entirety) having the following amino acid sequence: TIFF0007808226000171.tif80133.

[0356] In certain embodiments, the compounds of the present invention are capable of enzymatically rescuing mouse PINK1 (Accession No. XM_924521, incorporated by reference in its entirety), which has the following amino acid sequence: TIFF0007808226000172.tif80133.

[0357] In some embodiments, compounds of the invention are capable of enzymatically rescuing rat PINK1 (Accession No. XM_216565, incorporated by reference in its entirety), which has the following amino acid sequence: TIFF0007808226000173.tif80132.

[0358] In a further embodiment, the modulation is inhibition. In a further embodiment, the modulation is reduction.

[0359] In a further embodiment, the compound has an IC of less than about 30 μM 50 In still further embodiments, the compounds exhibit inhibition of PINK1 kinase activity at an IC of less than about 25 μM. 50 In still further embodiments, the compounds exhibit inhibition of PINK1 kinase activity at an IC of less than about 20 μM. 50 In yet a further embodiment, the compound exhibits inhibition of PINK1 kinase activity at an IC of less than about 15 μM. 50 In still further embodiments, the compounds exhibit inhibition of PINK1 kinase activity at an IC of less than about 10 μM. 50 In still further embodiments, the compounds exhibit inhibition of PINK1 kinase activity at an IC of less than about 5 μM. 50 In yet a further embodiment, the compound exhibits inhibition of PINK1 kinase activity at an IC of less than about 1 μM. 50 In still further embodiments, the compounds exhibit inhibition of PINK1 kinase activity at an IC of less than about 0.5 μM. 50 It inhibits PINK1 kinase activity.

[0360] In a further embodiment, the subject is a mammal. In yet a further embodiment, the subject is a human.

[0361] In a further embodiment, the subject has been diagnosed with a disorder associated with impaired PINK1 kinase function prior to the administering step. In yet a further embodiment, the method further comprises identifying the subject as at risk for a disorder associated with impaired PINK1 kinase function prior to treating the disorder.

[0362] 3. Methods for modulating PINK1 kinase activity in at least one cell In some embodiments, a method of modulating PINK1 kinase activity in at least one cell is disclosed, comprising contacting the at least one cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof.

[0363] Thus, in various embodiments, there is provided a method for modulating PINK1 kinase activity in at least one cell, comprising: The cells are encapsulated in a cell suspension containing a structure represented by the following formula: TIFF0007808226000174.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14 when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. and contacting the compound with an effective amount of

[0364] In various embodiments, a method for modulating PINK1 kinase activity in at least one cell is provided, comprising: The cells are encapsulated in a cell suspension containing a structure represented by the following formula: TIFF0007808226000175.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3 is a 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof. and contacting the compound with an effective amount of

[0365] In a further embodiment, the cell is mammalian. In yet a further embodiment, the cell is human. In yet a further embodiment, the cell has been isolated from a mammal prior to the contacting step.

[0366] In a further embodiment, the modulation is inhibition. In a further embodiment, the modulation is reduction.

[0367] In a further embodiment, the contacting is via administration to a mammal.

[0368] In a further embodiment, the contacting step is carried out in vitro.

[0369] 4. Use of the Compound Also provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder described herein. Also provided is a composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a disclosed compound or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder described herein.

[0370] Thus, in some embodiments, the invention relates to uses of the disclosed compounds or products of the disclosed methods. In further embodiments, the uses relate to the manufacture of a medicament for the treatment of a disorder associated with PINK1 kinase activity in a mammal.

[0371] Uses of the disclosed compounds and products are also provided. In some embodiments, the invention relates to the use of at least one of the disclosed compounds, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In further embodiments, the compound used is a product of the disclosed method of making.

[0372] In a further embodiment, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of the disclosed manufacturing method, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0373] In a further embodiment, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately admixed with the therapeutically effective amount of the compound or product of a disclosed method of making.

[0374] In various embodiments, the use relates to treating a disorder associated with PINK1 kinase activity in a mammal. In some embodiments, the use is characterized in that the mammal is a human. In some embodiments, the use is characterized in that the disorder associated with PINK1 kinase activity is a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy.

[0375] In a further embodiment, the use relates to the manufacture of a medicament for the treatment of a disorder associated with PINK1 kinase activity in a mammal.

[0376] It is understood that the disclosed uses can be used in connection with the disclosed compounds, products of the disclosed methods of making, methods, compositions, and kits. In a further embodiment, the invention relates to the use of the disclosed compounds or the disclosed products in the manufacture of a medicament for the treatment of a disorder associated with PINK1 kinase activity in a mammal.

[0377] 5. Drug manufacturing In some embodiments, the invention relates to a method for manufacturing a medicament for treating a disorder associated with PINK1 kinase activity in a mammal, comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0378] For these uses, the method comprises administering to an animal, particularly a mammal, more particularly a human, a therapeutically effective amount of a compound effective for treating disorders associated with PINK1 kinase activity.In the context of the present invention, the dose administered to an animal, particularly a human, should be sufficient to cause a therapeutic response in the animal over a reasonable time frame.Those skilled in the art will recognize that the dosage depends on various factors, including the condition and body weight of the animal.

[0379] The total amount of the compound of the present disclosure administered in a typical treatment is preferably about 1 mg / kg to about 100 mg / kg body weight in mice, about 10 mg / kg to about 50 mg / kg body weight in humans, and more preferably about 20 mg / kg to about 40 mg / kg body weight per day. This total amount is typically, but not necessarily, administered as a series of smaller doses about once to about three times daily for about 24 months, preferably twice daily for about 12 months.

[0380] The size of the dose will also be determined by the route, timing, and frequency of administration, as well as the existence, nature, and extent of any adverse side effects that may accompany the administration of the compound, and the desired physiological effect. As will be appreciated by those skilled in the art, various conditions or pathologies, particularly chronic conditions or pathologies, may require long-term treatment involving multiple administrations.

[0381] Any drug used for the purposes described herein can be used in combination therapy, simultaneous administration, or co-formulation with the above-mentioned compositions. Such additional drugs include cholesterol-lowering drugs, such as, but not limited to, niacin, acifran, and statins, such as, but not limited to, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin. Other additional drugs include, but are not limited to, ezetimibe, Trilipix (fenofibric acid), and the like. Other drugs and compositions include, but are not limited to, fish oil, red yeast rice, omega fatty acids, and the like.

[0382] The additional agent may be administered in combination therapy (including co-formulation) with one or more of the compounds described herein.

[0383] In some embodiments, the response of the disease or disorder to treatment is monitored, and the treatment regimen is adjusted as needed in light of such monitoring.

[0384] The frequency of administration typically provides an interval between administrations, e.g., the time between administrations during waking hours, of about 2 to about 12 hours, about 3 to about 8 hours, or about 4 to about 6 hours. As will be appreciated by those of skill in the art, an appropriate administration interval will depend on the amount of time the selected composition will provide to achieve a concentration (e.g., EC 50 The dose-dependent effect depends in part on the length of time that the EC50 concentration (the lowest concentration of compound that modulates receptor activity by 90%) can be maintained. Ideally, the concentration should be above the EC50 concentration for at least 100% of the dosing interval. 50 If this is not achievable, the concentration should remain above the EC 50 or maintain a level above 5% of EC 50 or maintain a level above 10% of EC 50 or EC 50 It is desirable to keep the temperature above 50%.

[0385] Thus, in some embodiments, the invention relates to the manufacture of a medicament, comprising combining a disclosed compound or a product of a disclosed method, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

[0386] 6. Kit In some embodiments, a structure represented by the following formula: TIFF0007808226000176.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11bare each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1d are each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -(CH2) n Cy 1 , -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , -CH(OH)Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C4-C9 cycloalkyl, a C3-C9 heterocycle having at least one O, S, or N atom, or a C2-C9 heteroaryl having at least one O, S, or N atom, and is not selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —(C1-C4)—O—(C1-C4 alkyl), —C(O)(C1-C4 alkyl), —S(O)R 14 , C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 14when present, is selected from —OH, —NH, —O(C-C alkyl), —NH(C-C alkyl), and —N(C-C alkyl)(C-C alkyl); R 3 is a 3- to 6-membered cycloalkyl, C-C haloalkyl, C-C haloalkoxy, or C-C halohydroxyalkyl, and R 4 is selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof; (a) at least one known agent for the treatment of a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy; (b) instructions for administering the compound associated with the treatment of a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy; and (c) instructions for the treatment of a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy. and one or more of A kit comprising:

[0387] In some embodiments, a structure represented by the following formula: TIFF0007808226000177.tif42165, In the formula, m is 0 or 1, and Q 1 and Q 2 are each independently N or CH, and Q 3 is CH2 or NH, and Z is CR 11a R 11b , N.R. 12 or O, wherein R 11a and R 11b each, if present, is independently selected from hydrogen, halogen, —OH, and C-C alkyloxy; or R 11a and R 11b are each, when present, together constitute =O, and R 12 is, if present, hydrogen, C-C alkyl, C-C cycloalkyl, or -(C-C alkyl)(C-C cycloalkyl), and R 1a , R 1b , R 1c , and R 1dare each independently selected from hydrogen, halogen, —CN, —NH, —OH, —NO, C-C alkyl, C-C alkenyl, C-C haloalkyl, C-C cyanoalkyl, C-C hydroxyalkyl, C-C haloalkoxy, C-C alkoxy, C-C alkylamino, and (C-C)(C-C)dialkylamino; R 2 But -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 wherein n, if present, is 0, 1, or 2; 13 is, when present, selected from hydrogen and C1-C4 alkyl; Cy 1 is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH2, —OH, —NO2, ═O, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; R 3 is a 3- to 6-membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof; (a) at least one known agent for the treatment of a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy; (b) instructions for administering the compound associated with the treatment of a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy; and (c) instructions for the treatment of a neurodegenerative disease, a mitochondrial disease, a fibrosis, and / or a cardiomyopathy. and one or more of A kit comprising:

[0388] In a further embodiment, the agent is known to treat a neurodegenerative disease. Examples of agents known to treat neurodegenerative disorders include, but are not limited to, cholinesterase inhibitors, antidepressants, memantine, Rilutek, Radicava, levodopa, carbidopa, dopamine agonists, MAO-B inhibitors, catechol-O-methyltransferase inhibitors, anticholinergics, Spinraza, tetrabenandine, antipsychotics, levetiracetam, clonazepam, antipsychotics, mood stabilizers, and amantadine.

[0389] In a further embodiment, the agent is known to treat mitochondrial diseases. Examples of agents known to treat mitochondrial diseases include, but are not limited to, vitamins and supplements such as coenzyme Q10, B complex vitamins (e.g., thiamine (B1) and riboflavin (B2)), alpha lipoic acid, L-carnitine, creatine, and L-arginine.

[0390] In a further embodiment, the agent is known to treat fibrosis, such as idiopathic pulmonary fibrosis (IPF), nonalcoholic fatty liver disease (NASH), liver fibrosis, cardiac fibrosis, mediastinal fibrosis, bone marrow fibrosis, retroperitoneal fibrosis, and renal fibrosis. Examples of agents known to treat fibrosis include, but are not limited to, pirfenidone, nintedanib, prostaglandins such as latanoprost and bimatoprost, beta-blockers such as timolol and betaxolol, alpha-adrenergic agonists such as apraclonidine and brimonidine, carbonic anhydrase inhibitors such as dorzolamide and brinzolamide, miotics or cholinergic agents such as pilocarpine, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, anti-inflammatory agents, and anti-fibrotic agents.

[0391] In further embodiments, the drug is known to treat cardiomyopathy. Examples of drugs known to treat cardiomyopathy include, but are not limited to, ACE inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, digoxin, and antiarrhythmic drugs. In various embodiments, the drug known to treat cardiomyopathy is a medical device, such as an implantable cardioverter-defibrillator (ICD), a ventricular assist device (VAD), or a pacemaker.

[0392] In a further embodiment, the at least one compound and the at least one agent are co-formulated. In a further embodiment, the at least one compound and the at least one agent are co-packaged.

[0393] In a further embodiment, the compound and agent are administered sequentially. In yet a further embodiment, the compound and agent are administered simultaneously.

[0394] The kits can also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a pharmaceutical company, drug distributor, physician, compounding pharmacy, or pharmacist can provide a kit that includes the disclosed compounds and / or products and other elements for delivery to a patient.

[0395] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be used in conjunction with the disclosed methods of use.

[0396] The foregoing description illustrates and describes the present disclosure. Additionally, while the present disclosure shows and describes only preferred embodiments, as noted above, it should be understood that the present disclosure can be used in various other combinations, modifications, and environments, and changes or modifications can be made within the scope of the inventive concept expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are intended to explain the best mode known to applicants and to enable those skilled in the art to utilize the present disclosure in such or other embodiments with various modifications as necessary for their particular application or use. Therefore, the description is not intended to limit the invention to the form disclosed herein. Nor is it intended that the appended claims be construed to include alternative embodiments.

[0397] All publications and patent applications cited herein are hereby incorporated by reference for all purposes to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. If there is a conflict between the present disclosure and any of the publications or patent applications incorporated by reference herein, the present disclosure will control. [Example]

[0398] F. Working Example Representative examples of the disclosed compounds are illustrated in the following non-limiting methods, schemes, and examples.

[0399] 1. General Experimental Methods Common starting materials used were obtained from commercial sources or prepared in other examples unless otherwise noted. All temperatures are in degrees Celsius (°C) and are uncorrected. Reagent-grade chemicals and anhydrous solvents were purchased from commercial sources and used without further purification unless otherwise noted. Product names were determined using the naming software included with the Biovia electronic lab notebook. Silica gel chromatography was performed on a Teledyne Isco instrument using prepackaged disposable SiO2 stationary phase columns with an eluent flow rate range of 15–200 mL / min and UV detection (254 and 280 nm). Reverse-phase preparative HPLC was performed using a C18 column with UV detection (214 and 254 nm) and eluted with a gradient of MeCN / HO (0.03% (NH4)2CO3 / 0.375% NH4OH, high pH) or MeCN / HO (0.1% HCOOH, low pH). Analytical HPLC chromatograms were performed using an Agilent 1100 series instrument with a DAD detector (190 nm to 300 nm). Mass spectra were recorded using a Waters Micromass ZQ detector at 130 °C. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in positive ion mode and was set to scan from m / z 150 to 750 with a scan time of 0.3 seconds. Products and intermediates were analyzed by HPLC / MS (B05) on a Gemini-NX (5 μM, 2.0 × 30 mm) with a 3.5 min run time using a high pH buffer gradient of 5% to 100% MeCN / HO (0.03% (NH)CO / 0.375% NHOH) in 2.5 min at 1.8 mL / min, and by HPLC / MS (A05) on an EVO C18 (5 μM, 3.0 × 50 mm) with a low pH buffer gradient of 5% to 100% MeCN / HO (0.1% HCOOH) in 2.5 min at 2.2 mL / min. 1 H NMR spectra were recorded on a Bruker UltraShield 500 MHz / 54 mm instrument (BZH43 / 500 / 70B, D221 / 54-3209). Chemical shifts are referenced to the solvent peak. 1The H NMR solvent peak appears at 7.26 ppm for CDCl3, 2.50 for DMSO-d6, and 3.31 ppm for CD3OD.

[0400] The following abbreviations have the indicated meanings: TIFF0007808226000178.tif146165

[0401] 2. Synthesis of adenine analogues The synthetic protocols used to access exemplary compounds disclosed herein are illustrated in Schemes 1-5 below. TIFF0007808226000179.tif115165TIFF0007808226000180.tif74165TIFF0007808226 000181.tif79165TIFF0007808226000182.tif115165TIFF0007808226000183.tif95165

[0402] 3. Evaluation of adenine analogs for PINK1 kinase activity A list of the compounds evaluated and their corresponding activities are shown in Tables 1 and 2 below.

[0403] [Table 1] TIFF0007808226000185.tif191165TIFF0007808226000186.tif191165TIFF0007808226000187.tif215165TIFF0007808226000188.tif203165TIFF0007808226000189.tif191165TIFF0007808226000190.tif191165TIFF0007808226000191.tif191165TIFF0007808226000192.tif191165TIFF0007808226000193.tif191165TIFF0007808226000194.tif191165TIFF0007808226000195.tif191165TIFF0007808226000196.tif198165TIFF0007808226000197.tif191165TIFF0007808226000198.tif191165TIFF0007808226000199.tif194165TIFF0007808226000200.tif197165TIFF0007808226000201.tif200165TIFF0007808226000202.tif207165TIFF0007808226000203.tif204165TIFF0007808226000204.tif198165TIFF0007808226000205.tif210165TIFF0007808226000206.tif206165TIFF0007808226000207.tif211165TIFF0007808226000208.tif217165TIFF0007808226000209.tif215165TIFF0007808226000210.tif229165TIFF0007808226000211.tif216165TIFF0007808226000212.tif184165TIFF0007808226000213.tif203165TIFF0007808226000214.tif196165TIFF0007808226000215.tif223165TIFF0007808226000216.tif207165TIFF0007808226000217.tif212165TIFF0007808226000218.tif201165TIFF0007808226000219.tif187165TIFF0007808226000220.tif231165TIFF0007808226000221.tif190165TIFF0007808226000222.tif175165TIFF0007808226000223.tif204165TIFF0007808226000224.tif182165TIFF0007808226000225.tif170165TIFF0007808226000226.tif191165TIFF0007808226000227.tif210165TIFF0007808226000228.tif203165TIFF0007808226000229.tif188165TIFF0007808226000230.tif218165TIFF0007808226000231.tif194165TIFF0007808226000232.tif226165TIFF0007808226000233.tif220165TIFF0007808226000234.tif187165TIFF0007808226000235.tif219165TIFF0007808226000236.tif178165TIFF0007808226000237.tif186165TIFF0007808226000238.tif231165TIFF0007808226000239.tif199165TIFF0007808226000240.tif217165TIFF0007808226000241.tif224165TIFF0007808226000242.tif192165TIFF0007808226000243.tif222165TIFF0007808226000244.tif169165TIFF0007808226000245.tif164165TIFF0007808226000246.tif187165TIFF0007808226000247.tif186165TIFF0007808226000248.tif198165TIFF0007808226000249.tif199165TIFF0007808226000250.tif198165TIFF0007808226000251.tif180165TIFF0007808226000252.tif149165TIFF0007808226000253.tif229165TIFF0007808226000254.tif180165TIFF0007808226000255.tif174165TIFF0007808226000256.tif183165TIFF0007808226000257.tif161165TIFF0007808226000258.tif185165TIFF0007808226000259.tif171165TIFF0007808226000260.tif180165TIFF0007808226000261.tif229165TIFF0007808226000262.tif227165TIFF0007808226000263.tif159165TIFF0007808226000264.tif185165TIFF0007808226000265.tif176165TIFF0007808226000266.tif179165TIFF0007808226000267.tif86165.

[0404]

Table 2A

[0405]

Table 2B

[0406]

Table 2C

[0407] 4. Preformed Fibril Model Mouse and human alpha-synuclein monomers were commercially obtained, and then preformed fibrils were generated according to the detailed protocol provided by MJFF. For in vitro experiments, primary hippocampal neurons isolated from P0 pups were grown for 7 days and then injected with 5 μg / ml of PFF. Preformed fibrils were introduced into the striatum of wild-type (C57BL / 6J, JAX #000664) and transgenic A53T mice (B6, C3-Tg(Prnp-SNCA*A53T)83Vle / J, JAX #004479) via stereotactic injection. Cohorts of drug-treated (gavage) and untreated animals were then aged for up to 6 months, at which point they were sacrificed and perfused. Brains were removed, fixed, and then sectioned for analysis. We predict that untreated A53T animals will show significant spread of aggregated alpha-synuclein pathology and pS129 staining, as well as some possible neurodegeneration, and that wild-type animals will also show pS129 synuclein staining and synuclein aggregation, albeit less than that seen in the A53T background. Drug-treated animals are expected to show significantly lower pS129 staining and reduced synuclein spread.

[0408] 5. Crystallization and Examination of Round Cells Briefly, Hela MKYP (Mito-Keima / YFP-Parkin) cells were seeded at 10K cells / well. EP / MTK compounds were added at the time of seeding (cells were still in suspension). Cells were incubated with EP / MTK compounds for 16 hours, after which 1 μM FCCP / oligomycin was added for 6 hours. Prior to harvesting, cells were visually scored under 20x magnification for the presence or absence of crystalline or aggregated compounds or round cells.

[0409] [Table 3]

[0410] The data corresponding to the visual inspection for crystallization (1=crystals present, 0=crystals absent) are shown in Table 4 below.

[0411] [Table 4]

[0412] 6. Human Phospho-ubiquitin (PS65) UB Assay Briefly, HeLa MKYP cells were plated in 10 cm plates at 1,300,000 cells / plate in 10 mL of medium containing various concentrations of compounds. After 16 h of incubation, cells were treated with 0.5 μM FCCP / oligomycin for 2 h and then harvested. Mitochondria were then isolated according to a published protocol (Ordureau et al., 2014, https: / / doi.org / 10.1016 / j.molcel.2014.09.007). Equal amounts of samples were loaded onto 26-well gradient gels, and Western blot analysis was performed using commercially available antibodies against various markers, including phosphoserine 65 (pS65) ubiquitin, MFN2, PINK1, parkin, and actin.

[0413] 7. Human Mitophagy Assay Briefly, HeLa MKYP cells were plated at 10,000 cells / well in 96-well plates with various concentrations of compounds. After 16 hours of incubation, cells were treated with 1 μM FCCP / oligomycin for 6 hours and then analyzed by FACS for the presence of mitochondria in lysosomes (determined by a spectral shift in emission from the pH-sensitive mtKeima tag).

[0414] 8. Cisplatin-related Protocol a. Cisplatin administration and administration regimen as in-life treatment Mice were acclimated to the animal facility for at least 1 week and housed in groups. Mice were injected intraperitoneally with 1 mg / ml cisplatin solution (BluePoint Labs) or 10 ml / kg sterile filtered saline using a 29G insulin syringe. Mice were weighed and administered vehicle, 35985, or 40180 by oral gavage according to the dosing regimen indicated in the figure. Mice were monitored for excessive weight loss and euthanized if moribund.

[0415] b. Preparations 35985 and 40180 35985 and 40180 are formulated at 10x the dosage strength in NMP (N-methylpyrrolidone) and then diluted with Solutol-15 and water to a final vehicle concentration of 10% NMP / 10% Solutol-15 / 80% water.

[0416] c. Slaughter and tissue collection and storage For tissue collection, mice were anesthetized using isofluorane. Blood was collected via cardiac puncture for serum collection. The blood was placed in a serum separator tube and allowed to clot at room temperature for 30 minutes to 1 hour. The serum was then separated by centrifugation (10,000 g, room temperature) for 2 minutes. The collected serum was transferred to an Eppendorf tube and frozen on dry ice. After cervical dislocation, the left and right kidneys were extracted and frozen until analysis.

[0417] d. Kidney homogenate preparation and mitochondrial isolation Kidneys were removed from -80°C and minced on ice. The minced tissue was transferred to a Dounce homogenizer and homogenized using 1 ml of cold mitochondrial isolation buffer (MIB, 50 mM Tris-HCl (pH 7.5), 70 mM sucrose, 210 mM sorbitol, 1 mM EDTA, 1 mM EGTA, 100 mM chloroacetamide, Halt™ protease and phosphatase inhibitor cocktail, EDTA-free (100x) (PI), 10 μM PR619) with 20 strokes of the "coarse" pestle and 20 strokes of the "fine" pestle. The kidney homogenate was transferred to a 1.5 ml Eppendorf tube and centrifuged at 300 x g for 5 minutes at 4°C. Approximately 800 μl of the supernatant was transferred to a new 1.5 ml microcentrifuge tube. The supernatant (cytosol + mitochondria) was transferred to a new tube and centrifuged at 10,000 g for 20 minutes at 4° C. to pellet the mitochondrial fraction. After removing the residual supernatant, the mitochondria were resuspended in lysis buffer (100 mM bicine (pH 8.0), 0.27 M sucrose, 1 mM EDTA, 1 mM EGTA, 5 mM NaPO, 100 mM Tris (pH 7.5), 1% Triton X-100) containing benzonase (1:1000), HALT protease / phosphatase inhibitor (1:100), and PR-619 deubiquitinase inhibitor (1:1000).

[0418] e. Blood urea nitrogen (BUN) measurement Serum was thawed on ice and then diluted 1:50 with MilliQ water. BUN levels in serum samples were analyzed using a ThermoFisher colorimetric urea nitrogen (BUN) detection kit. The assay was performed according to the manufacturer's published protocol.

[0419] f. Determination of kidney injury marker (KIM-1) Urine was collected from mice by pinching the scruff of the neck (continuous collection) or directly from the bladder using an insulin syringe during collection (terminal collection). KIM-1 was measured in mouse urine using the Mouse TIM-1 / KIM-1 / HAVCR DuoSet ELISA from R&D Systems according to the manufacturer's published protocol.

[0420] g. Kidney RNA extraction and quantitative PCR RNA was isolated from kidney samples using the Rneasy Mini Kit (Qiagen) according to the product manual. RNA concentration was measured using a NanoDrop™ 2000 / 2000c spectrophotometer (Thermo Scientific). 50 ng of RNA from each sample was used to generate cDNA. cDNA was synthesized using the High-Capacity RNA-to-cDNA™ Kit (Thermo Scientific) according to the product manual. Quantitative PCR was performed using Power SYBR™ Green PCR Master Mix (Applied Biosystems) according to the product manual. Gene expression levels in the kidney were analyzed using the following primers: Tnfrsf12a: 5′-GTGTTGGGATTCGGCTTGGT-3′ (SEQ ID NO: 4) and 5′-GTCCATGCACTTGTCGAGGTC-3′ (SEQ ID NO: 5), Atf3: 5′-GAGGATTTTGCTAACCTGACACC-3′ (SEQ ID NO: 6) and 5′-TTGACGGTAACTGACTCCAGC-3′ (SEQ ID NO: 7), Plk3: 5′-GCACATCCATCGGTCATCCAG-3′ (SEQ ID NO: 8) and 5′-GCCACAGTCAAACCTTCTTCAA-3′ (SEQ ID NO: 9), Gdf15: 5′-CTGGCAATGCCTGAACAACG-3′ (SEQ ID NO: 10) and 5′-GGTCGGGACTTGGTTCTGAG-3′ (SEQ ID NO: 11), b-act: 5′-GGGCATCCTGACCCTC AAG-3′ (SEQ ID NO: 12) and 5′-TCCATGTCGTCCCAGTTGGT-3′ (SEQ ID NO: 13).

[0421] All gene expression levels were normalized to the expression level of beta-actin using ΔΔCt and expressed as fold change compared to cisplatin vehicle-treated mice.

[0422] h. mTDNA / NUCDNA ratio Small pieces of frozen kidney tissue (approximately 12 mg) were homogenized and DNA extracted using the Qiagen QIAamp DNA Mini Kit. The mtDNA / nucDNA ratio was determined using the Aurwex lab's qPCR protocol (Quiros et al., 2017) with the following primers: 16S rRNA: 5'-CCGCAAGGGAAAGATGAAAGAC-3' (SEQ ID NO: 14) and 5'-TCGTTTGGTTTCGGGGTTTC-3' (SEQ ID NO: 15), ND1: 5'-CTAGCAGAAACAAACCGGGC-3' (SEQ ID NO: 16) and 5'-CCGGCTGCGTATTCTACGTT-3 (SEQ ID NO: 17), HK2: 5'-GCCAGCCTCTCCTGATTTTAGTGT-3' (SEQ ID NO: 18) and 5'-GGGAACACAAAAGACCTCTTCTGG-3' (SEQ ID NO: 19).

[0423] i.PS65-UB ELISA For the pS65-Ub ELISA, capture monoclonal rabbit antibody anti-pS65-Ub was diluted to 1 μg / ml in PBS and pipetted into a 96-well half-area polystyrene plate (50 μl / well). The sealed plate was shaken at 800 rpm for 5 minutes and incubated overnight at 4°C on a flat surface. The next day, blocking solution (5% BSA in TBST, sterile filtered) was added to each well (100 μl / well) and shaken at 800 rpm for 1 hour at room temperature. Plates were either used immediately or stored sealed at 4°C for up to 1 week. Samples were diluted to a concentration of 10 μg / μl in lysis buffer, and after washing five times with TBST using an automated plate washer (used for all subsequent wash steps), 50 μl was loaded onto the plate in duplicate. The standard protein, recombinant pS65-Ub, was diluted in lysis buffer plus 0.1% BSA, and serial dilutions (4000 ng / ml to 0 ng / ml) were added to sample plates (50 μl / well) in duplicate. The plates were shaken at 800 rpm for 2 hours at room temperature. After washing five times with TBST, 50 μl of mouse anti-Ub detection antibody (1 μg / ml in 5% BSA in TBST) was added to the wells. The plates were shaken at 800 rpm for 1 hour at room temperature, then washed five times with TBST and incubated with goat anti-mouse peroxidase-conjugated IgG antibody (1:10,000 dilution in 5% BSA in TBST) (50 μl / well) for 45 minutes at room temperature with shaking at 800 rpm. For the peroxidase reaction, 50 μl of TMB reagent (Pierce, #34029) was added to the wells after washing, and the wells were carefully monitored for reaction progress. To stop the ELISA reaction, 50 ul of 2N sulfuric acid was added. The absorbance was measured at 450 nm using a LifeTechnologies (SpectraMax).

[0424] j. Western blotting The total protein concentration of kidney mitochondrial preparations was measured using the Thermo Scientific Pierce BCA Protein Assay Kit (Thermo Scientific) according to the product manual. These samples were normalized to their respective lysis buffers. For SDS-PAGE, samples were prepared in 4x Laemmli sample buffer containing the reducing agent 2-mercaptoethanol. Ten micrograms per sample were loaded per lane of a 26-well gel (4-20% Criterion™ Tris-HCl Protein Gel, Bio-Rad Laboratories) and analyzed by Western blotting. The indicated bands were quantified using ImageStudio Lite and normalized to beta-actin band intensity.

[0425] 9. In Vitro Data As shown in Figure 28, the addition of 35985 or 40180 results in a dose-responsive increase in the percentage of cells undergoing mitophagy. Briefly, HeLa cells expressing the mitophagy indicator (mtKeima) protein were treated with 1 mM FCCP and oligomycin, followed by the specified doses of compounds, and then analyzed by FACS to quantify the percentage of cells undergoing mitophagy.

[0426] As shown in Figure 29, the addition of 35985 or 40180 results in a dose-responsive increase in the rate of Parkin recruitment to mitochondria. HeLa cells expressing YFP-tagged Parkin were treated with 1 mM FCCP and oligomycin, followed by the specified doses of compound, and then analyzed by longitudinal imaging. The percentage of cells in which Parkin was recruited to mitochondria at 60 minutes is shown.

[0427] 10. Pathway Binding Data Mice (C57B1 / 6) were given a single intraperitoneal dose of 30 mg / kg cisplatin. Mitochondrial preparations were examined for PINK1 using pS65-Ub ELISA (Figure 30A) or Western blot (Figure 30B). Referring to Figure 30C, there is a high correlation between PINK1 protein levels and its direct target, pS65-Ub, in kidney mitochondria.

[0428] Referring to Figure 31, mice (C57B1 / 6) were given a single intraperitoneal dose of 10 mg / kg cisplatin. Tissue lysates were examined for the mitochondrial gene ND1 and the nuclear gene beta-actin by quantitative PCR. A significant decrease in mitochondrial DNA was observed upon cisplatin administration.

[0429] 32A and 32B, mice (C57Bl / 6 or PINK1 knockout on a C57Bl / 6 background) were given a single intraperitoneal dose of saline or 30 mg / kg cisplatin. Blood urea nitrogen (BUN), a commonly used clinical marker of renal dysfunction, was increased in PINK1 knockout mice compared to wild-type mice.

[0430] Referring to Figure 33, mice (C57Bl / 6 or PINK1 knockout on a C57Bl / 6 background) were given a single intraperitoneal dose of 30 mg / kg of cisplatin. Kidney mitochondrial pS65-Ub levels were examined at different times as indicated. The fact that pS65 ubiquitin remained unchanged in PINK knockout mice after cisplatin administration indicates that PINK1 function is completely eliminated in these animals.

[0431] Referring to Figure 34, mice (C57Bl / 6 or PINK1 knockout on a C57Bl / 6 background) were intraperitoneally administered a single dose of 30 mg / k...

Claims

1. The following structure: or a pharmaceutically acceptable salt thereof.

2. The following structure: A compound having the formula:

3. The following structure: A pharmaceutically acceptable salt of a compound having the formula:

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