Compositions for the treatment of neurodegenerative diseases and mitochondrial diseases, and methods for using the same.

Abstract

Provided are compounds and compositions that can regulate PINK1 kinase activity, as well as methods for making and using them. 【Solution means】A compound having the structure of the following formula. TIFF2026067907000289.tif48165(Z: O, NH, CH2. R 1a , R 1b , R 1c , R 1d : H, halogen, CN, NH2, etc. R 2 : -(CH2) n Cy 1 , -O(CH2) n Cy 1 , Cy 1 etc. (Cy 1 : C4-C9 cycloalkyl, C3-C9 heterocycle, etc.).)

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Patent Application No. 62 / 980,143, filed on 21 February 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 filed on February 22, 2021, as a text file named "37930_0006P1_ST25.txt" with a size of 20,293 bytes, is incorporated herein by reference in accordance with Section 1.52(e)(5) of the U.S. Patent Law Enforcement Regulations. [Background technology]

[0003] background Maintaining mitochondrial function is essential for the health and survival of numerous cell types, including cardiomyocytes, hepatocytes, renal cells, and neurons. Abnormal mitochondrial quality control has been demonstrated as a critical factor in the development of neurodegenerative diseases, kidney diseases, and cardiomyopathy (Schapira, AH Mitochondrial disease. Lancet 379, 1825-1834, (2012) (Non-patent Literature 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 Literature 2)). The mitochondrial kinase PTEN-inducible kinase 1 (PINK1) plays a crucial role in mitochondrial quality control processes by responding to damage at the individual mitochondrial level. The PINK1 pathway is associated with the induction of mitochondrial neogenesis and, importantly, with the reduction of mitochondrial-induced apoptosis. For example, see Narendra, D.P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8, e1000298 (2010) (Non-Patent Literature 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 Literature 4), and Shin, J.Het al. PARIS (ZNF746) rejection of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 144, 689-702, (2011) (Non-Patent Literature 5).

[0004] Parkinson's disease (PD) is one of the most common neurodegenerative diseases, yet there are currently no approved disease-modifying therapies for treating PD. Both environmental and genetic factors contribute to the progression of apoptosis in dopaminergic neurons, a decrease in dopamine levels, and ultimately PD. PINK1 kinase activity appears to be essential for mediating its neuroprotective activity. The regulation of mitochondrial movement, distribution, and clearance is a crucial 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 above.

[0005] Cardiomyopathy refers to diseases of the myocardial tissue, and it is estimated that 5-10% of the 5-6 million patients already diagnosed with heart failure in the United States have cardiomyopathy. Based on etiology and pathophysiology, the World Health Organization has created a classification of cardiomyopathy, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmic 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 cardiomyopathies. Circulation 1996;93:841 (Non-Patent Literature 6). PINK1 kinase activity appears to mediate its cardioprotective activity. Regulation of mitochondrial movement, distribution, and clearance is part of the oxidative stress response of cardiac cells. Disruption of these regulatory pathways has been shown to contribute to cardiomyopathy. See Schapira and Chen above. 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 Literature 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 Literature 6). Recently, several cases of adult-onset LS have also been reported. For example, Longo, D, et al. Harrison's Internal Medicine. 18 thSee ed. (online), Ch.238 (2011) (Non-Patent Literature 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 Literature 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 Literature 9), and Geisler, S. et al. The PINK1 / Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 6, 871-878, (2010) (Non-Patent Literature 10).

[0006] In vivo imaging techniques such as MRI can reveal bilateral ultra-high intensity lesions in the basal ganglia, thalamus, substantia nigra, brainstem, cerebellar white matter and cortex, cerebral white matter, or spinal cord in LS patients. For example, see Longo, J. Shin, Het al. PARIS (ZNF746) rejection of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell 144, 689-702, (2011) (Non-patent Literature 5), Henchcliffe, C. & Beal, MF Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4, 600-609 (2008) (Non-patent Literature 11), Pridgeon, J. W. Olzmann, JA Chin, LS & Li, L. PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1. PLoS Biol 5, e172 (2007) (Non-patent Literature 12), and Haque, ME et al. Cytoplasmic Pink1 activity protects neurons from dopaminergic See neurotoxin MPTP. Proc Natl Acad Sci USA 105,1716-1721(2008) (Non-patent Literature 13). Lesions are usually associated 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 Literature 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 Literature 14). Behavioral symptoms in LS patients include developmental delay (accompanied by a wide variety of clinical symptoms), hypotonia, ataxia, spasticity, dystonia, weakness, optic nerve atrophy, oculomotor or blepharokinetic disorders, hearing impairment, respiratory abnormalities, dysarthria, dysphagia, growth retardation, and gastrointestinal disorders. For example, see Wang and Richardson mentioned above, as well as Samaranch, L. et al. PINK1-linked parkinsonism is associated with Lewy body pathology. Brain 133, 1128-1142, (2010) (Non-patent Literature 15), and Merrick, KA 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 Literature 16). The cause of death in most LS cases is unknown, and the lack of genetic models to study disease progression and mortality hinders the development of appropriate treatments. The prognosis for LS (and most diseases resulting from mitochondrial dysfunction) is very poor, there is no cure, and in many cases, treatment is ineffective.

[0007] Parkinson's disease (PD) is one of the most common neurodegenerative diseases, yet there are currently no approved disease-modifying therapies for treating PD. Both environmental and genetic factors contribute to the progression of apoptosis in dopaminergic neurons, a decrease in dopamine levels, and ultimately PD. PINK1 kinase activity appears to mediate its neuroprotective activity. The regulation of mitochondrial movement, distribution, and clearance is a crucial 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 above.

[0008] Despite the widespread prevalence of disorders associated with the PINK1 pathway, no compounds have yet been found that selectively target this pathway and therefore can treat disorders associated with it. Consequently, there is still a need for compounds and compositions that can modulate PINK1 kinase activity, as well as methods for their preparation and use. [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) [Overview of the project]

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

[0011] Therefore, the structure is represented by the following formula: A compound having TIFF2026067907000002.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R11b When each of them exists, it is independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b When each of them exists, they together form =O, and R 12 When it exists, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), and R 1a R 1b R 1c and R 1d are each independently selected from hydrogen, 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, and 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 is selected from, where n is 0, 1, or 2 when it exists, and R 13 is selected from hydrogen and C1-C4 alkyl when it exists, and Cy 1 is 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 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, substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14 However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4 However, compounds selected from hydrogen and C1-C4 alkyl groups, or pharmaceutically acceptable salts thereof, are provided herein.

[0012] The structure is represented by the following formula: A compound having TIFF2026067907000003.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it 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 halogens, -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, and R 3 However, compounds that are 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or pharmaceutically acceptable salts thereof, are also described.

[0013] While we do not wish to be bound by theory, the advantage of the compounds described in this invention is that they have improved potency and reduced toxicity. For example, the disclosed compounds have an EC of less than 0.3 μM with a toxicity of less than 10%. 50 This can be shown. For example, see Tables 2A and 2B, and Figures 1A-F, and compound number EP-0038098.

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

[0015] A pharmaceutical composition comprising a therapeutically effective amount of the disclosed compound and a pharmaceutically acceptable carrier is also provided.

[0016] A method for regulating PINK1 kinase activity in subjects requiring regulation of PINK1 kinase activity is also provided, comprising administering an effective amount of at least one disclosed compound to the subject requiring such regulation.

[0017] Also disclosed is a method for regulating 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 requiring treatment of the disorder, comprising administering an effective amount of at least one disclosed compound to the subject requiring treatment, wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy.

[0019] The disclosed compounds and (a) at least one drug known for the treatment of neurodegenerative disorders, mitochondrial disorders, fibrosis, and cardiomyopathy; (b) instructions for the administration of compounds associated with neurodegenerative disorders, mitochondrial disorders, fibrosis, or cardiomyopathy; and / or (c) instructions for the treatment of the disorder. One or more of the above A kit including this is also provided.

[0020] [Invention 1001] The structure is represented by the following formula: A compound having TIFF2026067907000004.tif42165, During the ceremony, m is 0 or 1, Q 1 and Q 2 Each of them is independently either N or CH, Q 3However, it is CH2 or NH, Z, CR 11a R 11b , NR 12 , or O, During the ceremony, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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. R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, During the ceremony, If n exists, it is 0, 1, or 2. R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl. Cy 1is C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 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)-O-(C1-C4 alkyl), -C(O)(C1-C4 alkyl), -S(O)R 14 and is substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, R 14 when present, is selected from -OH, -NH2, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)(C1-C4 alkyl), R 3 is 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, R 4 is selected from hydrogen and C1-C4 alkyl, said compound, or a pharmaceutically acceptable salt thereof. [Invention 1002] R 2 is -O(CH2)[[ID=2,3]] n Cy 1 -NR 13 (CH2) n Cy 1 and Cy 1 is selected from, Cy 1However, it 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 halogens, -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, and R 4 However, the compound of the present invention 1001 is hydrogen. [Invention 1003] A compound of the present invention 1001, wherein m is 1. [Invention 1004] Q 1 A compound of the present invention 1001, wherein CH is present. [Invention 1005] Q 2 A compound of the present invention 1001, wherein N is present. [Invention 1006] Q 3 A compound of the present invention 1001, wherein NH is present. [Invention 1007] Q 1 CH is Q 2 If N is Q 3 A compound of the present invention 1001, wherein NH is present. [Invention 1008] A compound of the present invention 1001, wherein Z is CH2. [Invention 1009] R 1a , R 1b , R 1c , and R 1d The compound of the present invention 1001, wherein each of the elements is independently hydrogen, a halogen, or a C1-C4 alkyl group. [Invention 1010] R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1, and Cy 1 A compound of the present invention 1001, selected from the above. [Invention 1011] R 2 Cy 1 The compound of the present invention 1001. [Invention 1012] Cy 1 The compound of the present invention 1011, which is an unsubstituted C3-C9 heterocycle having at least one O, S, or N atom. [Invention 1013] Cy 1 However, the structure is represented by an expression selected from the following: The compound of the present invention 1011, which is TIFF2026067907000005.tif29165. [Invention 1014] Cy 1 The compound of the present invention 1001, which is a C3-C9 heterocycle having at least one O, S, or N atom. [Invention 1015] The compound of the present invention 1014, wherein the C3-C9 heterocycle is a monocyclic heterocycle. [Invention 1016] The compound of the present invention 1014, wherein the C3-C9 heterocycle is a bicyclic heterocycle. [Invention 1017] The compound of the present invention 1014, wherein the C3-C9 heterocycle is a spirocyclic heterocycle. [Invention 1018] The compound of the present invention 1014, wherein the aforementioned C3-C9 heterocycle is a fused heterocycle. [Invention 1019] Cy 1 The compound of the present invention 1001, which is a C2-C9 heteroaryl having at least one O, S, or N atom. [Invention 1020] Cy 1The compound of the present invention 1001, which 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. [Invention 1021] R 3 The compound of the present invention 1001 is a 3-6 membered cycloalkyl or C1-C6 haloalkyl. [Invention 1022] R 3 The compound of the present invention 1001, wherein the compound is a 3-membered cycloalkyl or -CF3. [Invention 1023] R 4 A compound of the present invention 1001, wherein the compound is hydrogen. [Invention 1024] The structure is represented by the following formula: A compound of the present invention 1001 having TIFF2026067907000006.tif48165. [Invention 1025] The structure is represented by the following formula: A compound of the present invention 1001 having TIFF2026067907000007.tif48165. [Invention 1026] Structures represented by the following formulas: A compound of the present invention 1001 having TIFF2026067907000008.tif48165. [Invention 1027] Structures represented by the following formulas: A compound of the present invention 1001 having TIFF2026067907000009.tif48165. [Invention 1028] below: A compound of the present invention 1001, selected from TIFF2026067907000010.tif183165, TIFF2026067907000011.tif183165, and TIFF2026067907000012.tif229165. [Invention 1029] below: A compound of the present invention 1001, selected from TIFF2026067907000013.tif188165TIFF2026067907000014.tif185165TIFF2026067907000015.tif185165TIFF2026067907000016.tif137165. [Invention 1030] below: TIFF2026067907000017.tif175165TIFF2026067907000018.tif173165TIFF2026067907000019. tif173165TIFF2026067907000020.tif175165TIFF2026067907000021.tif183165TIFF20260679 07000022.tif180165TIFF2026067907000023.tif181165TIFF2026067907000024.tif178165TIF F2026067907000025.tif183165TIFF2026067907000026.tif175165TIFF2026067907000027.tif 177165TIFF2026067907000028.tif173165TIFF2026067907000029.tif178165TIFF20260679070 00030.tif177165TIFF2026067907000031.tif184165TIFF2026067907000032.tif176165TIFF20 A compound of the present invention 1001, selected from 26067907000033.tif146165TIFF2026067907000034.tif150165TIFF2026067907000035.tif153165TIFF2026067907000036.tif153165TIFF2026067907000037.tif97165. [Invention 1031] below: TIFF2026067907000038.tif175165TIFF2026067907000039.tif173165TIFF2026067907000040.tif173165TIFF2026067907000041. tif177165TIFF2026067907000042.tif190165TIFF2026067907000043.tif176165TIFF2026067907000044.tif182165TIFF20260679 07000045.tif177165TIFF2026067907000046.tif183165TIFF2026067907000047.tif184165TIFF2026067907000048.tif185165TIF F2026067907000049.tif180165TIFF2026067907000050.tif176165TIFF2026067907000051.tif170165TIFF2026067907000052.tif1 79165TIFF2026067907000053.tif179165TIFF2026067907000054.tif173165TIFF2026067907000055.tif180165TIFF202606790700 0056.tif172165TIFF2026067907000057.tif185165TIFF2026067907000058.tif185165TIFF2026067907000059.tif175165TIFF202 A compound of the present invention 1001, selected from 6067907000060.tif185165TIFF2026067907000061.tif185165TIFF2026067907000062.tif144165TIFF2026067907000063.tif150165TIFF2026067907000064.tif149165TIFF2026067907000065.tif148165TIFF2026067907000066.tif154165. [Invention 1032] below: The compound of the present invention 1001, which is TIFF2026067907000067.tif48165. [Invention 1033] A pharmaceutical composition comprising a therapeutically effective amount of any compound from invention 1001 to 1032 and a pharmaceutically acceptable carrier. [Invention 1034] A method for regulating PINK1 kinase activity in a subject requiring regulation of PINK1 kinase activity, comprising administering an effective amount of any compound from 1001 to 1032 of the present invention to the subject requiring such regulation. [Invention 1035] The method of the present invention 1034, wherein the aforementioned regulation is inhibition. [Invention 1036] A method for regulating PINK1 kinase activity in at least one cell, comprising contacting the cell with an effective amount of any compound from 1001 to 1032 of the present invention. [Invention 1037] The method of the present invention 1036, wherein the cells are mammalian cells. [Invention 1038] The method of the present invention 1037, wherein the cells are isolated from the mammal before the contact step. [Invention 1039] The method of the present invention 1036, wherein the cells include PINK1 kinase activity dysfunction. [Invention 1040] The method of the present invention 1036, wherein the contact step is performed in vitro. [Invention 1041] A method for treating a disorder in a subject requiring treatment, comprising administering an effective amount of any compound 1001 to 1032 of the present invention to the subject requiring treatment, wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy. [Invention 1042] The method of the present invention 1041, wherein the subject is a mammal. [Invention 1043] The method of the present invention 1041, wherein the subject is a human. [Invention 1044] The method of the present invention 1041, wherein the subject is diagnosed with the disorder before the administration step. [Invention 1045] The method of the present invention 1041, wherein the administration described above is achieved by oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, local administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, intrathecal administration, and intra-articular administration, or a combination thereof. [Invention 1046] The method of the present invention 1041, wherein the administration comprises administering about 1 to about 2000 micrograms of an expressible nucleic acid sequence. [Invention 1047] The method of the present invention 1041, wherein the neurodegenerative disorder is Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis. [Invention 1048] A compound according to any of the invention 1001 to 1032, (a) at least one drug known for the treatment of neurodegenerative disorders, mitochondrial disorders, fibrosis, and cardiomyopathy, (b) Instructions for the administration of the compound in relation to the neurodegenerative disorder, mitochondrial disorder, fibrosis, or cardiomyopathy, and / or (c) Instructions regarding the treatment of the aforementioned disorders One or more of the above A kit that includes this. Further purposes and advantages of this disclosure will be readily apparent to those skilled in the art from the modes for carrying out the invention described below, where only preferred embodiments are shown and described as mere illustrations of the best mode. As will be recognized, this disclosure is open to other different embodiments, some of which are open to modification in various obvious ways without departing from this disclosure. Therefore, this description should be considered essentially illustrative and not limiting. [Brief explanation of the drawing]

[0021] The accompanying drawings incorporated herein and constituting part of this specification illustrate several embodiments and, together with this description, serve to illustrate the principles of the present invention.

[0022] [Figure 1A] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0037821, EP-0038098, and EP-0038099 over 6 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 1B] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0037821, EP-0038098, and EP-0038099 over 6 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 1C] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0037821, EP-0038098, and EP-0038099 over 6 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 1D] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0037821, EP-0038098, and EP-0038099 over 6 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 1E] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0037821, EP-0038098, and EP-0038099 over 6 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 1F] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0037821, EP-0038098, and EP-0038099 over 6 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 2A] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, and EP-0038503 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 2B] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, and EP-0038503 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 2C] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, and EP-0038503 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 2D] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, and EP-0038503 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 2E]Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, and EP-0038503 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 2F] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, and EP-0038503 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 3A] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (no FO) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 3B] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (no FO) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 3C] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (no FO) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 3D]Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (no FO) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 3E] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (no FO) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 3F] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (no FO) are presented. Cell death, measured by DAPI staining, was controlled by H2O2 treatment. [Figure 4A] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, EP-0038503, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 4B] Representative data showing the potency and toxicity of compounds EP-0035985, EP-0038461, EP-0038463, EP-0038503, EP-0038504, EP-0038508, and EP-0038521 over 6.5 hours in the presence of 1 μM FCCP / oligomycin or in the absence of the toxin (FO-free) are presented. Cell death, measured by DAPI staining, was controlled with H2O2 treatment. [Figure 5A]Representative data showing that compounds EP-0038504 and EP-0038461 exhibit low mitochondrial toxicity are presented. [Figure 5B] Representative data showing that compounds EP-0038504 and EP-0038461 exhibit low mitochondrial toxicity are presented. [Figure 5C] Representative data showing that compounds EP-0038504 and EP-0038461 exhibit low mitochondrial toxicity are presented. [Figure 6A] Representative data showing that compounds EP-0038508 and EP-0038463 exhibit low mitochondrial toxicity are presented. [Figure 6B] Representative data showing that compounds EP-0038508 and EP-0038463 exhibit low mitochondrial toxicity are presented. [Figure 6C] Representative data showing that compounds EP-0038508 and EP-0038463 exhibit low mitochondrial toxicity are presented. [Figure 7A] Representative data showing that compounds EP-0038503 and EP-00338521 exhibit low mitochondrial toxicity are presented. [Figure 7B] Representative data showing that compounds EP-0038503 and EP-00338521 exhibit low mitochondrial toxicity are presented. [Figure 7C] Representative data showing that compounds EP-0038503 and EP-00338521 exhibit low mitochondrial toxicity are presented. [Figure 8A] Representative data are shown demonstrating that compounds 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 demonstrating that compounds 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 demonstrating that compounds 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 reduces pathological (pS129) α-synuclein (250-12) (Figure 9A) and pathological (pS129) α-synuclein (monomer) (Figure 9B) from the striatum induced by PFF administration. [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 reduces pathological (pS129) α-synuclein (250-12) (Figure 9A) and pathological (pS129) α-synuclein (monomer) (Figure 9B) from the striatum induced by PFF administration. [Figure 10A] Representative data are shown demonstrating that increasing the dose of EP-0040503 in primary neuron culture reduces pS129α-synuclein (Figure 10A). [Figure 10B] Representative data are presented showing that increasing the dose of EP-0040503 in primary neuronal culture reduces pS129α-synuclein (250-12). [Figure 10C]Representative data are presented showing that increasing the dose of EP-0040503 in primary neuron culture reduces pS129α-synuclein (monomer). [Figure 11A] Representative data are presented showing that increasing the dose of EP-0040850 in primary neuron culture reduces pS129α-synuclein. [Figure 11B] Representative data are presented showing that increasing the dose of EP-0040850 in primary neuron culture reduces pS129α-synuclein (250-12). [Figure 11C] Representative data are presented showing that increasing the dose of EP-0040850 in primary neuron culture reduces pS129α-synuclein (monomer). [Figure 12] Representative data shows that treatment with toxins resulted in an increase in cleavage caspase-3 levels, whereas EP-0040850 did not. [Figure 13A] Representative data are presented showing that increasing the dose of EP-0040857 reduces pS129α-synuclein in primary neuron cultures. [Figure 13B] Representative data are presented showing that increasing the dose of EP-0040857 in primary neuronal cultures reduces pS129α-synuclein (250-12). [Figure 13C] Representative data are presented showing that increasing the dose of EP-0040857 in primary neuron culture reduces pS129α-synuclein (monomer). [Figure 14A] Representative data are presented showing that increasing the dose of EP-0040270 in primary neuron culture reduces pS129α-synuclein. [Figure 14B] Representative data are presented showing that increasing the dose of EP-0040270 in primary neuron culture reduces pS129α-synuclein (250-12). [Figure 14C] Representative data are presented showing that increasing the dose of EP-0040270 in primary neuron cultures reduces pS129α-synuclein (monomer). [Figure 15] Representative data are shown demonstrating that treatment with toxins and high doses of EP-0040270 increases cleavage caspase-3 levels. [Figure 16A] Representative data are presented showing that increasing the dose of EP-0040587 in primary neuronal cultures reduces pS129α-synuclein. [Figure 16B] Representative data are presented showing that increasing the dose of EP-0040587 in primary neuronal cultures reduces pS129α-synuclein (250-12). [Figure 16C] Representative data are presented showing that increasing the dose of EP-0040587 in primary neuronal cultures reduces pS129α-synuclein (monomer). [Figure 17A] Representative data are presented showing that increasing the dose of EP-0040180 in primary neuron culture reduces pS129α-synuclein. [Figure 17B] Representative data are presented showing that increasing the dose of EP-0040180 in primary neuronal cultures reduces pS129α-synuclein (250-12). [Figure 17C] Representative data are presented showing that increasing the dose of EP-0040180 in primary neuron cultures reduces pS129α-synuclein (monomer). [Figure 18] Representative data are shown demonstrating that treatment with toxins and EP-0040180 does not significantly alter cleavage caspase-3 levels. [Figure 19]Figure 19A shows representative data illustrating the effect of EP-0040180 on the pS129 signal. Figure 19B shows representative data illustrating the effect of EP-0040180 on the pS129 signal. [Figure 20A] Representative data are presented showing that increasing the dose of EP-0041161 in primary neuronal cultures reduces pS129α-synuclein. [Figure 20B] Representative data are presented showing that increasing the dose of EP-0041161 in primary neuronal cultures reduces pS129α-synuclein (250-12). [Figure 20C] Representative data are presented showing that increasing the dose of EP-0041161 in primary neuron culture reduces pS129α-synuclein (monomer). [Figure 21] Representative data is shown to demonstrate that treatment with toxins alters cleavage caspase-3 levels, while treatment with EP-0041161 does not. [Figure 22] Figure 22A shows representative data illustrating the effect of EP-0041161 on the pS129 signal. Figure 22B shows representative data illustrating the effect of EP-0041161 on the pS129 signal. [Figure 23A] Representative data are presented showing that increasing the dose of EP-0041088 in primary neuronal culture reduces pS129α-synuclein. [Figure 23B] Representative data are presented showing that increasing the dose of EP-0041088 in primary neuronal culture reduces pS129α-synuclein (250-12). [Figure 23C] Representative data are presented showing that increasing the dose of EP-0041088 in primary neuronal cultures reduces pS129α-synuclein (monomer). [Figure 24]Figure 24A shows representative data illustrating the effect of EP-0041088 on the pS129 signal. Figure 24B shows representative data illustrating the effect of EP-0041088 on the pS129 signal. [Figure 25A] Representative data are presented showing that increasing the dose of EP-0040874 in primary neuronal culture reduces pS129α-synuclein. [Figure 25B] Representative data are presented showing that increasing the dose of EP-0040874 in primary neuronal culture reduces pS129α-synuclein (250-12). [Figure 25C] Representative data are presented showing that increasing the dose of EP-0040874 in primary neuronal culture reduces pS129α-synuclein (monomer). [Figure 26A] Representative data are presented showing that increasing the dose of EP-0041668 in primary neuronal cultures reduces pS129α-synuclein. [Figure 26B] Representative data are presented showing that increasing the dose of EP-0041668 in primary neuronal cultures reduces pS129α-synuclein (250-12). [Figure 26C] Representative data are presented showing that increasing the dose of EP-0041668 in primary neuronal cultures reduces pS129α-synuclein (monomer). [Figure 27A] Representative data are presented showing that increasing the dose of EP-0041670 in primary neuron cultures reduces pS129α-synuclein. [Figure 27B] Representative data are presented showing that increasing the dose of EP-0041670 in primary neuron cultures reduces pS129α-synuclein (250-12). [Figure 27C]Representative data are presented showing that increasing the dose of EP-0041670 in primary neuron cultures reduces pS129α-synuclein (monomer). [Figure 28] Representative data demonstrating that PINK1 activators 35985 and 40180 induce mitophagy in a dose-dependent manner are shown. ABC123 [Figure 29] Representative data are shown demonstrating that PINK1 activators 35985 and 40180 promote the recruitment of parkin to mitochondria. [Figure 30A] Representative data demonstrating that cisplatin induces PINK1 and its direct target pUb are shown. 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 demonstrating that cisplatin induces PINK1 and its direct target pUb are shown. 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 demonstrating that cisplatin induces PINK1 and its direct target pUb are shown. Specifically, Figure 30C shows the correlation between pUb and PINK1. [Figure 31] Representative data demonstrating that cisplatin causes a decrease in the mtDNA / nucDNA ratio are presented. [Figure 32] Figure 32A shows representative data demonstrating increased cisplatin-induced kidney injury in PINK1 knockout mice. Figure 32B shows representative data demonstrating increased cisplatin-induced kidney injury in PINK1 knockout mice. [Figure 33] Representative data demonstrating that cisplatin does not induce changes in pS65 ubiquitin in PINK1 knockout mice are presented. [Figure 34] Representative data demonstrating that cisplatin administration increases mitochondrial stress gene expression in PINK1 knockout mice are presented. [Figure 35] Representative data comparing the mouse plasma pharmacokinetics of 35985 and 40180 are shown. [Figure 36] Representative data showing that 40180 reduces KIM-1 in cisplatin-treated mice are presented. [Figure 37] Representative data showing that 40180 reduces the expression of mitochondrial stress-related genes is presented. [Modes for carrying out the invention]

[0023] Further advantages of the present invention are partially described below, partially evident from this description, or can be acquired through the practice of the invention. The advantages of the present invention will be realized and achieved by the elements and combinations particularly indicated in the appended claims. It should be understood that the above summary and the following embodiments for carrying out the invention are merely illustrative and descriptive and do not limit the claimed invention.

[0024] Detailed explanation The present invention can be more easily understood by referring to the embodiments for carrying out the invention and the examples included herein.

[0025] Before disclosing and describing the compounds, compositions, articles, systems, devices, and / or methods of the present invention, it should be understood that synthesis methods and reagents can naturally vary and are not limited to specific synthesis methods unless otherwise specified, nor are they limited to specific reagents unless otherwise specified. Furthermore, it should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of the present invention, but exemplary methods and materials are described herein.

[0026] While embodiments of the present invention may be described and claimed in a specific legal classification, such as a system class, this is merely for convenience, and those skilled in the art will understand that each embodiment of the present invention can be described and claimed in any legal classification. Unless otherwise specified, none of the methods or embodiments described herein are intended to be interpreted as requiring their steps to be performed in a particular order. Therefore, unless it is specifically stated in the claims or descriptions that the steps of a method claim should be limited to a particular order, there is absolutely no intention to imply any order. This also applies to any possible non-specified grounds for interpretation, including logical matters concerning the arrangement of steps or operational flows, simple interpretations arising 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 are incorporated herein by reference in their entirety for the purpose of providing a more comprehensive description of the context of the art in which this application pertains. The disclosed references are also incorporated herein by reference individually and specifically, including the material described in the texts on which the references are based. Nothing herein should be construed as an acknowledgment that the present invention does not have prior rights to such publications on the grounds of prior art. Furthermore, publication dates presented herein may differ from actual publication dates and may require individual verification.

[0028] A.Definition The definitions of various terms used to describe the present invention are listed below. These definitions apply throughout this specification wherever those terms are used, whether individually or as part of a larger group, unless they are specifically limited in particular cases.

[0029] Where used herein, the terms “a” or “an” mean “at least one” or “one or more” unless otherwise specified in the context. Where used herein and in the claims, the phrase “and / or” should be understood to mean “either or both” of the elements connected by that phrase, that is, elements that exist in some cases together and elements that exist in other cases separately. Unless otherwise specified, elements other than those specifically identified by the phrase “and / or” may be present at their discretion, whether related to or unrelated to the specifically identified elements. Thus, as a non-restrictive example, when used in conjunction with open-ended phrases such as “comprising,” in various embodiments, A without B (optionally including elements other than B) may be present; in another embodiment, B without A (optionally including elements other than A) may be present; and in yet another embodiment, both A and B (optionally including other elements) may be present, and so on.

[0030] Where used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when dividing items in a list, “or” or “and / or” should be interpreted as inclusive, that is, at least one of several elements or lists of elements, but including two or more, and including additional unlisted items of any choice. Only terms that explicitly indicate the opposite, such as “one of” or “exactly one of” or, where used in the claims, “consisting of,” would refer to the inclusion of exactly one element of several elements or lists of elements. In general, where used herein, the term “or” should be interpreted only as indicating an exclusive choice (i.e., “one or the other, but not both”) when preceded by the terms of exclusivity “either,” “one of,” “one of,” or “exactly one of,” and where used in the claims, “essentially consisting of” should have its usual 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”) are inclusive, or open, and do not exclude any additional elements or method steps not enumerated.

[0032] Where used herein, the term “about” means that a numerical value is approximate and that small variations will not materially affect the practice of the disclosed embodiments. Where “about” refers to measurable values ​​such as quantity and temporal duration, it is intended to include variations of ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate for performing the disclosed methods. Where numerical limitations are used, unless otherwise stated in the context, “about” means that the numerical value may vary by ±10%, ±5%, ±4%, ±3%, ±2%, or ±1%, and still remain within the scope of the disclosed embodiments.

[0033] The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed in accordance with the standard rules of chemical bond valency known in the field of chemistry.

[0034] In this specification and the concluding claims, any description of parts by weight of a particular element or component in a composition indicates the weight relationship between that element or component and 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 exist in a weight ratio of 2:5, and this ratio exists regardless of whether further components are present in the compound.

[0035] The weight percentage (W%) of an ingredient is based on the total weight of the preparation or composition containing that ingredient, unless otherwise specified.

[0036] Where used herein, the terms “optional” or “optional” mean that the event or situation described thereafter may or may not occur, and that the description includes both the possibility and the possibility of such event or situation occurring.

[0037] As used herein, the term “diagnosed” means having undergone a physical examination by a person skilled in the art, e.g., a physician, and being found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. In some embodiments of the methods disclosed, the subject has been diagnosed prior to the administration step as needing treatment for a disorder related to PINK1 kinase activity, e.g., neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy. As used herein, phrases such as “identified as needing treatment for a disorder” refer to the selection of a subject based on the need for treatment for a disorder. Identification may, in some embodiments, be performed by a person other than the one making the diagnosis. Furthermore, in further embodiments, administration may be performed by the person who subsequently administers the drug.

[0038] As used herein, the terms “administer” and “dosage” 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, nasal administration, topical administration, vaginal administration, eye drops, ear administration, intracerebral administration, rectal administration, and parenteral administration including injections such as intravenous, intra-arterial, intramuscular, and subcutaneous administration. Administration may be continuous or intermittent. In various embodiments, the preparation may be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the preparation may be administered prophylactically, i.e., administered to prevent a disease or symptom. As used herein, the terms “parenteral administration” and “administered parenterally” mean a form of administration other than intestinal and topical administration, usually by injection, and these terms include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. As used herein, the terms “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean the administration of a compound, drug, or other substance other than direct administration to the central nervous system, such as subcutaneous administration, so that the compound, drug, or other substance enters the patient’s system and therefore undergoes metabolism and other similar processes. In some embodiments, the compound is administered intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intraorbitally, intracardiacly, intradermally, intraperitoneally, transtracheally, subcutaneously, subepidermally, intraarticularly, subcapsularly, subarachnoidally, intraspineally, and intrasternally, or by injection or infusion.

[0039] As used herein, the term “to bring into contact” means bringing a disclosed compound together with a cell, target receptor, or other biological entity in a manner that allows the compound to influence the activity of the target (e.g., a 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] When used herein, "IC 50 " is intended to indicate the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process or its components by 50%, including proteins, subunits, organelles, ribonucleoproteins, etc. In some embodiments, IC is used to indicate the concentration of a substance required to inhibit a biological process or its components by 50%. 50 This may indicate the concentration of the substance required to achieve 50% in vivo inhibition, as further defined elsewhere in this specification.

[0041] When used herein, "EC 50 " is intended to indicate the concentration of a substance (e.g., a compound or drug) that causes a biological process, or a maximum of half of the components of a process, to respond (i.e., 50% of the maximum response), including proteins, subunits, organelles, ribonucleoproteins, etc. In some embodiments, EC 50 This may indicate the concentration of the substance required to achieve 50% of the maximum response in vivo, as further defined elsewhere in this specification.

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

[0043] The “derivatives” of the compounds disclosed herein include pharmaceutically acceptable salts, prodrugs, deuterated forms, radiolabeled forms, isomers, solvates, and combinations thereof. In this context, “combinations” refers to derivatives that are included in 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, etc.

[0044] The term "leaving group" refers to an atom (or group of atoms) that has electron-withdrawing ability and can be replaced as a stable species, taking into account the bonding electrons. Suitable examples of leaving groups include sulfonic acid esters, such as triflates, mesylates, tosylates, brosylates, and halides.

[0045] As used herein, the term “substituted” is intended to include all permissible substituents of an organic compound. In broad embodiments, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of an organic compound. Exemplary substituents are, for example, those listed below. There may be one or more permissible substituents for a given organic compound, and they may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of the organic compounds described herein that satisfy the valence of the heteroatom. This disclosure is by no means intended to limit itself to permissible substituents of organic compounds. Furthermore, the terms “substituted” or “substituted with” imply that such substitution conforms to the permissible valences of the atom being substituted and the substituent, and that the substitution results in a stable compound, such as a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc. Furthermore, in certain embodiments, unless explicitly stated otherwise, it is intended that individual substituents may be further optionally substituted (i.e., either further substituted or unsubstituted).

[0046] In the definition of various terms, "A 1 "A 2 "A 3 ", and "A 4 The symbols 'A' and 'B' are used herein as generic symbols to represent various specific substituents. These symbols are not limited to those disclosed herein and can represent any substituent; in some cases they may be defined as a specific substituent, while in other cases they may be defined as any other substituent.

[0047] As used herein, the terms "halo" and "halogen" refer to atoms selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iod, -I).

[0048] As used herein, the terms “aliphatic” or “aliphatic group” mean a hydrocarbon moiety that may be linear (i.e., unbranched), branched, or cyclic (including condensed, cross-linked, and spiro-condensed polycyclic) and may be fully saturated or contain one or more non-aromatic unsaturated units. Unless otherwise specified, an aliphatic group has 1 to 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched alkyl groups, alkenyl groups, and alkynyl groups, as well as their hybrids, e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0049] As used herein, the term “alkyl” refers to a monovalent saturated linear or branched hydrocarbon radical having 1 to 6 carbon atoms, unless otherwise specified. 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, and 2,3-dimethylbutane. Alkyl groups may be substituted or unsubstituted. For example, alkyl groups may 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. 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 refer to alkyl groups including C1-C24 and below, such as 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, and so on.

[0050] Throughout this specification, “alkyl” is generally used to refer to both unsubstituted and substituted alkyl groups, but substituted alkyl groups are also referred to specifically herein by specifying a particular substituent(s) on the alkyl group. For example, the terms “haloalkyl” or “haloalkyl” specifically refer to an alkyl group substituted with one or more halides, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group substituted with a single halide, e.g., 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 does not have to be the same halide as the other halide substituent, nor do multiple instances of halide substituents have to 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 hydroxyl groups. When "alkyl" is used in one context and a specific term such as "hydroxyalkyl" is used in another, this is not intended to imply that the term "alkyl" does not refer to a specific term such as "hydroxyalkyl."

[0051] This convention also applies to other groups described herein. That is, while terms such as “cycloalkyl” refer to both the unsubstituted and substituted cycloalkyl moieties, these substituted moieties may also be specifically identified herein; for example, certain substituted cycloalkyls may be referred to as, for example, “alkylcycloalkyl.” Similarly, substituted alkoxys may be specifically referred to as, for example, “halogenated alkoxy,” and certain substituted alkenyls may be, for example, “alkenyl alcohols.” Again, the convention of using general terms such as “cycloalkyl” and specific terms such as “alkylcycloalkyl” is not intended to imply that the general terms do not include the specific terms.

[0052] As used herein, the term "alkenyl" refers to a hydrocarbon group having 2 to 24 carbon atoms and having a structural formula containing at least one carbon-carbon double bond. (A 1 A 2 )C=C(A 3 A 4 Asymmetric structures such as ) are intended to include both E and Z isomers. This can be inferred in the structural formulas herein, where an asymmetric alkene is present or may be explicitly indicated by the bond symbol C=C. The alkenyl group may 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.

[0053] As used herein, the term "alkynyl" refers to a hydrocarbon group having 2 to 24 carbon atoms and having a structural formula containing at least one carbon-carbon triple bond. The alkynyl group may be unsubstituted or may 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.

[0054] As used herein, the term “heteroalkyl” refers to an alkyl group having at least one heteroatom. Preferred 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. Heteroalkyls can be substituted as defined above for alkyl groups.

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

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

[0057] A "haloalkoxy" is a haloalkyl group bonded to another part via an oxygen atom, such as -OCHCF2 or -OCF3, but not limited to these.

[0058] The term "9-10 membered carbocyclyl" refers to saturated or partially unsaturated 9- or 10-membered monocyclic, bicyclic (e.g., bridged or spiro-dicyclic rings), polycyclic (e.g., tricyclic), or condensed hydrocarbon ring systems. The term "9-10 membered carbocyclyl" also includes saturated or partially unsaturated hydrocarbon rings (e.g., dihydroindenyl and tetrahydronaphthalenyl) condensed with one or more aromatic or partially saturated hydrocarbon rings. Examples of bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo[4.3.1]decanyl. Examples of spiro-dicyclic cycloalkyl groups include spiro[3.6]decanyl, spiro[4.5]decanyl, and spiro[4.4]nonyl. Examples of condensed cycloalkyl rings include decahydronaphthalenyl, dihydroindenyl, decahydroazlenyl, octahydroazlenyl, and tetrahydronaphthalenyl. Naturally, if specified, optional substituents on the carbocyclyl (e.g., in the case of an optionally substituted cycloalkyl) may be located at any substitutable position, including, for example, the position to which the carbocyclyl group is attached.

[0059] As used herein, the term “cycloalkyl” 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, and norbornyl. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above and is included in the meaning of the term “cycloalkyl,” where at least one of the carbon atoms in the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkyl groups and heterocycloalkyl groups may be substituted or unsubstituted. Cycloalkyl groups and heterocycloalkyl groups may 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 groups, as described herein. In various embodiments, cycloalkyl groups and heterocycloalkyl groups may be monocyclic, bicyclic (e.g., crosslinked 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 condensed hydrocarbon ring systems (e.g., decahydronaphthalenyl, dihydroindenyl, decahydroazlenyl, octahydroazlenyl, tetrahydronaphthalenyl).

[0060] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbon-carbon ring consisting 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, and norbornenyl. The term "heterocycloalkenyl" is a type of cycloalkenyl group as defined above and is included in the meaning of the term "cycloalkenyl," where at least one of the carbon atoms in the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkenyl and heterocycloalkenyl groups may be substituted or unsubstituted. Cycloalkenyl and heterocycloalkenyl groups may 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 groups, as described herein.

[0061] As used herein, the term "cycloalkynyl" refers to a non-aromatic carbon-carbon ring consisting 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, cyclooctinyl, and cyclononinyl. The term "heterocycloalkynyl" is a type of cycloalkenyl group as defined above and is included in the meaning of the term "cycloalkynyl," where at least one of the carbon atoms of the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus. Cycloalkynyl and heterocycloalkynyl groups may be substituted or unsubstituted. Cycloalkynyl and heterocycloalkynyl groups may 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 “heterocyclic” or “heterocyclyl” are interchangeable and refer to monocyclic and polycyclic aromatic or non-aromatic ring systems in which at least one of the ring members is not carbon. Therefore, the terms include, but are not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocyclic,” and “polycyclic heterocyclic.” Heterocyclics can be saturated or partially saturated monocyclic, bicyclic (e.g., spiro or bridging), polycyclic, or fusion systems. Heterocyclic compounds 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, and triazine (including 1,2,4-triazine and 1,3,5-triazine). This includes tetrazine (including 1,2,4,5-tetrazine), pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, etc. The term heterocyclyl group can also refer to heterocyclyls containing C2-C18 or less, such as 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, etc. For example, C2 heterocyclyls include, but are not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxyranil, thyranil, etc., and include groups having two carbon atoms and at least one heteroatom.Alternatively, for example, C5 heterocyclyls include, but are not limited to, piperidinyl, tetrahydropyranil, tetrahydrothiopyranil, diazepanil, and pyridinyl, and include groups having five carbon atoms and at least one heteroatom. It should be understood that heterocyclyl groups may be bonded either by heteroatoms within the ring or by one of the carbon atoms comprising the heterocyclyl ring, where chemically possible.

[0063] As used herein, the terms “bicyclic heterocyclic” or “bicyclic heterocycline” refer to a ring system in which at least one of the ring members is not carbon. Bicyclic heterocyclines include ring systems in which an aromatic ring is fused with another aromatic ring, or an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclines include ring systems in which a benzene ring is fused with a five-membered or six-membered ring having one, two, or three ring heteroatoms, or a pyridine ring is fused with a five-membered or six-membered ring having one, two, or three ring heteroatoms. Examples of 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-benzodioxynyl, 3,4-dihydro-2H-clomenyl, 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] As used herein, the term “heterocycloalkyl” refers to aliphatic, partially unsaturated, or fully saturated 3- to 14-membered ring systems, including monocyclic, bicyclic, and tricyclic ring systems having 3 to 8 atoms. Heterocycloalkyl ring systems contain 1 to 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur, where the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may 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 condensed heterocyclyl” means a 9-membered saturated or partially unsaturated condensed monocyclic heterocyclic ring containing at least one oxygen heteroatom and, optionally, 2 to 4 further heteroatoms independently selected from N, O, and S. The terms “heterocyclic ring,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used synonymously herein. The heterocyclyl ring may be bonded to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of condensed saturated or partially unsaturated heterocyclic radicals containing at least one oxygen atom include, but are not limited to, dihydrobenzofuranyl, dihydrophlopyridinyl, and octahydrobenzofuranyl. Where there is a designation of optionally substituted, substituents on the heterocyclyl (e.g., in the case of optionally substituted heterocyclyls) may be located at any substitutable position, including, for example, the position to which the heterocyclyl group is bonded.

[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 consideration of aromaticity can be found in Morrison and Boyd, Organic Chemistry (5th Ed., 1987) (Chapter 13, titled “Aromaticity,” pp. 477-497), incorporated herein by reference. The term “aromatic group” includes both aryl and heteroaryl groups.

[0067] As used herein, the term “aryl” refers to any carbon-based aromatic group, including but not limited to benzene, naphthalene, phenyl, biphenyl, and anthracene. Aryl groups may be substituted or unsubstituted. Aryl groups may be substituted with one or more groups, including but not limited to alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, -NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein. The term “biaryl” refers to a specific type of aryl group and is included in the definition of “aryl.” In addition, aryl groups may include multiple ring structures, which may be a single ring structure, a fused ring structure, or linked via one or more bridging groups such as carbon-carbon bonds. For example, a biaryl may be two aryl groups linked together via a fused ring structure, similar to naphthalene, or linked via one or more carbon-carbon bonds, similar to biphenyl.

[0068] As used herein, the term “heteroaryl” refers to an aromatic group in which at least one heteroatom is incorporated into the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, and N-oxides, sulfur oxides, and dioxides are acceptable heteroatom substitutions. Heteroaryl groups may be substituted or unsubstituted. Heteroaryl groups may 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 groups, as described herein. Heteroaryl groups may be monocyclic or fused ring systems. Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinil, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridadinyl, pyrazinyl, benzofuranil, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyridinyl. Further non-limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyradinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyradinyl.

[0069] The term "5-membered or 6-membered heteroaryl" refers to a 5-membered 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, and pyrazinyl. Where specified, optional substituents on the heteroaryl group may be located at any substitutable position, including, for example, the position to which the heteroaryl is bonded.

[0070] As used herein, the term “aldehyde” is represented by the formula -C(O)H. Throughout this specification, “C(O)” is a simple notation for the carbonyl group, i.e., C=O.

[0071] As used herein, the terms "amine" or "amino" refer to formula -NA 1 A 2 It is expressed as, in the formula, A 1 and A 2 This can independently be hydrogen, or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of an amino is -NH2.

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

[0073] As used herein, the term "dialkylamino" is represented by the formula -N(-alkyl)2, where alkyl is one of the alkyl groups defined herein. Typical examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, and N-ethyl-N-propylamino group.

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

[0075] As used herein, the term "ester" refers to the formula -OC(O)A 1 or -C(O)OA 1 It is expressed as, in the formula, A 1 This may be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term "polyester" as used herein refers to the formula -(A 1 O(O)CA 2 -C(O)O) a -or-(A 1 O(O)CA 2 -OC(O)) a - is represented by, in the formula, A 1 and A 2 can independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, where "a" is an integer from 1 to 500. "Polyester" is a term used to describe a group produced by a 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 Formula A1 OA 2 It is expressed as, in the formula, A 1 and A 2 These may independently be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groups as described herein. As used herein, the term "polyether" refers to a group of the formula -(A 1 OA 2 O) a - is represented by, in the formula, A 1 and A 2 can independently be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein, where "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 include “optionally substituted” moieties. Generally, the term “substituted” means that one or more hydrogens of a given moiety are replaced with preferred substituents, whether preceded by the term “optionally.” Unless otherwise specified, an “optionally substituted” group may have preferred substituents at each of its substituted positions, and if it is substituted at two or more positions in any given structure by two or more substituents selected from the given group, the substituents may be the same or different at each position. The substituent combinations envisioned by the present invention preferably result in the formation of stable compounds or chemically feasible compounds. Furthermore, in certain embodiments, unless otherwise expressly denied, 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: TIFF2026067907000068.tif22165 This is understood to be equivalent to the following expression: In the formula TIFF2026067907000069.tif32165, n is typically an integer. That is, R n It has five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) It is understood that this represents the following. In each of these cases, the five R's n Each of these can be a hydrogen atom or one of the listed substituents. "Independent substituents" means that each R substituent can be defined independently. For example, in one case R n(a) If R is a halogen, n(b) In that particular case, it wasn't necessarily a halogen.

[0079] In some further embodiments, the structure of the compound can be represented by the following formula: TIFF2026067907000070.tif27165 formula, R y For example, A 1 , A 2 , and A 3 These represent 0 to 2 independent substituents selected from the following, and these formulas are understood to be equivalent to the following group of formulas. TIFF2026067907000071.tif43165TIFF2026067907000072.tif43165TIFF2026067907000073.tif93165

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

[0081] In some further embodiments, the structure of the compound can be represented by the following formula: In formula TIFF2026067907000074.tif32165, for example, Q comprises three substituents independently selected from hydrogen and A, which is understood to be equivalent to the following formula: TIFF2026067907000075.tif32165

[0082] In this case as well, "independent substituents" are defined as each Q substituent being independently defined as hydrogen or A, and this formula is understood to be equivalent to the group of formulas below. TIFF2026067907000076.tif64165

[0083] In some embodiments, the disclosed compounds exist as geometric isomers. “Geometric isomer” refers to isomers with different orientations of substituent atoms in relation to the cycloalkyl ring, i.e., cis isomers or trans isomers. If a disclosed compound is named or represented without indicating a specific cis or trans geometric isomer, it should be understood that the name or structure encompasses one geometric isomer, without including other geometric isomers, mixtures of geometric isomers, or mixtures that are richer in one geometric isomer than in their corresponding geometric isomers. When a specific geometric isomer, i.e., cis or trans, is indicated, the indicated isomer is at least about 60% by weight, 70% by weight, 80% by weight, 90% by weight, 99% by weight, or 99.9% by weight pure compared to the other geometric isomers.

[0084] The compounds described herein may exist in the form of pharmaceutically acceptable salts. When used in pharmaceuticals, salts of the compounds described herein refer to non-toxic “pharmaceutically acceptable salts.” As described above, the compounds of the present invention can be administered, in particular, 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 reacting the purified compounds separately with suitable organic or inorganic bases or acids in the form of their free bases or acids, and then isolating the salts thus formed. Typical 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 lauryl sulfonate. Salts may include, but are not limited to, 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 such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. See, for example, SMBerge, 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 include C5-C7 cycloalkyl esters, as well as arylalkyl 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 also be in the form of a five-membered or six-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 acids, or magnesium.

[0086] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound being formulated together. Examples of 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, buffering substances such as phosphates, saturated vegetable fatty acids such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, water, salts, or partial glyceride mixtures of electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0087] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form suitable for use in contact with human and animal tissues, within the bounds of safe medical judgment. In some embodiments, “pharmaceutically acceptable” means being approved by a federal or state regulatory agency, or being listed in the United States Pharmacopeia, or any other pharmacopoeia generally recognized for use in animals, and more specifically, in humans.

[0088] Disease, disorder, and condition are used synonymously in this specification.

[0089] As used herein, the terms “treatment,” “to treat,” and “to treat” mean to reverse, alleviate, delay the onset of, or inhibit the progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment may be administered after the onset of one or more symptoms, 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 before the onset of symptoms (e.g., considering a history of symptoms and / or exposure to a particular organism or other susceptibility factor), i.e., prophylactic treatment. Treatment may also be continued after the resolution of symptoms, for example, to delay their recurrence.

[0090] As used herein, the terms “prevent” or “prevention” mean making something impossible, avoiding, preventing, stopping, halting, or hindering the occurrence of something, particularly through prior action. Naturally, when “mitigate,” “suppress,” or “prevent” are used herein, the use of the other two terms is also explicitly disclosed unless otherwise stated. The term “prevention” means preventing the occurrence of a disease, disorder, or condition in a person or animal that may have a predisposition to such a disease, disorder, or condition but has not yet been diagnosed with one.

[0091] The term “effective dose” or “therapeutic effective dose” refers to a quantity sufficient to achieve a desired outcome (e.g., a quantity that elicits a biological or medical response in the subject; e.g., a dosage of 0.01–100 mg / kg body weight / day) or sufficient to have an effect on an undesirable condition. For example, “therapeutic effective dose” refers to a quantity sufficient to achieve a desired therapeutic outcome or sufficient to have an effect on an undesirable symptom. In some embodiments, “therapeutic effective dose” refers to a quantity that is sufficient to achieve a desired therapeutic outcome or sufficient to have an effect on an undesirable symptom, but is generally insufficient to cause adverse side effects. The specific therapeutic effective dose level for any particular patient will depend on various factors, including the disorder being treated and its severity; the specific composition used; the patient’s age, weight, overall health, sex, and diet; the time of administration; the route of administration; the elimination rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and other factors well known in the pharmaceutical field. For example, it is well within the scope of the art to start administration of a compound at a level lower than necessary to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. If desired, an effective daily dose can be divided into multiple doses for the purpose of administration. Thus, a single-dose composition may contain the amount that constitutes a daily dose, or a divided amount thereof. The dosage is adjustable by the individual physician in the event of any contraindications. The dosage is modifiable and is administered once or more times a day over a day or several days. Guidelines can be found in the literature on appropriate dosages for a given class of pharmaceutical products. In various further embodiments, the preparation may be administered in a “preventive effective dose,” i.e., an amount effective for the prevention of a disease or condition.

[0092] As used herein, the term “salt” refers to an acid salt or base salt of a compound used in the methods of this 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 compounds (such as methyl iodide and ethyl iodide).

[0093] The terms “subject” and “patient” may be used synonymously and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). In some embodiments, the subject is a human being in need of treatment. In some embodiments, “patient” or “subject in need” refers to an 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, bovines, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and non-mammalian animals. In some embodiments, the patient is a human being.

[0094] The terms "associated" or "associated with" mean, 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), that the disease (e.g., cardiomyopathy, a neurodegenerative disease, or Parkinson's disease) is caused (in whole or in part) by the substance or the activity or function of a substance, or that the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of a substance. For example, symptoms of a disease or condition associated with a decreased PINK1 activity level may be symptoms that are (in whole or in part) caused by a decreased PINK1 activity level (e.g., a functional mutation or gene deletion or regulation of the PINK1 signaling pathway). As used herein, what is described as associated with a disease may be a therapeutic target of the disease if it is the causative substance. For example, a disease associated with PINK1 may be treated with an agent (e.g., a compound described herein) that is effective in increasing the activity level of PINK1.

[0095] The terms "control" or "controlled experiment" are used according to their simple, ordinary meaning, referring to an experiment in which the subject or reagents of the experiment are treated as a parallel experiment, except for the omission of experimental procedures, reagents, or variables. In some cases, the control is used as a criterion for comparison in the evaluation of experimental effects.

[0096] "Contacting" is used in its plain, ordinary sense and refers to a process that allows at least two distinct species (e.g., chemical compounds containing biomolecules, or cells) to come close enough to react, interact, or physically touch. However, it should be understood that the resulting reactive organism may be produced directly from the reaction of the added reagents, or from intermediates derived from one or more of the added reagents that may be produced in the reaction mixture. The term "contacting" may also include causing two species to react, interact, or physically touch, and these two species may be the compounds and proteins or enzymes described herein (e.g., PINK1). In some embodiments, contacting includes causing the compounds described herein to interact with proteins or enzymes involved in a signaling pathway.

[0097] As defined herein, terms such as “inhibition,” “to inhibit,” and “to inhibit” in relation to the interaction between a protein and an inhibitor (e.g., an antagonist) mean that the inhibitor negatively affects (e.g., reduces) the activity or function of the protein compared to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to the alleviation of a disease or the symptoms of a disease. In some embodiments, inhibition refers to a reduction in the activity of a signaling pathway or signaling pathway. Thus, inhibition includes, at least in part, partially or completely blocking a stimulus, reducing, preventing or delaying activation, or inactivating, desensitizing or downregulating signaling or enzyme activity or the amount of a protein.

[0098] The symbol TIFF2026067907000077.tif4128 represents a bond point between a chemical part and the rest of a molecule or chemical formula.

[0099] As defined herein, terms such as “activation,” “to activate,” and “to activate” in relation to the interaction between a protein and an activator (e.g., an agonist) mean that the activity or function of a protein (e.g., PINK1) has a positive effect (e.g., increases) compared to the activity or function of the protein in the absence of the activator (e.g., a compound described herein). In several embodiments, activation refers to an increase in the activity of a signaling pathway or signaling pathway (e.g., the PINK1 pathway). Thus, activation may include, at least in part, increasing a stimulus partially or entirely, increasing or enabling activation, or activating, sensitizing, or upregulating reduced signaling or enzyme activity or protein levels in a 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 partially, increasing a stimulus, 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 may 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 or function of a target molecule. In some embodiments, the modulator is a PINK1 modulator. In some embodiments, the modulator is a PINK1 modulator and is a compound that reduces the severity of one or more symptoms of a PINK1-related disease (e.g., by reducing the level of PINK1 activity or protein associated with neurodegenerative diseases such as cardiomyopathy or Parkinson's disease). In some embodiments, the modulator is a compound that reduces the severity of one or more symptoms of a cardiomyopathy or neurodegenerative disease, which are not caused by or characterized by PINK1 (e.g., loss of PINK1 function), but in which the modulation of PINK1 activity (e.g., an increase in PINK1 levels or PINK1 activity levels) may be effective.

[0101] "Disease" or "condition" means a condition or health state of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. In some embodiments, the disease is a disease associated with (e.g., characterized by) a decrease in PINK1 levels. In some embodiments, the disease is a disease characterized by the loss of dopamine-producing cells (e.g., Parkinson's disease). In some embodiments, the disease is a disease characterized by neurodegeneration. In some embodiments, the disease is a disease characterized by neuronal cell death. In some embodiments, the disease is a disease characterized by a decrease in PINK1 activity levels. In some embodiments, the disease is Parkinson's disease. In some embodiments, the disease is a neurodegenerative disease. In some embodiments, the disease is cardiomyopathy.

[0102] As used herein, the term “cardiomyopathy” refers to a condition that adversely affects cardiac cell tissue, resulting in a measurable deterioration of myocardial function (e.g., systolic and diastolic function). Dilated cardiomyopathy is characterized by ventricular enlargement without hypertrophy, accompanied by systolic dysfunction. Hypertrophic cardiomyopathy is a genetic disorder transmitted as an autosomal dominant trait. Morphologically, hypertrophic cardiomyopathy is characterized by a hypertrophied left ventricle without dilation. Restrictive cardiomyopathy is characterized by ventricular filling impairment due to reduced ventricular volume, although it is morphologically neither dilated nor hypertrophied. Arrhythmogenic right ventricular cardiomyopathy is a hereditary heart disorder characterized by electrical instability of the myocardium. Unclassifiable cardiomyopathy is a category of cardiomyopathy that does not conform to the characteristics of any of the other types. Unclassifiable cardiomyopathy may have characteristics of multiple types, or it may have, for example, fibroelasticity, impaired noncompaction, or systolic dysfunction with only slight dilation.

[0103] As used herein, the term “neurodegenerative disease” refers to a disease or condition in which the function of the nervous system in question is impaired. Examples of neurodegenerative diseases that can be treated with the compounds or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia with capillary dilatation, 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-Strömming syndrome. Isra-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Kuru, Leigh disease (Leigh syndrome), Lewy body dementia, Machad-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 disease, Refsum disease, Sandhoff disease, Schilder's disease, Shy-Drager syndrome, subacute combined spinal cord disease secondary to pernicious anemia Degeneration, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olsewski disease, spinal fistula, 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 Lewy body parkinson's disease type 3 (PARK3), autosomal dominant Lewy body parkinson's disease type 4 (PARK4), parkinson's disease type 5 (PARK5) Examples include autosomal recessive early-onset Parkinson's disease type 6 (PARK6), autosomal recessive juvenile-onset 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 several embodiments, autonomic dysfunction is not a neurodegenerative disease.

[0104] As used herein, the term “signaling pathway” refers to a series of interactions between cellular and, optionally, extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) in which a change in one component can be transmitted to one or more other components, which in turn can transmit the change to further components, and this change can be propagated, optionally, to other signaling pathway components.

[0105] The term "preparation" is intended to include formulations of an active compound and an encapsulating material acting as a carrier, in which the active ingredient (with or without other carriers) is surrounded by the carrier and associated with it, forming a capsule. Similarly, cachets and lozenges are 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 “administer” means any form of administration including oral administration, suppository administration, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intrafocal, subarachnoid, intracranial, intranasal, or subcutaneous administration, or implantation of a sustained-release device, such as a small osmotic pump. Administration may be by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, transnasal, vaginal, rectal, or transdermal). Parenteral administration may include, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Other modes of delivery may include, but are not limited to, the use of liposomal formulations, intravenous injection, or transdermal patch. "Concurrent administration" means that the compositions described herein are administered simultaneously with, immediately before, or immediately after, the administration of one or more further therapies (e.g., cardiomyopathy therapy, e.g., angiotensin-converting enzyme inhibitors (e.g., enalipril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan), beta-blockers (e.g., Lopressor, Toprol-XL), digoxin, etc., or diuretics (e.g., Lasix; or Parkinson's disease therapy, e.g., levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, pyribezil, cabergoline, apomorphine, rislid), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, antipsychotics (e.g., clozapine), cholinesterase inhibitors, modafinil, or nonsteroidal anti-inflammatory drugs).

[0107] The compounds of this disclosure may be administered to a patient alone or concurrently. Concurrent administration is intended to include concurrent or sequential administration of individual or combined (two or more compounds or drugs) compounds. Accordingly, preparations may also be combined with other active substances (e.g., to reduce metabolic degradation) if desired. The compositions of this disclosure may be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, coatings, powders, and aerosols and delivered transdermally or via topical routes. Oral preparations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, and suspensions suitable for ingestion by patients. 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 this disclosure may further include components for providing sustained release and / or comfort. Such components include high molecular weight anionic mucous polymers, gelling polysaccharides, and micronized drug carrier substrates. These components are discussed in more detail in U.S. Patents 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for any purpose. The compositions of this disclosure may also be delivered to the body as sustained-release microspheres. For example, microspheres can be administered by intradermal injection of drug-containing microspheres that are released subcutaneously (see Rao, J. Biomator Sci. Polym. Ed. 7:623-645, 1995), as a biodegradable injectable gel formulation (see, for example, Gao Pharm. Res. 12:857-863, 1995), or as orally administered microspheres (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997).In several embodiments, formulations of the compositions of the present disclosure can be delivered by the use of liposomes that fuse with the cell membrane or are endocytosizable, i.e., by using receptor ligands bound to liposomes that bind to cell surface membrane protein receptors and result in endocytosis. By using liposomes, in particular, the delivery of the compositions of the present disclosure can be concentrated to target cells in vivo, especially when the liposome surface has a target cell-specific receptor ligand or is otherwise preferentially directed to a particular organ. (See, for example, 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 compositions of the present disclosure can also be delivered as nanoparticles.

[0108] The pharmaceutical compositions provided herein include compositions containing an active ingredient (e.g., a compound described herein, including embodiments or examples) in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular use depends, among other things, on the condition being treated. When administered in a method of treating a disease, such compositions will contain an amount of the active ingredient effective to achieve the desired result, e.g., modulation of the activity of a target molecule (e.g., PINK1), and / or reduction, elimination, or slowing of the progression of symptoms of the disease (e.g., symptoms of cardiomyopathy or neurodegenerative disease, e.g., symptoms of Parkinson's disease). Determining the therapeutically effective amount of the compounds of this disclosure is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosure herein.

[0109] The dosage and frequency (single or multiple doses) administered to mammals may vary depending on various factors, such as whether the mammal has another disease and the route of administration; the recipient's size, age, sex, health status, weight, body type index, and diet; the nature and severity of the symptoms of the disease being treated (e.g., symptoms of neurodegenerative diseases such as cardiomyopathy or Parkinson's disease, and the severity of such symptoms), the type of concomitant therapy, complications arising from the disease being treated, or other health-related problems. Other treatment regimens or therapeutic agents may be used in combination with the methods and compounds disclosed by the applicant. Adjustments and manipulations of established dosages (e.g., frequency and duration) are well within the capabilities of those skilled in the art.

[0110] For any of the compounds described herein, the therapeutically effective dose can first be determined by a cell culture assay. The target concentration is the concentration of the active compound(s) that can achieve the method described herein when measured using the methods described herein or known in the art.

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

[0112] Dosage may vary depending on the patient and the requirements of the compound used. In relation to this disclosure, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response over time. The magnitude of the dose will also be determined by the presence, nature, and severity of adverse side effects. Determining the appropriate dosage for a particular situation is within the scope of the physician's skill. Generally, treatment is initiated with a small dose, less than the optimal dose of the compound. The dose is then gradually increased until the optimal effect is achieved under those circumstances.

[0113] The dosage and interval of administration can be individually adjusted to deliver levels of the administered compound that are effective for the specific clinical symptoms being treated. This provides a treatment regimen that is tailored to the severity of the individual's condition.

[0114] Using the teachings provided herein, effective prophylactic or therapeutic regimens can be planned that are substantially non-toxic and effective in treating clinical symptoms observed in specific patients. This planning must involve careful selection of the active compound, taking into account factors such as the compound's potency, relative bioavailability, patient weight, presence and severity of adverse side effects, preferred administration method, and the toxicity profile of the chosen drug.

[0115] The compounds described herein may be used in combination with other activators known to be useful in the treatment of disease-related neurodegeneration (e.g., Parkinson's disease agents such as levodopa, dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, pyribezil, cabergoline, apomorphine, rislid), MAO-B inhibitors (e.g., selegiline or rasagiline), amantadine, anticholinergics, schizophrenia agents (e.g., clozapine), cholinesterase inhibitors, modafinil, or nonsteroidal anti-inflammatory drugs), or in combination with adjuvants that may not be effective on their own but may contribute to the efficacy of the activators.

[0116] The compounds described herein may be used in combination with other activators 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), disease-related neurodegenerative agents (e.g., Parkinson's disease agents), such as levodopa, dopamine agonists, etc. For example, it may be used in combination with bromocriptine, pergolide, pramipexole, ropinirole, pyribezil, cabergoline, apomorphine, rislide), 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 adjuvants that may not be effective on their own but may contribute to the efficacy of the activator.

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

[0118] "PINK1" is used according to its general and common meaning and refers to proteins of the same or similar name, as well as their functional fragments and homologs. The term includes recombinant or spontaneous 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 its variants that maintain PINK1 activity (e.g., activity within at least approximately 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to PINK1).

[0119] The term "neosubstrate" refers to a composition that is structurally similar to, but distinctly different from, the composition that serves as the substrate for the protein or enzyme when the protein or enzyme performs its normal function. In some embodiments, the composition contains a neosubstrate. In several embodiments, the neosubstrate is a better substrate than the normal substrate for the protein or enzyme (e.g., good reaction kinetics (e.g., fast), strong binding, high turnover, high reaction productivity, equilibrium state favorable for product formation). In several embodiments, the neosubstrate is a derivative of adenine, adenosine, AMP, ADP, or ATP. In several embodiments, the neosubstrate is a substrate for PINK1. In several embodiments, the neosubstrate is N6-substituted adenine, adenosine, AMP, ADP, or ATP.

[0120] The term “derivative” applied to a monophosphate, diphosphate, or triphophosphate group or moiety containing a phosphate indicates a chemical modification of such group, which may include the addition, removal, or substitution of one or more atoms of the monophosphate, diphosphate, or triphophosphate group or moiety containing a phosphate. In several embodiments, such derivatives are prodrugs of a phosphate-containing, monophosphate, diphosphate, or triphosphate group or moiety, which are converted from the derivative to a phosphate-containing, monophosphate, diphosphate, or triphosphate group or moiety after administration to a subject, patient, cell, biological sample, or after 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 several embodiments, derivatives of monophosphate, diphosphate, or triphopherate groups or portions containing phosphates include 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. Examples such as those described in 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 usual meaning and refers to abnormal activity or function of mitochondria, 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 within the mitochondrial membrane, and / or mitochondrial membrane permeability transitions.

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

[0123] The term "oxidative stress" is used according to its usual meaning and refers to an abnormal level of reactive oxygen species.

[0124] As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates, such as wild animals, domesticated animals, and livestock.

[0125] As used herein, the terms “antagonize” or “antagonize” mean reducing or completely eliminating the effect, such as the activity of GPR109a.

[0126] As used herein, the term “anti-receptor effective dose” of a compound is one that can be measured by the anti-receptor efficacy of the compound. In some embodiments, the anti-receptor effective dose 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, the “anti-receptor effective dose” is also the “therapeutic effective dose,” by which the compound reduces or eliminates at least one effect of GPR109a. In some embodiments, the effect is the B-arrestin effect. In some embodiments, the effect is the G protein-mediated effect.

[0127] As used herein, the term “carrier” means a diluent, adjuvant, or excipient administered with the compound. Pharmaceutical carriers may be liquids, such as water, and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, or sesame oil. Pharmaceutical carriers may also be saline solution, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, or urea. Furthermore, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may 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”) are inclusive, or open, and do not exclude any additional elements or method steps not enumerated.

[0129] As used herein, the term “contact” means bringing two elements together in vitro or in vivo. For example, “contact” the compounds disclosed herein with an individual, patient, or cells includes, in addition to administering the compounds to an individual or patient such as a human, introducing the compounds into a sample containing a cell preparation or purified preparation containing the compounds or pharmaceutical compositions disclosed herein.

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

[0131] As used herein, the phrase “needs it” means that an animal or mammal is identified as needing a particular method or treatment. In some embodiments, identification may be by any diagnostic means. In any of the methods and treatments described herein, an animal or mammal may need it. In some embodiments, an animal or mammal is in or will be in 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 including both endpoints. 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 isolated, for example, by prior art, 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 rodents (i.e., mice, rats, or guinea pigs), monkeys, cats, dogs, cattle, horses, pigs, or humans. In some embodiments, the mammal is a human.

[0135] As used herein, the term “prodrug” means a derivative of a known direct-acting drug that has enhanced delivery properties and therapeutic value compared to the 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 modification is cleaved either by conventional methods or in vivo to form the parent compound. Examples of prodrugs include the compounds of this disclosure described herein that contain one or more molecular moieties attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, which are cleaved in vivo upon administration to a patient to form free hydroxyl, amino, sulfhydryl, or carboxyl groups, respectively. Examples of prodrugs include, but are not limited to, acetic acid derivatives, formic acid derivatives, and benzoic acid derivatives of alcohol and amine functional groups in the compounds of this disclosure. The preparation and use of prodrugs are described in T. Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACSSymposium 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 entirety.

[0136] As used herein, the term “purified” means that when an isolate is isolated, it contains at least 90%, at least 95%, at least 98%, or at least 99% of the compounds described herein by weight.

[0137] As used herein, the term "solubilizer" means an agent that results in the formation of a micelle or true solution of a drug.

[0138] As used herein, the term “solution / suspension” means a liquid composition in which a first portion of the activator is dissolved and a second portion of the activator is suspended in a liquid matrix in the form of particulate matter.

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

[0140] As used herein, the term “therapeutic dose” means the amount of an active compound or drug that elicits a desired biological or pharmacological response in a tissue, system, animal, individual, or human, as determined by a researcher, veterinarian, physician, or other clinician. The therapeutic effect depends on the disorder being treated or the desired biological effect. Thus, the therapeutic effect may 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, a cure, prevention or elimination of the disorder or side effects. The amount required to elicit a therapeutic response may be determined based on the age, health status, size, and sex of the subject. The optimal amount may also be determined based on monitoring the subject's response to treatment.

[0141] Naturally, certain features described herein, while explained in relation to separate embodiments for clarity, can also be provided in combination as a single embodiment. Conversely, various features, while explained in relation to a single embodiment for conciseness, can also be provided separately or in any preferred partial combination.

[0142] It should be noted that in any embodiment of the present invention, one or more embodiments may be arbitrarily excluded for the purpose of asserting rights to the subject matter of the invention.

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

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

[0145] In various embodiments, the compound is useful for treating disorders related to PINK1 kinase activity in mammals. In a further embodiment, the compound is useful for treating PINK1 kinase activity in humans.

[0146] It is intended that each of the disclosed derivatives may be further substituted at will. It is also intended that one or more derivatives may be optionally omitted from the present invention. It is understood that the disclosed compounds may be provided by the disclosed method. It is also understood that the disclosed compounds may be used in the disclosed uses.

[0147] 1. Structure In some embodiments, the structure is represented by the following formula: A compound having TIFF2026067907000078.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11aand R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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, substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14 However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4 However, compounds selected from hydrogen and C1-C4 alkyl groups, or pharmaceutically acceptable salts thereof, are provided. In further embodiments, R 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 halogens, -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, and R 4 It is hydrogen.

[0148] In some embodiments, the structure is represented by the following formula: A compound having TIFF2026067907000079.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12, or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it 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 halogens, -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, and R 3The provided compounds, or pharmaceutically acceptable salts thereof, are 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl.

[0149] In some embodiments, the structure is represented by an expression selected from the following: A compound having TIFF2026067907000080.tif42165 is provided.

[0150] In some embodiments, the structure is represented by an expression selected from the following: A compound having TIFF2026067907000081.tif42165 is provided.

[0151] In some embodiments, the following structure: A compound having TIFF2026067907000082.tif48165, or a pharmaceutically acceptable salt thereof, is provided.

[0152] In some embodiments, the structure is represented by the following formula: A compound having TIFF2026067907000083.tif48165, or a pharmaceutically acceptable salt thereof, is provided.

[0153] In some embodiments, the structure is represented by the following formula: A compound having TIFF2026067907000084.tif48165, or a pharmaceutically acceptable salt thereof, is provided.

[0154] In some embodiments, the structure is represented by an expression selected from the following: A compound having TIFF2026067907000085.tif48165, or a pharmaceutically acceptable salt thereof, is provided.

[0155] In some embodiments, the structure is represented by an expression selected from the following: A compound having TIFF2026067907000086.tif48165, or a pharmaceutically acceptable salt thereof, is provided.

[0156] In some embodiments, the compound is selected from the following: TIFF2026067907000087.tif183165TIFF2026067907000088.tif223165.

[0157] In some embodiments, the compound is selected from the following: TIFF2026067907000089.tif188165TIFF2026067907000090.tif235165.

[0158] In some embodiments, the compound is selected from the following: TIFF2026067907000091.tif175165TIFF2026067907000092.tif212165.

[0159] In some embodiments, the compound is selected from the following: TIFF2026067907000093.tif175165TIFF2026067907000094.tif173165TIFF2026067907000095.tif93165.

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

[0161] Therefore, in some embodiments, m is 0 or 1. In further embodiments, m is 0. In even further embodiments, m is 1.

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

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

[0164] aQ 1 Base and Q 2 base In some embodiments, Q 1 and Q 2 Each is independently N or CH. In a further embodiment, Q 1 and Q 2 Each of these is CH. In further embodiments, Q 1 and Q 2 Each of these is N. In yet another embodiment, Q 1 is N and Q 2 is CH. In yet another embodiment, Q 1 CH is Q 2 It is N.

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

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

[0167] bQ 3 base In some embodiments, Q 3 is CH2 or NH. In further embodiments, Q 2 This is CH2. In further embodiments, Q 2 It is NH.

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

[0169] In some embodiments, Z is CR 11a R 11b Or O. In further embodiments, Z is CR 11a R 11b In further embodiments, Z is CH2. In yet another embodiment, Z is O.

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

[0171] dR 1A Group, R 1B Group, R 1C Base, and R 1D Group (R 1 basis) In some embodiments, R 1a , R 1b , R 1c , and R 1dEach is independently selected from hydrogen, 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. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is 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, ethox Selected from C, n-propoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH(CH3)CH2F, -OCH2CH2CH2F, -OCCl3, -OCHCl2, -OCH2Cl, -OCH2CH2Cl, -OCH(CH3)CH2Cl, -OCH2CH2CH2Cl, -NHCH3, -NHCH2CH3, -NHCH(CH3)CH3, -NHCH2CH2CH3, -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH(CH3)CH3, and -N(CH3)CH2CH2CH3. In further embodiments, R 1a , R 1b , R 1c , and R 1dEach is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, methyl, ethyl, ethenyl, -CH2F, -CH2CH2F, -CH2Cl, -CH2CH2Cl, -CH2CN, -CH2CH2CN, -CH2OH, -CH2CH2OH, methoxy, ethoxy, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCCl3, -OCHCl2, -OCH2Cl, -OCH2CH2Cl, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH3)CH2CH3. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, methyl, -CH2F, -CH2Cl, -CH2CN, -CH2OH, methoxy, -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2, -OCH2Cl, -NHCH3, and -N(CH3)2.

[0172] In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of them is hydrogen.

[0173] In various embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In further embodiments, R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -CH2OH, -CH2CH2OH, -CH(CH3)CH2OH, -CH2CH2CH2OH, methoxy, ethoxy, n-propoxy, isopropoxy, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCH(CH3)CH2F, -OCH2CH2CH2F, -OCCl3, -OCHCl2, -OCH2Cl, -OCH2CH2Cl, -OCH(CH3)CH2Cl, and -OCH2CH2CH2Cl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -CH2OH, -CH2CH2OH, methoxy, ethoxy, -OCF3, -OCHF2, -OCH2F, -OCH2CH2F, -OCCl3, -OCHCl2, -OCH2Cl, and -OCH2CH2Cl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -CH2OH, methoxy, -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2, and -OCH2Cl.

[0174] In various embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In further embodiments, R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -NHCH3, -NHCH2CH3, -NHCH(CH3)CH3, -NHCH2CH2CH3, -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH(CH3)CH3, and -N(CH3)CH2CH2CH3. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH3)CH2CH3. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -NHCH3, and -N(CH3)2.

[0175] In various embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -CH2F, -CH2CH2F, -CH(CH3)CH2F, -CH2CH2CH2F, -CH2Cl, -CH2CH2Cl, -CH(CH3)CH2Cl, -CH2CH2CH2Cl, -CH2CN, -CH2CH2CN, -CH(CH3)CH2CN, and -CH2CH2CH2CN. In further embodiments, R 1a , R 1b , R 1c , and R 1dEach is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -CH2F, -CH2CH2F, -CH2Cl, -CH2CH2Cl, -CH2CN, and -CH2CH2CN. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, -CH2F, -CH2Cl, and -CH2CN.

[0176] In various embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, methyl, ethyl, n-propyl, isopropyl, ethenyl, and propenyl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, methyl, ethyl, and ethenyl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, F, -Cl, -CN, -NH2, -OH, -NO2, and methyl.

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

[0178] In various embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen and halogen. In a further embodiment, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, -F, -Cl, and -Br. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen, -F, and -Cl. In a further embodiment, R 1a , R 1b , R 1c , and R 1d Each is independently selected from hydrogen and -Cl. In further embodiments, R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen and -F.

[0179] In some embodiments, R 1a , R 1b , R 1c , and R 1d Each is independently hydrogen, halogen, or C1-C4 alkyl. In further embodiments, R 1a , R 1b , R 1c , and R1d Each of these is independently hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, or isopropyl. In further embodiments, R 1a , R 1b , R 1c , and R 1d These are independently hydrogen, -F, -Cl, methyl, and ethyl. In further embodiments, R 1a , R 1b , R 1c , and R 1d These are, 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 Selected from. In further embodiments, R 2 is, -(CH2) n Cy 1 and -CH(OH)Cy 1 Selected from. In further embodiments, R 2 is, -(CH2) n Cy 1 In a further embodiment, R 2 is -CH(OH)Cy 1 That is the case.

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

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

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

[0184] fR 3 base In some embodiments, R 3 is a 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl. In further embodiments, R 3 is a 3-6 membered cycloalkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, or C1-C4 halohydroxyalkyl. In further embodiments, R 3is a 3-6 membered cycloalkyl, -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. In further embodiments, R 3 These are 3-6 membered cycloalkyl groups, -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2, or -OCH2Cl.

[0185] In some embodiments, R 3 is a C1-C6 haloalkyl, a C1-C6 haloalkoxy, or a C1-C6 halohydroxyalkyl. In further embodiments, R 3 is a C1-C4 haloalkyl, a C1-C4 haloalkoxy, or a C1-C4 halohydroxyalkyl. In further embodiments, R 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. In further embodiments, R 3These are -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -OCF3, -OCHF2, -OCH2F, -OCCl3, -OCHCl2, or -OCH2Cl.

[0186] In some embodiments, R 3 is a C1-C6 haloalkyl. In further embodiments, R 3 is a C1-C4 haloalkyl. In further embodiments, R 3 is -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CCl3, -CH2CHCl2, or -CH2CH2Cl. In further embodiments, R 3 These are -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, or -CH2Cl.

[0187] In some embodiments, R 3 is a 3-6 membered cycloalkyl group. In further embodiments, R 3 In further embodiments, R 3 is a 3-4 membered cycloalkyl group. In further embodiments, R 3 is a 3-membered cycloalkyl. In yet another embodiment, R 3 It is a four-membered cycloalkyl group.

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

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

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

[0191] In further embodiments, R 3 is hydrogen or (C1-C4) alkyl. In further embodiments, R 3 R is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In further embodiments, R 3 is hydrogen, methyl, or ethyl. In a further embodiment, R 3 R is hydrogen or ethyl. In further embodiments, R 3 It is either hydrogen or methyl.

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

[0193] In further embodiments, R 3 is a (C1-C4) alkyl group. In further embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, methyl halide, ethyl halide, propyl halide, CF3, CCl3, or CBr3. In further embodiments, R 3 is methyl or ethyl. In a further embodiment, R 3 R is ethyl. In further embodiments, R 3R is methyl. In further embodiments, R 3 These are CF3, CCl3, or CBr3.

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

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

[0196] In further embodiments, R 3 R is hydrogen or a 3-6 membered cycloalkyl group. In further embodiments, R 3 is hydrogen, cyclopropyl, cyclobutyl, or cyclopentyl. In further embodiments, R 3 is hydrogen, cyclopropyl, or cyclobutyl. In 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 It is not an acyclic alkyl chain containing approximately 1 to 5 substituted or unsubstituted carbon atoms.

[0197] In further embodiments, R 3 In further embodiments, R3 In further embodiments, R 3 is a 3-4 membered cycloalkyl group. In yet another embodiment, R 3 In further embodiments, R 3 In further embodiments, R 3 is cyclobutyl. In yet another embodiment, R 3 It is cyclopropyl.

[0198] In further embodiments, R 3 is a 3-6 membered cycloalkyl or C1-C6 haloalkyl. In further embodiments, R 3 is cyclopropyl, cyclobutyl, cyclopentyl, CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CCl3, -CHCl2, -CH2Cl, -CH2CCl3, -CH2CHCl2, or -CH2CH2Cl. In further embodiments, R 3 is cyclopropyl, cyclobutyl, CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CCl3, -CHCl2, -CH2Cl, or -CH2CCl3. In further embodiments, R 3 These are cyclopropyl, CF3, -CHF2, -CH2F, -CCl3, or -CHCl2.

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

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

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

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

[0203] hr 11A Base and R 11B Group (R 11 basis) In some embodiments, R 11a and R 11b Each of these, if present, is independently selected from hydrogen, halogen, -OH, and C1-C4 alkoxy, or R 11a and R 11b If each exists, together they form = O.

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

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

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

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

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

[0209] In some embodiments, R 11a and R 11b If each exists, together they form = O.

[0210] iR 12 base In some embodiments, R 12 If present, R is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl). In further embodiments, R 12If present, R is 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 further embodiments, R 12 If present, R is hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, -CH2(cyclopropyl), -CH2CH2(cyclopropyl), -CH2(cyclobutyl), -CH2CH2(cyclobutyl), -CH2(cyclopentyl), or -CH2CH2(cyclopentyl). In further embodiments, R 12 If present, these are hydrogen, methyl, cyclopropyl, -CH2(cyclopropyl), -CH2(cyclobutyl), or -CH2(cyclopentyl).

[0211] In some embodiments, R 12 If present, R is hydrogen or a C1-C4 alkyl group. In further embodiments, R 12 If present, R is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In further embodiments, R 12 If present, R is hydrogen, methyl, or ethyl. In further embodiments, R 12 If present, it is hydrogen or methyl.

[0212] In some embodiments, R 12 If present, R is a C1-C4 alkyl group. In further embodiments, R 12 If present, R is methyl, ethyl, n-propyl, or isopropyl. In further embodiments, R 12If present, R is methyl or ethyl. In further embodiments, R 12 If present, it is methyl.

[0213] In some embodiments, R 12 If present, R is C3-C6 cycloalkyl or -(C1-C4 alkyl)(C3-C6 cycloalkyl). In further embodiments, R 12 If present, R is 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 further embodiments, R 12 If present, R is -CH2(cyclopropyl), -CH2CH2(cyclopropyl), -CH2(cyclobutyl), -CH2CH2(cyclobutyl), -CH2(cyclopentyl), or -CH2CH2(cyclopentyl). In further embodiments, R 12 If present, it is -CH2(cyclopropyl), -CH2(cyclobutyl), or -CH2(cyclopentyl).

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

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

[0216] In some embodiments, R 13 If present, R is a C1-C4 alkyl group. In further embodiments, R 13 If present, R is selected from methyl, ethyl, n-propyl, and isopropyl. In further embodiments, R 13 If present, R is selected from methyl and ethyl. In further embodiments, R 13 If present, it is ethyl. In further embodiments, R 13 If present, it is methyl.

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

[0218] kR 14 base In some embodiments, R 14 If present, R is selected from -OH, -NH2, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)(C1-C4 alkyl). In further embodiments, R 14 If present, R is selected from -OH, -NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCH2CH2CH3, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2CH3, -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH(CH3)2, and -N(CH3)CH2CH2CH3. In further embodiments, R 14 If present, R is selected from -OH, -NH2, -OCH3, -OCH2CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH3)CH2CH3. In further embodiments, R14 If present, it is selected from -OH, -NH2, -OCH3, -NHCH3, and -N(CH3)2.

[0219] In some embodiments, R 14 If present, R is selected from -OH and -O(C1-C4 alkyl). In further embodiments, R 14 If present, it is selected from -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, and -OCH2CH2CH3. In further embodiments, R 14 If present, R is selected from -OH, -OCH3, and -OCH2CH3. In further embodiments, R 14 If present, it is selected from -OH and -OCH3.

[0220] In some embodiments, R 14 If present, R is selected from -NH2, -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)(C1-C4 alkyl). In further embodiments, R 14 If present, it is selected from -NH2, -NHCH3, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2CH3, -N(CH3)2, -N(CH3)CH2CH3, -N(CH3)CH(CH3)2, and -N(CH3)CH2CH2CH3. In further embodiments, R 14 If present, it is selected from -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH3)CH2CH3. In further embodiments, R 14 If present, it is selected from -NH2, -NHCH3, and -N(CH3)2.

[0221] In some embodiments, R 14 If present, R is selected from -OH and -NH2. In further embodiments, R 14 If present, it is -OH. In further embodiments, R 14 If present, it is -NH2.

[0222] l.CY 1 base In some embodiments, Cy 1 This is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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 It is substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino groups.

[0223] In some embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14 These are C4-C9 cycloalkyls substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. Examples of C4-C9 cycloalkyls include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and spiro[2.4]heptane. In further embodiments, Cy 1These include halogens, -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), and -S(O)R. 14 These are C4-C9 cycloalkyl groups substituted with 0, 1, or 2 groups independently selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. In further embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14 These are C4-C9 cycloalkyl groups substituted with zero or one group selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. In further embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14 , C4-C9 cycloalkyl monosubstituted with a group selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino. In yet another embodiment, Cy 1 It is an unsubstituted C4-C9 cycloalkyl group.

[0224] In some embodiments, Cy1 These include halogens, -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), and -S(O)R. 14 The C3-C9 heterocycle has at least one O, S, or N atom substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. 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-flu[3,4-c]pyrrole. In further embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14 A C3-C9 heterocycle substituted with 0, 1, or 2 groups independently selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. In further embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14A C3-C9 heterocycle substituted with zero or one group selected from C1-C4 alkylaminos and (C1-C4)(C1-C4)dialkylaminos. In further embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14 , a C3-C9 heterocycle monosubstituted with a group selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino. In yet another embodiment, Cy 1 This is an unsubstituted C3-C9 heteroalgebra.

[0225] In some embodiments, Cy 1 This has at least one O, S, or N atom and is a 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 14These are C2-C9 heteroaryls substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. Examples of C2-C9 heteroaryls include furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridadinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl Examples include, but are not limited to, lysinyl, pyrazolopyrimidinyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyradinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyradinyl. Further embodiments include Cy 1 These include halogens, -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), and -S(O)R. 14 These are C2-C9 heteroaryl compounds substituted with 0, 1, or 2 groups independently selected from C1-C4 alkylaminos and (C1-C4)(C1-C4) dialkylaminos. In further embodiments, Cy 1These include halogens, -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), and -S(O)R. 14 The C2-C9 heteroaryl is substituted with zero or one group selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino. In further embodiments, Cy 1 These include halogens, -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), and -S(O)R. 14 , C2-C9 heteroaryl monosubstituted with a group selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino. In yet another embodiment, Cy 1 It is an unsubstituted C2-C9 heteroaryl compound.

[0226] In some embodiments, Cy 1This 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 halogens, -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, thian, 1,3-dithiane, 1,4-dithiane, thiomorpholine, dioxane, morpholine, and hexahydro-1H-flu[3,4-c]pyrrole. In further embodiments, Cy 1 This 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 halogens, -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. In further embodiments, Cy 1 This is a C3-C9 heterocycle having at least one O, S, or N atom and substituted with zero or one group selected from halogens, -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. In further embodiments, Cy 1This is 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. In further embodiments, Cy 1 This is an unsubstituted C3-C9 heterocycle having at least one O, S, or N atom.

[0227] In some embodiments, Cy 1 This is a C3-C9 heterocycle having at least one oxygen atom and substituted with 0, 1, 2, or 3 groups independently selected from halogens, -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. In further embodiments, Cy 1 This is a C3-C9 heterocycle having at least one oxygen atom and substituted with 0, 1, or 2 groups independently selected from halogens, -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. In further embodiments, Cy 1This is a C3-C9 heterocycle having at least one oxygen atom and substituted with zero or one group selected from halogens, -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. In further embodiments, Cy 1 This is a C3-C9 heterocycle having at least one oxygen 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. In further embodiments, Cy 1 This is an unsubstituted C3-C9 heterocycle having at least one oxygen atom.

[0228] In some embodiments, Cy 1 This is a C3-C9 heterocycle having at least one S atom and substituted with 0, 1, 2, or 3 groups independently selected from halogens, -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. In further embodiments, Cy 1This is a C3-C9 heterocycle having at least one S atom and substituted with 0, 1, or 2 groups independently selected from halogens, -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. In further embodiments, Cy 1 This is a C3-C9 heterocycle having at least one S atom and substituted with zero or one group selected from halogens, -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. In further embodiments, Cy 1 This 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. In further embodiments, Cy 1 It is an unsubstituted C3-C9 heterocycle having at least one sulfur atom.

[0229] In some embodiments, Cy 1This is a C3-C9 heterocycle having at least one N atom and substituted with 0, 1, 2, or 3 groups independently selected from halogens, -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. In further embodiments, Cy 1 This is a C3-C9 heterocycle having at least one N atom and substituted with 0, 1, or 2 groups independently selected from halogens, -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. In further embodiments, Cy 1 This is a C3-C9 heterocycle having at least one N atom and substituted with zero or one group selected from halogens, -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. In further embodiments, Cy 1 This 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. In further embodiments, Cy 1 This is an unsubstituted C3-C9 heterocycle having at least one N atom.

[0230] In some embodiments, Cy 1 This 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 yet another embodiment, the C3-C9 heterocycle is a bicyclic heterocycle. In yet yet another embodiment, the C3-C9 heterocycle is a spirocyclic heterocycle. In yet yet another embodiment, the C3-C9 heterocycle is a fused heterocycle.

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

[0232] In some embodiments, Cy 1 This 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 halogens, -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 This is a structure represented by an expression selected from the following: TIFF2026067907000096.tif29165

[0234] In some embodiments, Cy 1 This structure is represented by the following formula: TIFF2026067907000097.tif27165

[0235] In some embodiments, Cy 1 This structure is represented by the following formula: TIFF2026067907000098.tif22165

[0236] 2. Examples of compounds In some embodiments, the compound may exist as one or more of the following structures, or as a pharmaceutically acceptable salt thereof. TIFF2026067907000099.tif176165TIFF2026067907000100.tif212165.

[0237] In some embodiments, the compound may exist as one or more of the following structures, or as a pharmaceutically acceptable salt thereof. TIFF2026067907000101.tif175165TIFF2026067907000102.tif173165TIFF2026067907000103.tif93165.

[0238] In some embodiments, the compound may exist as one or more of the following structures, or as a pharmaceutically acceptable salt thereof. TIFF2026067907000104.tif173165TIFF2026067907000105.tif175165TIFF20260679070 00106.tif183165TIFF2026067907000107.tif180165TIFF2026067907000108.tif134165.

[0239] In some embodiments, the compound may exist as one or more of the following structures, or as a pharmaceutically acceptable salt thereof. TIFF2026067907000109.tif172165TIFF2026067907000110.tif178165TIFF2026067907000111.tif190165 TIFF2026067907000112.tif178165TIFF2026067907000113.tif175165TIFF2026067907000114.tif181165.

[0240] In some embodiments, the compound may exist as one or more of the following structures, or as a pharmaceutically acceptable salt thereof. TIFF2026067907000115.tif178165TIFF2026067907000116.tif183165TIFF2026067907000117.tif177165TIFF202 6067907000118.tif175165TIFF2026067907000119.tif175165TIFF2026067907000120.tif174165TIFF20260679070 00121.tif176165TIFF2026067907000122.tif185165TIFF2026067907000123.tif180165TIFF2026067907000124.ti f185165TIFF2026067907000125.tif150165TIFF2026067907000126.tif153165TIFF2026067907000127.tif201165.

[0241] In some embodiments, the compound may exist as one or more of the following structures, or as a pharmaceutically acceptable salt thereof. TIFF2026067907000128.tif184165TIFF2026067907000129.tif184165TIFF20260679070001 30.tif185165TIFF2026067907000131.tif178165TIFF2026067907000132.tif178165TIFF202 6067907000133.tif170165TIFF2026067907000134.tif179165TIFF2026067907000135.tif17 4165TIFF2026067907000136.tif173165TIFF2026067907000137.tif185165TIFF20260679070 00138.tif172165TIFF2026067907000139.tif185165TIFF2026067907000140.tif185165TIFF 2026067907000141.tif175165TIFF2026067907000142.tif185165TIFF2026067907000143.ti f185165TIFF2026067907000144.tif148165TIFF2026067907000145.tif150165TIFF20260679 07000146.tif150165TIFF2026067907000147.tif147165TIFF2026067907000148.tif107165.

[0242] 3. Examples of expected compounds Examples of the following compounds are expected and can be prepared using the synthetic methods described herein and, as necessary, other general methods that would be known to those skilled in the art. It is anticipated that the expected compounds will be active as regulators of RNA polymerase-I signaling, and that such activity can be determined using the assay methods described below herein.

[0243] In one embodiment, the compound is selected from the following: TIFF2026067907000149.tif183165TIFF2026067907000150.tif223165.

[0244] In one embodiment, the compound is selected from the following: TIFF2026067907000151.tif188165TIFF2026067907000152.tif223165.

[0245] In one embodiment, the compound is selected from the following: TIFF2026067907000153.tif226165.

[0246] In one embodiment, the compound is selected from the following: TIFF2026067907000154.tif186165TIFF2026067907000155.tif99165.

[0247] It is intended that one or more compounds may be optionally 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 may also be used in connection with the disclosed methods, compositions, kits, and uses. pharmaceutically acceptable derivatives of the compounds may include any suitable derivatives, such as pharmaceutically acceptable salts, isomers, radiolabeled analogs, tautomers, etc., as discussed below.

[0250] C. Pharmaceutical Compositions Pharmaceutical compositions comprising a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are also provided herein. Thus, in various embodiments, pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound and a pharmaceutically acceptable carrier are disclosed. In a further embodiment, a pharmaceutical composition comprising a therapeutically effective amount of at least one disclosed compound may be provided. In yet another embodiment, a pharmaceutical composition comprising a preventive effective amount of at least one disclosed compound may be provided. In yet another 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] Therefore, in various embodiments, the structure is represented by the following formula: A compound having TIFF2026067907000156.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, 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, R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14 However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4However, pharmaceutical compositions are provided herein that include a therapeutically effective amount of a compound 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 following formula: A compound having TIFF2026067907000157.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy1 However, it 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 halogens, -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, and R 3 The following pharmaceutical compositions are provided herein, comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, which is a 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, and a pharmaceutically acceptable carrier.

[0253] pharmaceutically acceptable salts of compounds are conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases, retaining the biological efficacy and properties of the compound. Examples of acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamidic acid, phosphoric acid, and nitric acid, as well as 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 into salts is a known technique for improving the physical and chemical stability, hygroscopicity, fluidity, and solubility of compounds. For example, see pages 196 and 1456-1457 of H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995).

[0254] Pharmaceutical compositions contain a compound in a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier refers to a sterile aqueous or non-aqueous solution, suspension, or emulsion, as well as a sterile powder for reconstitution into a sterile injection or dispersant 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. Compounds can be formulated with a pharmaceutically acceptable carrier or diluent, as well as any other known adjuvants and excipients, in accordance with the prior art, for example, disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. The term "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering the compounds of the present invention to mammals. The carrier includes liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials involved in transporting or delivering the drug of the subject from one organ or body part to another. Each carrier must be "acceptable" in the sense that it is compatible with other components of the formulation and is not harmful to the patient.Some examples of materials that can function as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic compatible substances used in pharmaceutical formulations. Suitable pharmaceutical carriers are described in E.W. Martin's "Remington's Pharmaceutical Sciences," which is incorporated entirely herein by reference.

[0255] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants may also be present in this composition.

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

[0257] The formulations of the present invention include those suitable for oral, intranasal, topical, buccal, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may be conveniently presented in unit dosage forms and may be prepared by any method well known in the field of pharmacy. The amount of active ingredient that can be combined with a carrier material to yield a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, out of 100 percent, this amount is in the range of about 1 percent to about 99 percent, preferably about 5 percent to about 70 percent, and most preferably about 10 percent to about 30 percent, of the active ingredient. Methods for preparing these formulations or compositions include the step of associating the compounds of the present invention with a carrier and, optionally, one or more minor components. Generally, formulations are prepared by homogeneously and closely associating the compounds of the present invention with a liquid carrier, or a pulverized solid carrier, or both, and then shaping the product as needed.

[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 solutions or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as pastils (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia), and / or mouthwashes, each containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present disclosure may also be administered as boluses, licks, or pastes.

[0259] The present invention provides a solid dosage form for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.) in which the active ingredient is one or more pharmaceutically acceptable carriers, e.g., sodium citrate or dicalcium phosphate, and / or fillers or expanders, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid, binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, humectants, e.g., glycerol, disintegrants, e.g., agar. It is mixed with any of the following: calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, dissolution retarders such as paraffin, absorption enhancers 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 colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also include a buffer. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules with excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0260] Tablets may be prepared by compression or molding, with one or more optional adjuncts. Compressed tablets may be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), a surfactant, or a dispersant. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0261] The tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, may optionally be scored or prepared using coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. These may also be formulated to provide sustained or controlled release of the active ingredient therein, using, for example, hydroxypropyl methylcellulose (used in various proportions to provide a desired release profile), other polymer matrices, liposomes, catanionic vesicles, and / or microspheres. They may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water or other sterile injection medium immediately before use. These compositions may optionally also contain an opaque agent and may be composed to release the active ingredient(s) only to the gastrointestinal tract, or preferentially to a specific part of the gastrointestinal tract, in an optionally delayed manner. Examples of embedding compositions that can be used include polymer substances and waxes. The active ingredient may also be encapsulated in microencapsulations, if appropriate, together with one or more of the excipients mentioned above.

[0262] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may include 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, as well as mixtures thereof.

[0263] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances, and preservatives. Suspensions may include, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, as well as mixtures thereof.

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

[0265] Ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Sprays may further contain conventional propellants such as chlorofluorohydrocarbons, as well as volatile unsubstituted hydrocarbons such as butane and propane.

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

[0267] Ophthalmic preparations, eye ointments, powders, solutions, etc., are also intended to be within the scope of the present invention.

[0268] A pharmaceutical composition of the present invention suitable for parenteral administration comprises one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injection solutions or dispersions immediately before use, which may include antioxidants, buffers, bacteriostatic agents, solutes that are isotonic with the blood of the recipient of the formulation, or suspending agents or thickeners. Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical composition of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate 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, humectants, emulsifiers, and dispersants. Prevention of microbial activity can be ensured by the inclusion of various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, sustained absorption of the injectable pharmaceutical form can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

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

[0271] Depot formulations for injection are prepared by forming a microcapsule matrix of the target compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the ratio of the drug to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Depot formulations for injection can also be prepared by encapsulating the drug in liposomes or microemulsions compatible with body tissues.

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

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

[0274] In further embodiments, the pharmaceutical composition is administered after identifying mammals that require treatment for disorders related to PINK1 kinase activity. In further embodiments, the mammals are diagnosed with requiring treatment for disorders related to PINK1 kinase activity prior to the administration step.

[0275] In various embodiments, the disclosed pharmaceutical compositions comprise a disclosed compound (including pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions of the present invention include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, but in any case, the optimal route will depend on the specific host and the nature and severity of the condition for which the active ingredient is administered. The pharmaceutical compositions can be conveniently provided in unit dosage forms and can be formulated by any method well known in the pharmaceutical field.

[0276] The choice of carrier will be determined in part by the specific method used to administer the composition. Therefore, a wide variety of suitable formulations exist for the pharmaceutical compositions of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, subarachnoid, rectal, and intravaginal administration are illustrative and not limiting.

[0277] Formulations suitable for oral administration may consist of (a) liquid formulations, for example, 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 troches, each containing a predetermined amount of the active ingredient as a solid or granule; (c) powders; (d) suspensions added to a suitable liquid; and (e) suitable emulsifiers. Liquid formulations may contain diluents, such as water, cyclodextrin, dimethyl sulfoxide, and alcohols, such as ethanol, benzyl alcohol, propylene glycol, glycerin, and polyethylene alcohol, with or without the addition of pharmaceutically acceptable surfactants, suspensions, or emulsifiers. Capsule forms may be of the usual hard-shell or soft-shell gelatin type, for example, containing surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. The tablet form may contain 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 one or more other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavoring agents, and pharmacokinetically compatible carriers. The lozenge form may contain the active ingredient in a flavoring agent, usually sucrose and acacia or tragacanth; the pastille form may contain the active ingredient in an inert base, e.g., gelatin and glycerin or sucrose and acacia; the emulsion and gel form may contain additional active ingredients in an inert base, e.g., gelatin and glycerin or sucrose and acacia; and the emulsion and gel form may contain carriers known in the art in addition to the active ingredient.

[0278] The compounds of this disclosure can be used alone or in combination with other suitable ingredients to form aerosol formulations for administration by inhalation. Such aerosol formulations can be encapsulated in a pressurized, acceptable propellant, such as dichlorodifluoromethane, propane, and nitrogen. These can also be formulated, for example, as pharmaceuticals for use in non-pressurized preparations contained in nebulizers or atomizers.

[0279] Suitable formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions and aqueous and non-aqueous sterile suspensions. The injection solutions may contain antioxidants, buffers, bacteriostatic agents, and solutes to make the formulation isotonic with the blood of the target recipient. The suspensions may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The compound may be administered with a pharmaceutically acceptable diluent in a pharmaceutically acceptable carrier, such as a sterile liquid or mixture of liquids containing water, physiological saline, dextrose aqueous solution, and related sugar solution, with or without a pharmaceutically acceptable surfactant, such as soap or detergent; a suspending agent, such as pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or an emulsifier; and other pharmaceutically acceptable diluents, such as a pharmaceutically acceptable carrier, such as water, physiological saline, dextrose aqueous solution, and related sugar solution; an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol; a glycol, such as propylene glycol or polyethylene glycol such as poly(ethylene glycol) 400; a glycerol ketal, such as 2,2-dimethyl-1,3-dioxolane-4-methanol; an ether; an oil; a fatty acid; a fatty acid ester or glyceride; or an acetylated fatty acid glyceride.

[0280] Oils that can be used in parenteral formulations include petroleum, animal oils, vegetable oils, or synthetic oils. Specific examples of oils include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum, and mineral oil. Fatty acids suitable for use in parenteral formulations include 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 metals, ammonium compounds, 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, alkylolefins, ethers, 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 the solution. Suitable preservatives and buffers can be used in such formulations. For the purpose of minimizing or eliminating irritation at the injection site, such compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such formulations is in the range of about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and high molecular weight adducts of ethylene oxide and hydrophobic bases formed by the condensation of propylene oxide and propylene glycol.

[0282] Pharmaceutically acceptable excipients are also well known to those skilled in the art. The selection of excipients will be determined in part by the specific compound and the specific method used to administer the composition. Therefore, a wide variety of suitable formulations exist for the pharmaceutical compositions of the present invention. The following methods and excipients are illustrative and not limiting. Pharmaceutically acceptable excipients are preferably those that 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, as well as solid absorbents and diluents, surfactants, suspending agents, tablet binders, lubricants, flavoring agents, and colorants.

[0283] The formulations can be provided in sealed containers of unit or multiple doses, such as ampoules and vials, and can be stored under lyophilized conditions requiring only the addition of a sterile liquid excipient for injection, such as water, immediately before use. Immediate injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. The requirements for effective pharmaceutical carriers for injection compositions are well known to those skilled in the art. (Pharmaceutics and Pharmacy Practice, JBLippincott Co., Philadelphia, PA, Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4) th See ed., 622-630 (1986).

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

[0285] In addition, formulations suitable for rectal administration can be provided as suppositories by mixing with various substrates, such as emulsifying substrates or water-soluble substrates. 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, a carrier known to be suitable in the art.

[0286] Those skilled in the art will understand that suitable methods are available for administering the compounds of this disclosure to animals from outside the body, and that while two or more routes may be available for administering a particular compound, one particular route may produce a more immediate and effective response than another.

[0287] With regard to these applications, the methods of the present invention involve administering a therapeutically effective dose of a compound effective for the treatment (e.g., prevention or treatment) of a disorder related to PINK1 kinase activity to an animal, more specifically a mammal, and more specifically a human. The methods also include administering a therapeutically effective dose of a compound for the treatment of a patient who is predisposed to suffering from a disorder related to PINK1 kinase activity. In connection with 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 a variety of factors, including the animal's condition, its body weight, and the severity and stage of the disorder.

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

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

[0290] In certain embodiments, the compositions described herein are formulated for administration to patients requiring such compositions. The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intraarachnoid, intrahepatic, intrafocal, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injection forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting and suspending agents.

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

[0292] The compounds described herein may be administered alone or in combination with additional therapeutic agents. Therefore, the preparations may also be combined with other active substances (for example, to reduce metabolic degradation) if desired. Additional therapeutic agents include, but are not limited to, other activators known to be useful in the treatment of disease-related neurodegeneration (e.g., Parkinson's disease drugs, e.g., levodopa), dopamine agonists (e.g., bromocriptine, pergolide, pramipexole, ropinirole, pyribezil, cabergoline, apomorphine, rislid), 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 can be delivered in vesicles, particularly liposomes (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); see Lopez-Berestein, ibid., pp. 317-327; see ibid. in general).

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

[0295] The compounds described herein or their pharmaceutically acceptable salts include purified water, propylene glycol, PEG400, glycerin, DMA, ethanol, benzyl alcohol, citrate / sodium citrate (pH 3), citrate / sodium citrate (pH 5), tris(hydroxymethyl)aminomethane HCl (pH 7.0), 0.9% physiological saline, 1.2% physiological saline, acetate, aspartate, benzenesulfonate, benzoate, besilate, bicarbonate, bicarbonate, bicarbonate, bromide, camusylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, and glyceptide. Numerous excipients, including but not limited to toates, glucons, glutamates, glycolates, hexanoates, hydroxynaphthoates, iodides, isethions, lactates, lactobions, malates, maleates, mandelates, mesylates, methylsulfates, mucinates, napsylates, nitrates, octanates, oleates, pamonates, pantothenates, phosphates, polygalacturonic acids, propions, salicylates, stearates, succinates, sulfates, tartrates, theoclates, tosylates, and any combination thereof, can be used to formulate the product. In some embodiments, the excipients are selected from propylene glycol, purified water, and glycerin.

[0296] In some embodiments, the formulation may be freeze-dried to a solid and reconstituted with, for example, water before use.

[0297] When administered to mammals (for example, to animals for veterinary use or to humans for clinical use), the compound may be administered in an isolated form.

[0298] When administered to humans, the compounds may be sterile. Water is a suitable carrier when administering the compounds of formula I intravenously. Saline solution, glucose aqueous solution, and glycerol aqueous solution can also be used as liquid carriers, especially for injection solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol. The compositions of the present invention may also contain small amounts of wetting agents or emulsifiers, or pH buffers, if desired.

[0299] The compositions described herein may take the form of solutions, suspensions, emulsions, tablets, pills, pellets, capsules, liquid-containing capsules, powders, sustained-release formulations, suppositories, aerosols, sprays, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, ARGennaro (Editor), Mack Publishing Co.

[0300] In some embodiments, the compound is formulated as a pharmaceutical composition suitable for administration to humans, following conventional procedures. Typically, the compound is a solution in a sterile isotonic aqueous buffer. If necessary, the composition may also contain a solubilizer. Compositions for intravenous administration may optionally contain a local anesthetic, such as lidocaine, to alleviate pain at the injection site. Generally, the components are supplied in unit dosage forms, for example, as a dry, lyophilized powder or a water-free concentrate, in airtight containers such as ampoules or sachets indicating the amount of the active ingredient, or mixed together. When the compound is administered by injection, it can be dispensed, for example, using an injection bottle containing pharmaceutical-grade sterile water or saline. When the compound is administered by injection, ampoules of sterile water or saline for injection may be provided so that the components can be mixed before administration.

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

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

[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 location in the eye, for example, between the eye and the eyelid, or into the conjunctival sac, to release an active agent, as described in U.S. Patents No. 3,863,633, 3,867,519, 3,868,445, 3,960,150, 3,963,025, 4,186,184, 4,303,637, 5,443,505, and 5,869,079. Release from such an article is usually carried out to the cornea, either via the tear film that immerses the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in close contact. Solid articles suitable for implantation in the eye in this manner are generally composed primarily of polymers and may be biodegradable or non-biodegradable. Biodegradable polymers that can be used to prepare intraocular implants having one or more of the compounds described herein in accordance with this disclosure include, but are not limited to, poly(glycolides), poly(lactides), poly(epsilon-caprolactone), poly-(hydroxybutyrates) and poly(hydroxyvalerates), polyamino acids, polyorthoesters, polyacid anhydrides, aliphatic polycarbonates and polyetherlactone polymers and copolymers, and aliphatic polyesters. Suitable non-biodegradable polymers include silicone elastomers.

[0304] The compositions described herein may contain preservatives. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercury salts (e.g., 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; disodium EDTA; and sorbic acid and its salts.

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

[0306] Naturally, the disclosed compositions can be prepared from the disclosed compounds. Similarly, naturally, the disclosed compositions can be used in the disclosed uses.

[0307] D. Method for preparing the compound In various embodiments, the present invention relates to a method for producing compounds useful for treating disorders related to PINK1 kinase activity. Accordingly, in some embodiments, a method for producing the disclosed compounds is disclosed.

[0308] The compounds described herein can be prepared, for example, by several methods outlined below. Those skilled in the art will understand the appropriate use of protecting groups [see Greene and Wuts, Protective Groups in Organic Synthesis] and the preparation of known compounds found in the literature using standard methods of organic synthesis. While it may occasionally be necessary to rearrange the order of recommended synthetic steps, this will be evident to the judgment of the chemist in the field of organic synthesis. The following examples are provided to help the invention be better understood and are illustrative only; they should not be construed as limitations.

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

[0310] 1. Route I In some embodiments, the compound can be prepared as shown below. TIFF2026067907000158.tif90165

[0311] The compounds are presented in their general form, and the substituents are as described elsewhere in this specification. More specific examples are given below. TIFF2026067907000159.tif90165

[0312] In some embodiments, compounds of type 1.14 and similar compounds can be prepared according to reaction scheme 1B described above. Thus, compounds of type 1.11 can be prepared by a suitable arylbromine, for example, by the Grignard reaction of 1.8 shown above. Suitable arylbromines are commercially available or can be prepared by methods known to those skilled in the art. The Grignard reaction is carried out in a suitable solvent, for example, tetrahydrofuran (THF), in the presence of a suitable metal source, for example, magnesium metal, and then reacted with a suitable carbonyl analog, for example, 1.10 shown above. Suitable carbonyl analogs are commercially available or can be prepared by methods known to those skilled in the art. Compounds of type 1.12 can be prepared by a suitable ketone, for example, by the reduction of 1.11 shown above. The reduction is carried out in the presence of a suitable reducing agent, for example, hydrogen gas, and a suitable catalyst, for example, palladium carbon. Compounds of type 1.13 can be prepared by a suitable arylcarboxylic acid analog, for example, by the cyclization of 1.12 shown above. 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 a suitable ketone, e.g., 1.13 shown above. Reduction is carried out in the presence of a suitable activator, e.g., p-toluenesulfonic acid, and a suitable reducing agent, e.g., sodium borohydride. As those skilled in the art will understand, the above reaction provides an example of a generalized approach, in which compounds similar in structure 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 yield compounds similar to formula 1.7.

[0313] 2. Pathway II In some embodiments, the compound can be prepared as shown below. TIFF2026067907000160.tif54165

[0314] The compounds are presented in their general form, and the substituents are as described elsewhere in this specification. More specific examples are given below. TIFF2026067907000161.tif90165

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

[0316] 3. Pathway III In some embodiments, the compound can be prepared as shown below. TIFF2026067907000162.tif48165

[0317] The compounds are presented in their general form, and the substituents are as described elsewhere in this specification. More specific examples are given below. TIFF2026067907000163.tif64165

[0318] In some embodiments, type 3.4 compounds and similar compounds can be prepared according to reaction scheme 3B described above. Thus, type 3.3 compounds can be prepared by epoxidation of a suitable alkene, e.g., 3.1 shown above. Epoxidation is carried out in a suitable solvent, e.g., dichloromethane (DCM), in the presence of a suitable oxidizing agent, e.g., metachloroperoxybenzoic acid (mCPBA), and then ring-opening is performed in the presence of a suitable amine, e.g., 3.2 shown above. Suitable amines are commercially available or prepared by methods known to those skilled in the art. Ring-opening is carried out in a suitable solvent, e.g., chloroform (CHCl3), in the presence of a suitable base, e.g., triethylamine (TEA). Type 3.4 compounds can be prepared by rearrangement of a suitable alcohol, e.g., 3.3 shown above. The rearrangement is carried out in a suitable solvent, e.g., DCM, in the presence of a suitable activator, e.g., methanesulfonic anhydride, a suitable base, e.g., TEA, and then reacts with a suitable imine, e.g., benzophenone imine. As those skilled in the art will understand, the above reaction provides an example of a generalized approach, in which compounds similar in structure to the specific reactants described above (compounds similar to compounds of types 3.1, 3.2, and 3.3) can be substituted during the reaction to yield compounds similar to formula 3.4.

[0319] 4. Pathway IV In some embodiments, the compound can be prepared as shown below. TIFF2026067907000164.tif90165

[0320] The compounds are presented in their general form, and the substituents are as described elsewhere in this specification. More specific examples are given below. TIFF2026067907000165.tif95165

[0321] In some embodiments, compounds of type 4.10 and similar compounds can be prepared according to reaction scheme 4B described above. Thus, compounds of type 4.7 can be prepared by halogenation of a suitable ketone, e.g., 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 a suitable solvent, e.g., DCM, in the presence of a suitable halogen source, e.g., bromine. Compounds of type 4.9 can be prepared by substitution of a suitable halide, e.g., 4.7 shown above. The substitution reaction is carried out in a suitable solvent, e.g., acetonitrile, in the presence of a suitable nucleophile, e.g., 4.8 shown above, and a suitable base, e.g., potassium carbonate. 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, e.g., 4.9 shown above. Reductive amination is carried out in a suitable solvent, e.g., ethanol, in the presence of a suitable amine, e.g., hydroxylamine, and a suitable base, e.g., pyridine, and then reacts with a suitable reducing agent, e.g., hydrogen gas, a suitable catalyst, e.g., palladium carbon, and a suitable acid, e.g., acetic acid, in a suitable solvent, e.g., ethanol. As those skilled in the art will understand, the above reaction provides an example of a generalized approach, in which compounds similar in structure to the specific reactants described above (compounds similar to those of types 4.1, 4.2, 4.3, and 4.4) can be substituted during the reaction to yield compounds similar to formula 4.5.

[0322] 5. Route V In some embodiments, adenine analogs can be prepared as shown below. TIFF2026067907000166.tif54165

[0323] The compounds are shown in general form, where X is a halogen and the other substituents are as described elsewhere in this specification. More specific examples are given below. TIFF2026067907000167.tif59165

[0324] In some embodiments, compounds of type 5.3 and similar compounds can be prepared according to reaction scheme 5B described above. Thus, compounds of type 5.3 can be prepared by arylation with a suitable amine, e.g., 5.1 shown above. The arylation is carried out in a suitable solvent, e.g., ethanol (EtOH), in the presence of a suitable halide, e.g., 5.2 shown above, and a suitable base, e.g., diisopropylethylamine (DIPEA). Suitable halides are commercially available or prepared by methods known to those skilled in the art. As will be understood 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 described above (compounds similar to the compounds of types 5.1 and 5.2) can be substituted during the reaction to yield adenine analogs similar to formula 5.3.

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

[0326] E. Method using compounds The compounds and pharmaceutical compositions of the present invention are useful for the treatment or control of disorders related to PINK1 kinase activity. To treat or control the disorder, the compounds and pharmaceutical compositions containing the compounds are administered to subjects in need, such as vertebrates, such as mammals, fish, birds, reptiles, or amphibians. Subjects may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. This term does not indicate a specific age or sex; that is, it is intended to include adult and neonatal subjects, as well as fetuses, regardless of sex. Subjects are preferably mammals such as humans. Subjects may have been diagnosed with a need for treatment of a disorder related to PINK1 kinase activity prior to administration of the compounds or compositions.

[0327] Compounds or compositions may 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, nasal administration, topical administration, vaginal administration, ophthalmic administration, intraotoral administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration including injections such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration may be continuous or intermittent. Preparations may be administered therapeutically, i.e., to treat an existing disease or condition. Preparations may also be administered prophylactically, i.e., to prevent a disease or condition.

[0328] The therapeutically effective dose or dosage of a compound can be modified within a wide range of limits. Such dosages are adjusted to the individual needs of each specific case, including the specific compound(s) administered, the route of administration, the symptoms being treated, and the patient being treated. Generally, for oral or parenteral administration to adults weighing approximately 70 kg or more, a daily dose of approximately 10 mg to 10,000 mg, preferably approximately 200 mg to 1,000 mg, should be appropriate, although it may exceed the upper limit. The daily dose can be administered as a single dose, in divided doses, or, in the case of parenteral administration, as a continuous intravenous infusion. A single-dose composition may contain the amount of compound or composition constituting the daily dose, or a divided amount thereof. The dosage can be adjusted by the individual physician in the event of any contraindications. The dosage is modifiable and is administered once or more times a day over a day or several days.

[0329] 1. Treatment The compounds disclosed herein are useful for treating or controlling disorders related to PINK1 kinase activity. Accordingly, a method is provided comprising administering a composition containing the disclosed compounds to a subject in a therapeutically effective dose.

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

[0331] In some embodiments, the Disclosure provides a method for treating or preventing mitochondrial disease in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof from among the compounds described herein, or one or more compounds or pharmaceutically acceptable salts thereof from among the compounds described herein. In some embodiments, treatment of mitochondrial disease involves improving symptoms by stimulating PINK1 or mutant PINK1.

[0332] In some embodiments, the Disclosure provides a method for treating or preventing fibrosis in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof from among the compounds described herein, or one or more compounds or pharmaceutically acceptable salts thereof from among the compounds described herein. In some embodiments, treatment of fibrosis involves improving symptoms by stimulating PINK1 or mutant PINK1.

[0333] In some embodiments, the Disclosure provides a method for treating or preventing cardiomyopathy in a subject, comprising administering to the subject a pharmaceutical composition comprising one or more compounds or pharmaceutically acceptable salts thereof from among the compounds described herein, or one or more compounds or pharmaceutically acceptable salts thereof from among the compounds described herein. In some embodiments, treatment of cardiomyopathy involves improving symptoms by stimulating PINK1 or mutant PINK1.

[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 involves administering to the subject one or more of the compounds described herein or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, the method involves administering to the subject a compound that functions as a PINK1 substrate or a pharmaceutically acceptable salt thereof together with one or more of the compounds described herein or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising one or more of the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, the cholesterol treatment agent is niacin or asifran. In some embodiments, the subject is a subject that requires it.

[0335] a. Treatment of disorders related to PINK1 activity In some embodiments, the compounds and compositions described herein are useful for treating disorders related to PINK1 function. Accordingly, a method for treating a disorder related to PINK1 function is provided herein, comprising administering to a subject in need 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 cardiomyopathy.

[0336] Therefore, in various embodiments, a method for treating a disorder in an object requiring treatment of the disorder, wherein the object requiring treatment has a structure represented by the following formula: A compound having TIFF2026067907000168.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1However, it is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14 However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4 However, a compound selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. A method is disclosed comprising administering an effective dose of a substance, wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy.

[0337] In various embodiments, a method for treating a disorder in an object requiring treatment of the disorder, the following: For objects that require it, the structure is represented by the following formula: A compound having TIFF2026067907000169.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it 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 halogens, -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, and R 3 A compound, or a pharmaceutically acceptable salt thereof, that is a 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl. A method is disclosed comprising administering an effective dose of a substance, wherein the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy.

[0338] Examples of neurodegenerative diseases that can be treated with the compounds or compositions described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia with capillary dilatation, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, epilepsy, Friedreich's ataxia, frontotemporal dementia, and Gerstmann-Schönlin disease. Loessler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Kuru, Leigh disease (Leigh syndrome), Lewy body dementia, Machad-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 disease, Refsum disease, Sandhoff disease, Schilder's disease, Shy-Drager syndrome, subacute association of spinal cord diseases secondary to pernicious anemia Parkinson's disease, schizophrenia, spinocerebellar ataxia (multiple types with different characteristics), spinal muscular atrophy, Steele-Richardson-Olsewski disease, spinal fistula, 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 Lewy body parkinson's disease type 3 (PARK3), autosomal dominant Lewy body parkinson's disease type 4 (PARK4), parkinson's disease type 5 (PARK 5) Examples include autosomal recessive early-onset Parkinson's disease type 6 (PARK6), autosomal recessive juvenile-onset 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, autonomic dysfunction is not a neurodegenerative disease.

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

[0340] Cardiomyopathy refers to a condition that adversely affects cardiac cell tissue, resulting in a measurable deterioration of myocardial function (e.g., systolic and diastolic function). Dilated cardiomyopathy is characterized by ventricular chamber enlargement without hypertrophy, accompanied by systolic dysfunction. Hypertrophic cardiomyopathy is a genetic disorder transmitted as an autosomal dominant trait. Morphologically, hypertrophic cardiomyopathy is characterized by a hypertrophied left ventricle without dilation. Restrictive cardiomyopathy is characterized by ventricular filling impairment due to a decrease in ventricular volume, although it is morphologically neither dilated nor hypertrophied. Arrhythmogenic right ventricular cardiomyopathy is a hereditary heart disease characterized by electrical instability of the myocardium. Unclassifiable cardiomyopathy is a category of cardiomyopathy that does not conform to the characteristics of any of the other types. Unclassifiable cardiomyopathy may have characteristics of multiple types, or it may have characteristics of fibroelasticity, impaired noncompaction, or systolic dysfunction with only slight dilation.

[0341] In certain embodiments, the compounds and compositions described herein may be used to treat Parkinson's disease by reducing Lewy body production, reducing alpha-synuclein accumulation, 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 the loss of motor function, reducing tremors or slowing the increase of tremors, reducing rigidity or the increase of rigidity, reducing bradykinesia or slowing of movement, alleviating sensory symptoms, alleviating insomnia, reducing drowsiness, improving mental health, improving mental function, slowing the decline of mental function, reducing dementia, delaying the onset of dementia, improving cognitive skills, reducing the loss of cognitive skills, improving memory, reducing memory deterioration, or extending survival time. 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 compound or composition is a disease characterized by a decrease in PINK1 levels. In certain embodiments, the disease is a disease characterized by the 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 decrease in PINK1 activity levels. In certain embodiments, the disease is Parkinson's disease. In certain embodiments, the disease is a neurodegenerative disease. In certain embodiments, the disease is cardiomyopathy.

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

[0344] In further embodiments, the subject is diagnosed with a need for treatment of a disorder related to PINK1 kinase activity prior to the administration step.

[0345] In further embodiments, the subject is a mammal. In even further embodiments, the mammal is a human.

[0346] In further embodiments, the method further includes the step of identifying subjects who require treatment for disorders related to PINK1 kinase activity.

[0347] In further embodiments, administration is achieved by oral administration, parenteral administration, sublingual administration, transdermal administration, rectal administration, transmucosal administration, topical administration, inhalation, buccal administration, intrapleural administration, intravenous administration, intra-arterial administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, intranasal administration, subarachnoid administration, and intra-articular administration, or a combination thereof.

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

[0349] Therefore, in various embodiments, a method for regulating PINK1 kinase activity in subjects requiring regulation of PINK1 kinase activity is provided, as follows: For objects that require it, the structure is represented by the following formula: A compound having TIFF2026067907000170.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12, or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14 However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4 However, a compound selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. A method is disclosed that includes administering an effective amount of [a substance].

[0350] In various embodiments, a method for regulating PINK1 kinase activity in subjects requiring regulation of PINK1 kinase activity is provided, as follows: For objects that require it, the structure is represented by the following formula: A compound having TIFF2026067907000171.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it 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 halogens, -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, and R 3 A compound, or a pharmaceutically acceptable salt thereof, that is a 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl. A method is disclosed that includes administering an effective amount of [a substance].

[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 inhibition and / or activation of PINK1-dependent activity, such as a decrease in parkin recruitment. In some embodiments, modulation refers to inhibition or activation of parkin recruitment. In some embodiments, the 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 the methods described herein.

[0352] The compounds described herein are novel substrates for PINK1. The ability of compounds to stimulate or inhibit PINK1 activity can be measured using any assay known in the art 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 a mutant PINK1 in cells, administering the compounds disclosed herein, and measuring the extent to which the cells expressing the mutant PINK1 were able to phosphorylate enzymatically active substrates compared to cells expressing wild-type PINK1.

[0353] PINK1 activity is measured in the time required to recruit 50% of the substrate ("R 50 It can be measured by the change in R50. In some embodiments, the compound reduces R50 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%. In some embodiments, the compound reduces R 50 It reduces R by approximately 1% to approximately 50%. In some embodiments, the compound is R 50Reduce by about 2% to about 50%. In some embodiments, the compound is R 50 Reduce by about 3% to about 50%. In some embodiments, the compound is R 50 Reduce by about 4% to about 50%. In some embodiments, the compound is R 50 Reduce by about 5% to about 50%. In some embodiments, the compound is R 50 Reduce by about 6% to about 50%. In some embodiments, the compound is R 50 Reduce by about 7% to about 50%. In some embodiments, the compound is R 50 Reduce by about 8% to about 50%. In some embodiments, the compound is R 50 Reduce by about 9% to about 50%. In some embodiments, the compound is R 50 Reduce by about 10% to about 50%. In some embodiments, the compound is R 50 Reduce by about 15% to about 50%. In some embodiments, the compound is R 50 Reduce by about 20% to about 50%. In some embodiments, the compound is R 50 Reduce by about 25% to about 50%. In some embodiments, the compound is R 50 Reduce by about 30% to about 50%. In some embodiments, the compound is R 50 Reduce by about 35% to about 50%. In some embodiments, the compound is R 50 Reduce by about 40% to about 50%. In some embodiments, the compound is R 50 Reduce by about 45% to about 50%. In some embodiments, the compound is R 50 Reduce by about 10% to about 40%. In some embodiments, the compound is R 50 Reduce by about 10% to about 30%. In some embodiments, the compound is R 50 Reduce by about 10% to about 20%.

[0354] Plasmids expressing PINK1 may be transfected into isolated cells, expressed in the isolated cells, expressed in cell-derived membranes, expressed in tissues, or expressed in animals. For example, PINK1 activity can be tested using nerve cells, immune system cells, transformed cells, or membranes. Regulation is tested using one of the in vitro or in vivo assays described herein. Compounds can also be tested using other commonly known assays. Signaling can also be investigated in vitro using lysed or solid-phase reactions, using chimeric molecules such as the extracellular domain of a receptor covalently bound to a heterologous signaling domain, or a heterologous extracellular domain covalently bound to the transmembrane and / or cytoplasmic domain of a receptor. Furthermore, ligand binding can also be assayed using the ligand-binding domain of the protein of interest in in vivo lysed or solid-phase reactions.

[0355] In some embodiments, the effect of the compound on the regulation of PINK1 is measured using cells expressing mutant and wild-type PINK1. PINK1 is generally known. In some embodiments, enzyme rescue is measured. An enzyme rescue experiment is an experiment that allows for the reactivation of mutant PINK1 enzyme activity by contacting cells expressing mutant PINK1 with reduced or deficient enzyme activity with the compound of the present invention. The PINK1 molecule is known. In some embodiments, the compound of the present invention can enzymatically rescue human PINK1 having the following amino acid sequence (acceptance number NM_032409.3, the whole sequence is incorporated by reference): TIFF2026067907000172.tif80133.

[0356] In one embodiment, the compound of the present invention can enzymatically rescue mouse PINK1 (acceptance number XM_924521, the whole of which is incorporated by reference) having the following amino acid sequence: TIFF2026067907000173.tif80133.

[0357] In some embodiments, the compounds of the invention can enzymatically rescue rat PINK1 (accession number XM_216565, incorporated herein by reference in its entirety) having the following amino acid sequence: TIFF2026067907000174.tif80132。

[0358] In further embodiments, the modulation is an inhibition. In further embodiments, the modulation is a decrease.

[0359] In further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 30 μM. In still further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 25 μM. In even further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 20 μM. In yet even further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 15 μM. In still further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 10 μM. In even further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 5 μM. In yet even further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 1 μM. In still further embodiments, the compound exhibits inhibition of PINK1 kinase activity with an IC 50 less than about 0.5 μM.

[0360] In further embodiments, the subject is a mammal. In still further embodiments, the subject is a human.

[0361] In further embodiments, the subject is diagnosed with a disorder related to PINK1 kinase dysfunction prior to the administration step. In further embodiments, the method further includes the step of identifying subjects at risk of infection with a disorder related to PINK1 kinase dysfunction prior to treatment of the disorder.

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

[0363] Therefore, in various embodiments, a method for regulating PINK1 kinase activity in at least one cell, the following: The cell has a structure that can be represented by the following formula: A compound having TIFF2026067907000175.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, 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, R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14 However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4However, a compound selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. A method is disclosed that includes contacting with an effective amount of [the substance].

[0364] In various embodiments, a method for regulating PINK1 kinase activity in at least one cell, the following: The cell has a structure that can be represented by the following formula: A compound having TIFF2026067907000176.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it 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 halogens, -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, and R 3 A compound, or a pharmaceutically acceptable salt thereof, that is a 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl. A method is disclosed that includes contacting with an effective amount of [the substance].

[0365] In further embodiments, the cells are mammalian. In even further embodiments, the cells are human. In yet another embodiment, the cells are isolated from the mammal before the contact step.

[0366] In further embodiments, regulation is inhibition. In further embodiments, regulation is reduction.

[0367] In further embodiments, contact is achieved through administration to a mammal.

[0368] In further embodiments, the contact step is performed in vitro.

[0369] 4. Use of the compound The use of a composition comprising the compound described herein or a pharmaceutically acceptable salt thereof, or a disclosed compound or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the treatment of the disorders described herein is also provided. The use of a composition comprising the 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 the disorders described herein is also provided.

[0370] Accordingly, in some embodiments, the present invention relates to the use of the disclosed compound or the product of the disclosed method. In further embodiments, the use relates to the production of agents for the treatment of disorders related to PINK1 kinase activity in mammals.

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

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

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

[0374] In various embodiments, the use relates to the treatment of disorders associated with PINK1 kinase activity in mammals. In some embodiments, the use is characterized in that the mammal is human. In some embodiments, the use is characterized in that the disorders associated with PINK1 kinase activity are neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy.

[0375] In further embodiments, the use relates to the manufacture of agents for the treatment of disorders related to PINK1 kinase activity in mammals.

[0376] It should be understood that the disclosed uses can be used in connection with the disclosed compounds, the products of the disclosed methods of production, methods, compositions, and kits. In further embodiments, the present invention relates to the use of the disclosed compounds or products in the manufacture of agents for the treatment of disorders related to PINK1 kinase activity in mammals.

[0377] 5. Manufacturing of pharmaceuticals In some embodiments, the present invention relates to a method for producing a drug for the treatment of a disorder related to PINK1 kinase activity in mammals, comprising combining a therapeutically effective amount of a disclosed compound or product of the disclosed method with a pharmaceutically acceptable carrier or diluent.

[0378] For these applications, the method involves administering a therapeutically effective dose of a compound effective in treating disorders related to PINK1 kinase activity to an animal, specifically a mammal, and more specifically, a human. In connection with 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 animal's condition and body weight.

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

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

[0381] Any agent used in the applications described herein may be used in combination therapy, concurrent administration, or co-formulation with the compositions described above. Such additional agents include, but are not limited to, agents for cholesterol, such as niacin, asifran, and statins, such as, but are not limited to, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin, and simvastatin. Other additional agents include, but are not limited to, ezetimibe and Trilipix (fenofibric acid). Other agents and compositions include, but are not limited to, fish oil, red yeast rice, and omega fatty acids.

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

[0383] In some embodiments, the disease or impairment response to treatment is monitored, and the treatment regimen is adjusted as necessary, taking such monitoring into consideration.

[0384] The frequency of administration is typically such that the dosing interval, e.g., the time between one administration and the next during waking hours, is from about 2 to about 12 hours, from about 3 to about 8 hours, or from about 4 to about 6 hours. As will be understood by those skilled in the art, the appropriate dosing interval depends in part on the length of time the selected composition can maintain the concentration of the compound(s) (e.g., EC 50 sup (the minimum concentration of the compound that modulates 90% of the receptor activity) in the subject and / or target tissue. Ideally, the concentration maintains an EC 50 sup state for at least 100% of the dosing interval. If this is not achievable, the concentration is desired to maintain a state greater than 5% of EC 50 or greater than 10% of EC 50 or greater than 25% of EC 50 or greater than 50% of EC 50 over the dosing period.

[0385] Thus, in some embodiments, the present 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: A compound having TIFF2026067907000177.tif42165, wherein m is 0 or 1, Q 1 and Q 2 are each independently N or CH, Q 3 is CH2 or NH, Z is CR 11a R 11b NR 12 or O, wherein R 11a and R 11b are each, when present, independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11bIf each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1d Each of these is independently selected from hydrogen, 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, R 2 However, -(CH2) n Cy 1 -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 -CH(OH)Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it is a C4-C9 cycloalkyl, a C3-C9 heterocyclic ring 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 a 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 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R 14However, if present, it is selected from -OH, -NH2, -O(C1-C4alkyl), -NH(C1-C4alkyl), and -N(C1-C4alkyl)(C1-C4alkyl), R 3 However, R is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, 4 However, a compound selected from hydrogen and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof, (a) at least one known drug for the treatment of neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy; (b) instructions for the administration of compounds related to the treatment of neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy; and (c) instructions for the treatment of neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy. One or more of the above A kit containing the following is disclosed.

[0387] In some embodiments, the structure is represented by the following formula: A compound having TIFF2026067907000178.tif42165, In the formula, m is 0 or 1, Q 1 and Q 2 Each of them is independently N or CH, and Q 3 However, it is CH2 or NH, and Z is CR 11a R 11b , NR 12 , or O, in the formula, R 11a and R 11b If each of these is present, they are independently selected from hydrogen, halogen, -OH, and C1-C4 alkyloxy, or R 11a and R 11b If each exists, together they form = O, R 12 However, if present, it is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or -(C1-C4 alkyl)(C3-C6 cycloalkyl), R 1a , R 1b , R 1c , and R 1dEach of these is independently selected from hydrogen, 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, R 2 However, -O(CH2) n Cy 1 , -NR 13 (CH2) n Cy 1 , and Cy 1 Selected from, where n is 0, 1, or 2 if present, R 13 However, if present, it is selected from hydrogen and C1-C4 alkyl, Cy 1 However, it 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 halogens, -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, and R 3 However, a compound that is a 3-6 member cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof, (a) at least one known drug for the treatment of neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy; (b) instructions for the administration of compounds related to the treatment of neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy; and (c) instructions for the treatment of neurodegenerative diseases, mitochondrial diseases, fibrosis, and / or cardiomyopathy. One or more of the above A kit containing the following is disclosed.

[0388] In further embodiments, the drugs are known for treating neurodegenerative diseases. Examples of drugs known for treating neurodegenerative disorders include, but are not limited to, cholinesterase inhibitors, antidepressants, memantine, rilutek, radiocava, levodopa, carbidopa, dopamine agonists, MAO-B inhibitors, catechol-O-methyltransferase inhibitors, anticholinergics, spinraza, tetrabenandin, antipsychotics, levetiracetam, clonazepam, tranquilizers, and amantadine.

[0389] In further embodiments, the drugs are known for treating mitochondrial diseases. Examples of drugs known for treating mitochondrial diseases include, but are not limited to, coenzyme Q10, vitamin B complex (e.g., thiamine (B1) and riboflavin (B2)), alpha-lipoic acid, L-carnitine (Carnitor), creatine, and vitamins and supplements such as L-arginine.

[0390] In further embodiments, the agents are known for treating fibrosis, such as idiopathic pulmonary fibrosis (IPF), non-alcoholic fatty liver disease (NASH), hepatic fibrosis, cardiac fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, and renal fibrosis. Examples of agents known for treating 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 cholinergics such as pilocarpine, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, anti-inflammatory agents, and antifibrotic agents.

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

[0392] In further embodiments, at least one compound and at least one drug are co-formulated. In further embodiments, at least one compound and at least one drug are co-packaged.

[0393] In further embodiments, the compound and the drug are administered sequentially. In even further embodiments, the compound and the drug are administered simultaneously.

[0394] This kit may 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, pharmacy, or pharmacist may provide a kit containing the disclosed compounds and / or products, as well as other elements for delivery to a patient.

[0395] Naturally, the disclosed kit can be prepared from the disclosed compounds, products, and pharmaceutical compositions. Similarly, naturally, the disclosed kit can be used in connection with the disclosed uses.

[0396] The foregoing description illustrates and explains the present disclosure. In addition, although the present disclosure shows and describes only preferred embodiments, as stated above, it is naturally possible to use them in a variety of other combinations, modifications, and environments, and can be modified or altered within the scope of the concept of the invention as expressed herein, in accordance with the teachings and / or art or knowledge of the related field. The embodiments described herein above are intended to describe the best known modes to the applicant and to enable the use of the present disclosure by making various modifications necessary for their particular application or use in such embodiments or other embodiments. Accordingly, this description is not intended to limit the invention to the forms disclosed herein. Furthermore, the appended claims are intended to be interpreted as including alternative embodiments.

[0397] All publications and patent applications referenced herein are incorporated herein by reference for all purposes to the same extent as each individual publication or patent application is specifically and individually described as being invoked by reference. In the event of any conflict between this disclosure and any of the publications or patent applications incorporated herein by reference, this disclosure shall prevail. [Examples]

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

[0399] 1. General experimental methods The common starting materials used were obtained from commercial sources or prepared in other examples unless otherwise specified. All temperatures are in Celsius (°C) and are uncorrected. Reagent-grade chemicals and anhydrous solvents were purchased from commercial sources and used without further purification unless otherwise specified. Product names were determined using naming software included in the Biovia electronic laboratory notebook. Silica gel chromatography was performed using a Teledyne Isco instrument with a packaged, disposable SiO2 stationary phase column, 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 and UV detection (214 and 254 nm), eluting with a gradient of MeCN / H2O (0.03% (NH4)2CO3 / 0.375% NH4OH, high pH) or MeCN / H2O (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 at 130°C using a Waters Micromass ZQ detector. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in cation mode and was set to scan at m / z 150 to 750 with a scan time of 0.3 seconds. The products and intermediates were analyzed by HPLC / MS (B05) using a Gemini-NX (5 μM, 2.0 × 30 mm) with a high pH buffer gradient of 5% to 100% MeCN / H2O (0.03% (NH4)2CO3 / 0.375% NH4OH) at a flow rate of 1.8 mL / min for 2.5 minutes, and by HPLC / MS (A05) using an EVO C18 (5 μM, 3.0 × 50 mm) with a low pH buffer gradient of 5% to 100% MeCN / H2O (0.1% HCOOH) at a flow rate of 2.2 mL / min for 2.5 minutes, for a run time of 3.5 minutes. 1 ¹H NMR spectra were recorded using a Bruker UltraShield 500MHz / 54mm instrument (BZH43 / 500 / 70B, D221 / 54-3209). Chemical shifts were referenced to the solvent peak. 1The solvent peaks in 1H NMR appear at 7.26 ppm for CDCl3, 2.50 ppm for DMSO-d6, and 3.31 ppm for CD3OD.

[0400] The following abbreviations have the meanings indicated. TIFF2026067907000179.tif146165

[0401] 2. Synthesis of adenine analogs The synthetic protocols used to access the exemplary compounds disclosed herein are described in the following schemes 1 to 5. TIFF2026067907000180.tif115165TIFF2026067907000181.tif74165TIFF2026067907 000182.tif79165TIFF2026067907000183.tif115165TIFF2026067907000184.tif95165

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

[0403] [Table 1] TIFF2026067907000186.tif191165TIFF2026067907000187.tif191165TIFF2026067907000188.tif215165TIFF2026067907000189.tif203165TIFF2026067907000190.tif191165TIFF2026067907000191.tif191165TIFF2026067907000192.tif191165TIFF2026067907000193.tif191165TIFF2026067907000194.tif191165TIFF2026067907000195.tif191165TIFF2026067907000196.tif191165TIFF2026067907000197.tif198165TIFF2026067907000198.tif191165TIFF2026067907000199.tif191165TIFF2026067907000200.tif194165TIFF2026067907000201.tif197165TIFF2026067907000202.tif200165TIFF2026067907000203.tif207165TIFF2026067907000204.tif204165TIFF2026067907000205.tif198165TIFF2026067907000206.tif210165TIFF2026067907000207.tif206165TIFF2026067907000208.tif211165TIFF2026067907000209.tif217165TIFF2026067907000210.tif215165TIFF2026067907000211.tif229165TIFF2026067907000212.tif216165TIFF2026067907000213.tif184165TIFF2026067907000214.tif203165TIFF2026067907000215.tif196165TIFF2026067907000216.tif223165TIFF2026067907000217.tif207165TIFF2026067907000218.tif212165TIFF2026067907000219.tif201165TIFF2026067907000220.tif187165TIFF2026067907000221.tif231165TIFF2026067907000222.tif190165TIFF2026067907000223.tif175165TIFF2026067907000224.tif204165TIFF2026067907000225.tif182165TIFF2026067907000226.tif170165TIFF2026067907000227.tif191165TIFF2026067907000228.tif210165TIFF2026067907000229.tif203165TIFF2026067907000230.tif188165TIFF2026067907000231.tif218165TIFF2026067907000232.tif194165TIFF2026067907000233.tif226165TIFF2026067907000234.tif220165TIFF2026067907000235.tif187165TIFF2026067907000236.tif219165TIFF2026067907000237.tif178165TIFF2026067907000238.tif186165TIFF2026067907000239.tif231165TIFF2026067907000240.tif199165TIFF2026067907000241.tif217165TIFF2026067907000242.tif224165TIFF2026067907000243.tif192165TIFF2026067907000244.tif222165TIFF2026067907000245.tif169165TIFF2026067907000246.tif164165TIFF2026067907000247.tif187165TIFF2026067907000248.tif186165TIFF2026067907000249.tif198165TIFF2026067907000250.tif199165TIFF2026067907000251.tif198165TIFF2026067907000252.tif180165TIFF2026067907000253.tif149165TIFF2026067907000254.tif229165TIFF2026067907000255.tif180165TIFF2026067907000256.tif174165TIFF2026067907000257.tif183165TIFF2026067907000258.tif161165TIFF2026067907000259.tif185165TIFF2026067907000260.tif171165TIFF2026067907000261.tif180165TIFF2026067907000262.tif229165TIFF2026067907000263.tif227165TIFF2026067907000264.tif159165TIFF2026067907000265.tif185165TIFF2026067907000266.tif176165TIFF2026067907000267.tif179165TIFF2026067907000268.tif86165.

[0404]

Table 2A

[0405]

Table 2B

[0406]

Table 2C

[0407] 4. Pre-formed fibril model Mouse and human alpha-synuclein monomers were commercially sourced, and pre-formed fibrils were then generated according to a detailed protocol provided by MJFF. For in vitro experiments, primary hippocampal neurons isolated from P0 offspring were grown for 7 days, after which 5 ug / ml of PFF was introduced. The pre-formed fibrils were introduced by stereotactic injection into the striatum of wild-type (C57BL / 6J, Jax number 000664) and transgenic A53T mice (B6, C3-Tg(Prnp-SNCA*A53T)83Vle / J, Jax number 004479). Subsequently, cohorts of drug-treated (forced oral administration) and untreated animals were aged for up to 6 months, at which point they were sacrificed and perfused. The brains were removed, fixed, and then segmented for analysis. We predict that untreated A53T animals will exhibit aggregated alpha-synuclein pathology and pS129 staining, as well as significant diffusion of some possible neurodegeneration. Wild-type animals are also expected to show pS129 synuclein staining and synuclein aggregation, albeit to a lesser degree than those seen in A53T backgrounds. Animals treated with drugs are expected to show significantly lower pS129 staining and reduced synuclein diffusion.

[0408] 5. Examination of crystallization and round cells In short, Hela MKYP (Mito-Keima / YFP-Parkin) cells were seeded at 10K cells / well. EP / MTK compounds were added at seeding (the cells were still in suspension). The cells were incubated with the EP / MTK compounds for 16 hours, followed by the addition of 1 μM FCCP / oligomycin over 6 hours. Before harvesting, the cells were visually scored at 20x magnification for the presence of crystalline compounds, aggregated compounds, or round cells.

[0409] [Table 3]

[0410] Table 4 below shows the data corresponding to the visual inspection of crystallization (1 = crystals present, 0 = no crystals).

[0411] [Table 4]

[0412] 6. Human phosphoubiquitin (PS65) UB assay In short, HeLa MKYP cells were plated in 10 cm plates at a density of 1,300,000 cells / plate in 10 mL of medium containing various concentrations of compounds. After incubation for 16 hours, the cells were treated with 0.5 μM FCCP / oligomycin for 2 hours 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 volumes of the sample 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 In short, HeLa MKYP cells were plated in 96-well plates at 10,000 cells / well with various concentrations of compounds. After incubation for 16 hours, the cells were treated with 1 μM FCCP / oligomycin for 6 hours, and then analyzed by FACS for the presence of mitochondria in lysosomes ...

Claims

1. The structure is represented by the following formula: A compound having, During the ceremony, Z is O, NH, or CH ２ And, R １ａ , R １ｂ , R １ｃ , and R １ｄ Each of these independently produces hydrogen, halogen, -CN, and -NH. ２ -OH, -NO ２ Selected from 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 ２ is selected from -(CH ２ ), ｎ Cy １ , -O(CH ２ ), ｎ Cy １ , -NR １３ (CH ２ ), ｎ Cy １ , -CH(OH)Cy １ , and Cy １ ; During the ceremony, If n exists, it is 0, 1, or 2. R １３ However, if present, it is selected from hydrogen and C1-C4 alkyl. Cy １ However, it 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 contains halogens, -CN, -NH ２ -OH, -NO ２ ,=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 , substituted with 0, 1, 2, or 3 groups independently selected from C1-C4 alkylamino and (C1-C4)(C1-C4) dialkylamino, R １４ However, if present, -OH, -NH ２ Selected from -O(C1-C4 alkyl), -NH(C1-C4 alkyl), and -N(C1-C4 alkyl)(C1-C4 alkyl), R ３ However, the compound is a 3-6 membered cycloalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 halohydroxyalkyl, or a pharmaceutically acceptable salt thereof.

2. The compound, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a therapeutically effective amount of any compound according to claim 1 to 3 and a pharmaceutically acceptable carrier.

5. Use of a compound according to any one of claims 1 to 3, or a composition according to claim 4, for the manufacture of a therapeutic agent for a disorder in a subject requiring treatment of the disorder, wherein the treatment comprises administering an effective amount of the compound according to any one of claims 1 to 3, or the composition according to claim 4, to the subject requiring the treatment, and the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy.

6. The use according to claim 5, wherein the subject is a mammal.

7. The use according to claim 5, wherein the subject is a human.

8. The use according to any one of claims 5 to 7, wherein the subject is diagnosed with the disorder before the administration step.

9. The use according to any one of claims 5 to 8, wherein the neurodegenerative disorder is Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis.

10. The use according to any one of claims 5 to 8, wherein the neurodegenerative disorder is Parkinson's disease.

11. A pharmaceutical composition for the treatment of a disorder in a subject requiring treatment of the disorder, comprising a therapeutically effective amount of any compound of claims 1 to 3, wherein the treatment comprises administering to the subject requiring treatment the effective amount of any compound of claims 1 to 3 or the composition of claim 4, and the disorder is a neurodegenerative disorder, a mitochondrial disorder, fibrosis, or cardiomyopathy.

12. The pharmaceutical composition according to claim 11, wherein the subject is a human.

13. The pharmaceutical composition according to any one of claims 11 to 12, wherein the neurodegenerative disorder is Parkinson's disease, Huntington's disease, or amyotrophic lateral sclerosis.

14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the neurodegenerative disorder is Parkinson's disease.

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