Methods and agents for stimulating mitochondrial turnover to treat disease - Patents.com

Abstract

Provided herein is a method for stimulating mitophagy in a subject in need thereof, comprising administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist or a substance that induces the endogenous production of a MAS receptor agonist. The present disclosure also relates to medical interventions and medicaments, i.e., methods and medicaments for stimulating mitochondrial turnover for the treatment of disease in a mammal. The present disclosure includes a method for stimulating increased mitochondrial turnover in a mammal, comprising administering to the mammal a pharmacologically suitable dose of a MAS receptor agonist, a MAS receptor modulator, a substance that induces the endogenous production of a MAS receptor agonist, a substance that induces the endogenous production of a MAS receptor modulator, or any combination thereof. The pharmacological activity acting on the MAS receptor then stimulates increased mitochondrial turnover in the host cell, alleviating the disease state in the host mammalian organism.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 142,683, filed January 28, 2021, the entirety of which is incorporated herein by reference.

[0002] The present disclosure relates to medical intervention methods and agents, namely, methods and agents for stimulating mitochondrial turnover for the treatment of disease in a mammal.

[0003] Incorporation by Reference The following documents are incorporated by reference in their entirety: Bakula and Scheibye-Knudsen, Front. Cell. Dev. Biol. 2020, 8:239; Bose and Beal, J. Neurochem., 2016 Oct. 139 Suppl. () 216-231; Joshi & Kundu, Autophagy 2013 Nov 1 9(11) 1737-49, Killackey et al., J. Cell Biol., 2020, 219:11; Morciano et al., J Clin. Med., 2020 March; 9(3):892; Morgia et al. al., J. Int. Med. 2020, 287;592-608.; U.S. Patent No. 6,235,766; U.S. Patent No. 6,538,144; U.S. Patent No. 9,943,509(B2); U.S. Patent No. 10,301,298(B2); U.S. Patent Application Publication No. 2008 / 0039363; U.S. Patent Application Publication No. 2020 / 0179407; and European Patent No. 2991663(B1). [Background technology]

[0004] Mitochondria are the respiratory organelles of eukaryotic cells. Aerobic eukaryotes require mitochondria to produce most of their cellular adenosine triphosphate (ATP), the primary vehicle for intracellular chemical energy transfer via oxidative phosphorylation (OXPHOS). Without sufficient mitochondria, a cell lacks the chemical energy required to perform basic functions and the cell will malfunction and / or die.

[0005] Mitochondria are semi-autonomous, with their own genome and cell cycle independent of the nuclear genome and cell cycle of the host organism. Each mitochondrion is guided by complex signal sequences between the mitochondrion, its host cell, and the host cell's environment to survive, grow, maintain homeostasis, divide, and die within our cells.

[0006] Healthy mitochondria are essential for cell survival, and therefore it is not surprising that many serious medical disorders are associated with mitochondrial dysfunction. As an example, mitochondrial dysfunction has been discussed as an important contributor to the pathogenesis of familial Parkinson's disease. (Bose & Beal, J.Neurochem. 2016 Oct.139 Suppl.()216-231.) Mitochondrial genetic disorders, while individually rare, collectively represent the most common form of genetic disease in humans. (Morgia et al., J.Int.Med. 2020,287;592-608.) Cells maintain a healthy population of mitochondria through a homeostatic "turnover" process, whereby new mitochondria are produced and grown while old mitochondria die and are recycled. Entire categories of diseases are associated with subnormal rates of mitochondrial maintenance and turnover. (Bakula & Scheibye-Knudsen, Front. Cell. Dev. Biol. 2020, 8:239; Killackey et al., J. Cell Biol., 2020, 219:11.) Novel agents and methods for treating such diseases would therefore be highly desirable. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Bose & Beal, J. Neurochem.” 2016 Oct.139 Suppl.()216-231. [Non-Patent Document 2] Morgia et al.,J.Int.Med.2020,287;592-608. [Non-Patent Document 3] Bakula & Scheibye-Knudsen,Front.Cell.Dev.Biol.2020,8:239 [Non-Patent Document 4] Killackey et al.,J.Cell Biol.,2020,219:11. Summary of the Invention

[0008] Heretofore, it was not known that MAS agonists stimulate mitophagy distinct from mitochondrial dysfunction, and thus provide the desired therapeutic benefit in various diseases. Provided herein is a method of stimulating mitophagy in a subject in need thereof, comprising administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist.

[0009] It is believed that MAS agonists can target the mitophagy pathway and promote mitophagy through several mechanisms (mTORC1; NRF2 activation; TFEB expression; inhibition of ATP hydrolysis by mitochondrial complex V; mitochondrial dynamics, etc.) in a tissue-specific manner. It is further believed that such mitophagy pathways may include stimulation of biogenesis (i.e., maintenance of mitochondrial mass through mitochondrial biogenesis), promotion of autophagosome formation, lysosome formation and acidification, autophagosome / lysosome fusion, and degradation of autophagolysosome content.

[0010] The present disclosure relates to methods and agents for stimulating mitochondrial turnover for the treatment of disease in a mammal.

[0011] In some aspects, the disclosure includes a method of stimulating increased mitochondrial turnover in a mammal, comprising administering to the mammal a pharmacologically suitable dose of a MAS receptor agonist, a MAS receptor modulator, an agent that induces the endogenous production of a MAS receptor agonist, an agent that induces the endogenous production of a MAS receptor modulator, or any combination thereof. In some embodiments, the mammal is a human patient.

[0012] In some aspects, the substance that induces the endogenous production of the MAS receptor agonist is a substance that induces the endogenous production of angiotensin (1-7). In some embodiments, the substance that induces the endogenous production of angiotensin (1-7) is either an ACE2 enzyme or an analog thereof, an ACE2 activator or an analog thereof, an ACE inhibitor or an analog thereof, or any combination thereof. In some embodiments, the substance that induces the endogenous production of angiotensin (1-7) is either an ACE2 enzyme, an ACE2 activator, an ACE inhibitor, or any combination thereof. In some embodiments, the ACE2 enzyme is a recombinant human ACE2 enzyme. In some embodiments, the ACE2 activator is xanthenon or diminazene aceturate. In some embodiments, the ACE inhibitor is enazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or any combination thereof.

[0013] In some embodiments, the MAS receptor agonist of the present disclosure is a heterocyclic non-peptidic angiotensin(1-7) mimetic of its analogs (such as those defined herein as formula (III)), Nle 3 In one embodiment, the Nle is selected from the group consisting of Nle-A(1-7) or an analog thereof, angiotensin(1-7) or an analog thereof, 20-hydroxyecdysone or an analog thereof, and 1-(p-thienylbenzyl)imidazole analog. 3 -A(1-7) or an analog thereof, or angiotensin(1-7) or an analog thereof, is glycosylated.

[0014] In another embodiment, the MAS receptor agonist is selected from the group consisting of 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole.

[0015] In yet another embodiment, the MAS receptor agonist is Compound 7 (as defined in the disclosure herein), Compound 10 (as defined in the disclosure herein), Nle 3 In yet another embodiment, the MAS receptor agonist is selected from the group consisting of Compound 7, Compound 10, Nle(1-7), Ang-1-6-Ser-0-glycosylated analog of Angiotensin(1-7), and 1-(p-thienylbenzyl)imidazole. 3 -A(1-7), and angiotensin(1-7).

[0016] In some embodiments, stimulation of increased mitochondrial turnover results in the treatment of a disease, disorder, or condition in a mammal (such as a human). In some embodiments, stimulation of increased mitochondrial turnover results in the treatment of a disease. In some embodiments, the disease is a disease associated with having subnormal mitochondrial turnover. In some embodiments, the disease associated with subnormal mitochondrial turnover is an inflammatory disease, a neurodegenerative disease, an eye disease, or a combination thereof.

[0017] In some embodiments, the inflammatory disease is primary biliary cirrhosis / cholangitis (PBC), sepsis, and / or renal trauma / injury, wherein the neurodegenerative disease is schizophrenia, and the eye disease is Fuchs endothelial dystrophy, microphthalmia syndrome 7, Werner's syndrome, and / or Fanconi anemia.

[0018] In some embodiments, the disease associated with subnormal mitochondrial turnover is any of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), cardiovascular disease, frontotemporal dementia, hematopoietic disorders, Parkinson's disease, primary biliary cirrhosis / cholangitis (PBC), sepsis, renal trauma / injury, or any combination thereof.

[0019] In some embodiments, the disease associated with subnormal mitochondrial turnover is ataxia telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguenay spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disorder with short stature and variable skeletal anomalies; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON); Leigh syndrome; mental retardation, X-linked, syndromic, Turner type, MRXST); maternally inherited diabetes and deafness syndrome (MIDD); microcephaly 18 (MIDDMCPH18); microphthalmia syndrome 7; mitochondrial DNA depletion syndrome (microcephaly 18, MIDDMDDS); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (microcephaly 18, MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); mitochondrial recessive ataxia syndrome (MIRAS); mtDNA heteroplasmy; methylmalonic acidemia (MMA); mucolipidosis II (MIDDML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (mucolipidosis II, MIDDNADGP);Myoclonic epilepsy with ragged red fibers (mucolipidosis II, MIDDMERRF);neurodegeneration with brain iron accumulation 5, NBIA5;neurodevelopment disorder with spastic quadriplegia and brain abnormalities with or without seizures, NEDSBAS;neural ceroid lipofuscinosis;Niemann-Pick disease;neuropathy, ataxia, and retinitis pigmentosa, NARP;Pearson syndrome;Pompe disease;rhabdomyosarcoma;schizophrenia;spastic paraplegia type 15;spastic paraplegia type 49;spinocerebellar ataxia 4, SCA4;spinocerebellar ataxia 25 25, SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) Group A; Zellweger syndrome; or any combination thereof.

[0020] In another embodiment, the disease associated with subnormal mitochondrial turnover is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; cardiovascular disease; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; frontotemporal dementia; Fuchs endothelial dystrophy; Gaucher disease; hematopoietic disorders; intellectual developmental disability with short stature and malformed skeletal anomalies; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis. encephalopathy;Lafora disease;Leber's hereditary optic neuropathy (LHON);Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonic epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Parkinson's disease; Pearson syndrome; Pompe disease; primary biliary cirrhosis / cholangitis (PBC); rhabdomyosarcoma; schizophrenia; sepsis; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0021] In yet another embodiment, the disease associated with subnormal mitochondrial turnover is any of mitochondrial DNA depletion syndrome (MDDS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); mitochondrial recessive ataxia syndrome (MIRAS); Leber's hereditary optic neuropathy (LHON); myoclonus epilepsy with ragged-red fibers (MERRF); neuropathy, ataxia, and retinitis pigmentosa (NARP); maternally inherited diabetes and deafness syndrome (MIDD); mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Pearson syndrome; Barth syndrome; mtDNA heteroplasmy; rhabdomyosarcoma; Friedreich's ataxia; methylmalonic acidemia (MMA); lactic acidosis; Leigh syndrome; Kearns-Sayre syndrome; or any combination thereof.

[0022] In yet another embodiment, the disease associated with subnormal mitochondrial turnover is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); ataxia telangiectasia; autosomal dominant optic atrophy; Barth syndrome; cardiovascular disease; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; frontotemporal dementia; Gaucher disease; hematopoietic disorders; intellectual disability with short stature and skeletal abnormalities; Krabbe disease; Lafora disease; microcephaly; mental retardation, X-linked, syndromic, Turner type (MRXST); mucolipidosis. cis II; multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; Parkinson's disease; Pompe disease; spastic paraplegia type 15; spastic paraplegia 49; spinocerebellar degeneration 4; spinocerebellar degeneration 25; Vici syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0023] In some embodiments, stimulating increased mitochondrial turnover in a mammal comprises administering to the mammal a pharmacologically suitable dose of a MAS receptor agonist, a MAS receptor modulator, a substance that induces the endogenous production of a MAS receptor agonist, a substance that induces the endogenous production of a MAS receptor modulator, or any combination thereof, further comprising co-administering a pharma- ceutically acceptable excipient, carrier, adjuvant, buffering agent, preservative, chelating agent, nuclease, antifungal agent, antibacterial agent, or any combination thereof. In some embodiments, the MAS receptor agonist, MAS receptor modulator, a substance that induces the endogenous production of a MAS receptor agonist, a substance that induces the endogenous production of a MAS receptor modulator, or any combination thereof, further comprises a pharma- ceutically acceptable excipient, carrier, adjuvant, buffering agent, preservative, chelating agent, nuclease, antifungal agent, antibacterial agent, or any combination thereof.

[0024] In some embodiments, the pharmacologically suitable dose of the MAS receptor agonist is between 0.01 and 500 mg. 薬剤 / kg 患者 In some embodiments, a pharmacologically suitable dose of a MAS receptor agonist, a MAS receptor modulator, an agent that induces the endogenous production of a MAS receptor agonist, an agent that induces the endogenous production of a MAS receptor modulator, or any combination thereof, is between 0.01 and 500 mg. 薬剤 / kg 患者 It is.

[0025] In some embodiments, the MAS receptor agonist, MAS receptor modulator, substance that induces the endogenous production of a MAS receptor agonist, substance that induces the endogenous production of a MAS receptor modulator, or any combination thereof, is administered topically, orally, intravenously, intramuscularly, intraocularly, intradermally, rectally, by oral inhalation, by nasal inhalation, parenterally, bucally, epidurally, intracerebrally, intracerebroventricularly, or any combination thereof. In some embodiments, the MAS receptor agonist, MAS receptor modulator, substance that induces the endogenous production of a MAS receptor agonist, substance that induces the endogenous production of a MAS receptor modulator, or any combination thereof, is delivered via intravenous infusion, hypodermic needle, capsule, tablet, topical gel / cream / solution, transdermal patch, or any combination thereof. In another embodiment, the MAS receptor agonist is administered topically, orally, intravenously, intramuscularly, intraocularly, intradermally, rectally, by oral inhalation, by nasal inhalation, parenterally, bucally, epidurally, intracerebrally, intracerebroventricularly, or any combination thereof. In some embodiments, the MAS receptor agonist, MAS receptor modulator, substance that induces the endogenous production of the MAS receptor agonist, substance that induces the endogenous production of the MAS receptor modulator, or any combination thereof, is delivered via intravenous infusion, hypodermic needle, capsule, tablet, topical gel / cream / solution, transdermal patch, or any combination thereof. In one embodiment, the MAS receptor agonist is delivered via intravenous infusion, hypodermic needle, capsule, tablet, topical gel / cream / solution, transdermal patch, or any combination thereof.

[0026] In another aspect, the disclosure includes a method of treating a human patient having a disorder associated with subnormal mitochondrial turnover, the method comprising the steps of diagnosing the patient having a disorder associated with subnormal mitochondrial turnover and administering a pharmacologically effective amount of a mitochondrial turnover stimulating drug. In some embodiments, the mitochondrial turnover stimulating drug is an analog of a heterocyclic nonpeptidic angiotensin(1-7) mimetic compound, angiotensin(1-7) or an analog thereof, an Nle(1-7) or an analog thereof, 3In some embodiments, the mitochondrial turnover stimulating drug is selected from the group consisting of a heterocyclic non-peptidic angiotensin (1-7) mimetic or an analog thereof, an Nle-A(1-7) analog, a 20-hydroxyecdysone or an analog thereof, and an analog of 1-(p-thienylbenzyl)imidazole. 3 -A(1-7) or an analog thereof, angiotensin(1-7) or an analog thereof, 1-(p-thienylbenzyl)imidazole analog, and 20-hydroxyecdysone or an analog thereof. In some embodiments, the mitochondrial turnover stimulating drug further comprises a pharma- ceutically acceptable excipient, carrier, adjuvant, buffer, preservative, chelating agent, nuclease, antifungal agent, antibacterial agent, or any combination thereof. In some embodiments, the mitochondrial turnover stimulating drug is delivered via intravenous infusion, hypodermic needle, capsule, tablet, topical gel / cream / solution, transdermal patch, or any combination thereof. In some embodiments, the mitochondrial turnover stimulating drug is administered topically, orally, intravenously, intramuscularly, intraocularly, intradermally, rectally, by oral inhalation, by nasal inhalation, parenterally, bucally, epidurally, intracerebrally, intracerebroventricularly, or any combination thereof.

[0027] In one embodiment, the disease associated with subnormal mitochondrial turnover is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; cardiovascular disease; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; frontotemporal dementia; Fuchs endothelial dystrophy; Gaucher disease; hematopoietic disorders; intellectual developmental disability with short stature and malformed skeletal anomalies; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis. encephalopathy;Lafora disease;Leber's hereditary optic neuropathy (LHON);Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonic epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Parkinson's disease; Pearson syndrome; Pompe disease; primary biliary cirrhosis / cholangitis (PBC); rhabdomyosarcoma; schizophrenia; sepsis; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0028] In one embodiment, the patient is diagnosed using at least a mitophagy assay. In some embodiments, the mitophagy assay is used to assess mitochondrial function and is an assay that measures oxygen consumption; the amount of mitochondrial DNA (mtDNA) mutations or deletions, or the amount of mutations and deletions; mtDNA copy number; or the activity of mitochondrial enzymes.

[0029] In some embodiments, a pharmacologically effective amount of a mitochondrial turnover stimulating drug, i.e., a MAS receptor agonist, a MAS receptor modulator, an agent that induces the endogenous production of a MAS receptor agonist, an agent that induces the endogenous production of a MAS receptor modulator, or any combination thereof, is between 0.01 and 500 mg. 薬剤 / kg 患者 It is.

[0030] In yet another embodiment, the MAS receptor agonist further comprises a pharma- ceutically acceptable excipient, carrier, adjuvant, buffer, preservative, chelating agent, nuclease, antifungal agent, antibacterial agent, or any combination thereof. In some embodiments, the MAS receptor agonist is administered topically, orally, intravenously, intramuscularly, intraocularly, intradermally, rectally, by oral inhalation, by nasal inhalation, parenterally, bucally, epidurally, intracerebrally, intracerebroventricularly, or any combination thereof. The MAS receptor agonist may be delivered via intravenous infusion, hypodermic needle, capsule, tablet, topical gel / cream / solution, transdermal patch, or any combination thereof.

[0031] In one embodiment, the disclosure includes a method of treating a human patient having a disease associated with subnormal mitochondrial turnover, the method comprising the step of diagnosing a patient having a disease associated with subnormal mitochondrial turnover, the diagnosis being made using at least a mitophagy assay, the disease associated with subnormal mitochondrial turnover being Alzheimer's disease; amyotrophic lateral sclerosis (ALS); ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; cardiovascular disease; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; frontotemporal dementia; Fuchs' intracranial syndrome; Dystrophia;Gaucher disease;Hematopoietic disorders;Intellectual retardation with short stature and skeletal abnormalities;Kerns-Sayre syndrome;Krabbe disease;Lactic acidosis;Lafora disease;Leber's hereditary optic neuropathy (LHON);Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II);Multiple sulfatase deficiency;Neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP);Myoclonus epilepsy with ragged red fibers (MERRF);Neurodegeneration with cerebral iron deposition 5 (NBIA5);Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS);Neuronal ceroid lipofuscinosis;Niemann-Pick disease;Neuropathy, ataxia, and retinitis pigmentosa (NARP);Parkinson's disease;Pearson syndrome;Pompe disease;Primary biliary cirrhosis / cholangitis (PBC);Rhabdomyosarcoma;Schizophrenia;Sepsis;Spastic paraplegia type 15;Spastic paraplegia type 49;Spinocerebellar degeneration 4 (SCA4);Spinocerebellar degeneration 25 (SCA25);Vici syndrome;Werner syndrome;Wolfram syndrome;Xeroderma pigmentosum (XP) group A;Zellweger syndrome;or any combination thereof; and administering a pharmacologically effective amount of a mitochondrial turnover stimulating drug, the mitochondrial turnover stimulating drug being selected from the group consisting of a heterocyclic non-peptidic angiotensin(1-7) mimetic compound or analog thereof; angiotensin(1-7) or analog thereof; Nle; 3 -A(1-7) or an analog thereof; 20-hydroxyecdysone or an analog thereof; and an analog of 1-(p-thienylbenzyl)imidazole.

[0032] In some embodiments, a pharmacologically effective amount of a mitochondrial turnover stimulating drug, i.e., a MAS receptor agonist; a MAS receptor modulator; an agent that induces the endogenous production of a MAS receptor agonist; an agent that induces the endogenous production of a MAS receptor modulator; or any combination thereof, is in the range of 0.01 to 500 mg. 薬剤 / kg 患者 It is.

[0033] In one embodiment, the MAS receptor agonist further comprises a pharma- ceutically acceptable excipient, carrier, adjuvant, buffer, preservative, chelating agent, nuclease, antifungal agent, antibacterial agent, or any combination thereof. In another embodiment of the method, the MAS receptor agonist is administered topically, orally, intravenously, intramuscularly, intraocularly, intradermally, rectally, by oral inhalation, by nasal inhalation, parenterally, bucally, epidurally, intracerebrally, intracerebroventricularly, or any combination thereof.

[0034] In one embodiment, the disclosure includes a method of treating a human patient having a disease associated with subnormal mitochondrial turnover comprising administering a pharmacologically effective amount of a MAS receptor agonist, wherein the disease associated with subnormal mitochondrial turnover is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; cardiovascular disease; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; frontotemporal dementia; Fuchs endothelial dystrophy; Gaucher disease; hematopoietic disorders; Intellectual disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; Lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON); Leigh syndrome; Mental retardation, X-linked, syndromic, Turner type (MRXST); Maternally inherited diabetes and deafness syndrome (MIDD); Microcephaly 18 (MCPH18); Microphthalmia 7; Mitochondrial DNA depletion syndrome (MDDS); Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); Mitochondrial recessive ataxia syndrome (MIRAS); mtDNA heteroplasmy; Methylmalonic acidemia (MMA); Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonic epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Parkinson's disease; Pearson syndrome; Pompe disease; primary biliary cirrhosis / cholangitis (PBC); rhabdomyosarcoma; schizophrenia; sepsis; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0035] In some embodiments, a pharmacologically effective amount of a MAS receptor agonist, a MAS receptor modulator, an agent that induces endogenous production of a MAS receptor agonist, an agent that induces endogenous production of a MAS receptor modulator, or any combination thereof, is between 0.01 and 500 mg. 薬剤 / kg 患者 In some embodiments, the pharmacologically effective amount of the MAS receptor agonist is 0.01 to 500 mg. 薬剤 / kg 患者 It is.

[0036] In one embodiment, the MAS receptor agonist further comprises a pharma- ceutically acceptable excipient, carrier, adjuvant, buffer, preservative, chelating agent, nuclease, antifungal agent, antibacterial agent, or any combination thereof. In another embodiment, the MAS receptor agonist is administered topically, orally, intravenously, intramuscularly, intraocularly, intradermally, rectally, by oral inhalation, by nasal inhalation, parenterally, bucally, epidurally, intracerebrally, intracerebroventricularly, or any combination thereof.

[0037] In any one of the embodiments of the present disclosure, the 1-(p-thienylbenzyl)imidazole analog has the formula (I) in any stereoisomeric form or mixtures thereof in any ratio:

[0038] [ka] [wherein R(1) is (1) halogen, (2) hydroxyl, (3) (C1-C4)-alkoxy, (4) (C1-C8)-alkoxy (wherein 1 to 6 carbon atoms are replaced by heteroatoms O, S, or NH), (5) (C1-C4)-alkoxy substituted by saturated cyclic ethers, (6) O-(C1-C4)-alkenyl, (7) O-(C1-C4)-alkylaryl, or (8) phenoxy, which is unsubstituted or substituted by a substituent selected from halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, and trifluoromethyl; R (2) is (1) CHO; R(3) is (1) (C1-C4)-alkyl, or (2) aryl; R(4) is (1) hydrogen, (2) halogen, or (3) (C1-C4)-alkyl; X is (1) oxygen, or (2) sulfur; Y is (1) oxygen, or (2) -NH-; R(5) is (1) hydrogen, (2) (C1-C6)-alkyl, or (3) (C1-C4)-alkylaryl, where R(5) may be hydrogen only if Y has the meaning given in (2), and R(6) is (1) (C1-C5)-alkyl, or a physiologically acceptable salt thereof.

[0039] In any one of the embodiments of the present disclosure, the 1-(p-thienylbenzyl)imidazole analog has the formula (II) in all stereoisomers and mixtures thereof in all ratios:

[0040] [ka] [In the formula, R(1) is 1. (C1-C5)-alkyl which is unsubstituted or substituted with a radical selected from NH2, halogen, O-(C1-C3)-alkyl, CO-O-(C1-C3)-alkyl, and CO2H; 2. (C3-C8)-cycloalkyl; 3. (C1-C3)-alkyl-(C3-C8)-cycloalkyl; 4. (C6-C7)-alkyl which is unsubstituted or substituted with a radical selected from halogen and O-(C1-C3-alkyl; 10)-aryl, 5.(C1-C3)-alkyl-(C6-C 10 )-aryl, where the aryl radical is unsubstituted or substituted by a radical selected from halogen and O-(C1-C3)-alkyl, 6. (C3-C5)-heteroaryl, and 7. (C1-C3)-alkyl-(C1-C5)-heteroaryl; R(2) is selected from 1. hydrogen, 2. (C1-C6)-alkyl, unsubstituted or substituted by a radical selected from halogen and O-(C1-C3-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C1-C3)-alkyl-(C3-C8)-cycloalkyl, 5. unsubstituted or substituted by a radical selected from halogen, O-(C1-C3)-alkyl and CO-O-(C1-C3)-alkyl, (C6-C 10 )-aryl, and 6. (C1-C3)-alkyl-(C6-C8) which is unsubstituted or substituted by a radical selected from halogen and O-(C1-C3)-alkyl. 10 )-aryl; R(3) is selected from 1. hydrogen, 2. COOH, and 3. COO-(C1-C4)-alkyl; R(4) is selected from 1. hydrogen, 2. halogen, and 3. (C1-C4)-alkyl; R(5) is selected from 1. hydrogen, and 2. (C1-C6)-alkyl; R(6) is selected from hydrogen, 2. (C1-C6)-alkyl, 3. (C1-C3)-alkyl-(C3-C8)-cycloalkyl, and 4. (C2-C6)-alkenyl; X is selected from 1. oxygen, and 2. NH; and physiologically tolerated salts thereof.

[0041] In some embodiments, 1-(p-thienylbenzyl)imidazole is 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, which is the compound depicted below.

[0042] [ka]

[0043] In any embodiment of the present disclosure, the heterocyclic non-peptidic angiotensin(1-7) mimetic compound has formula (III):

[0044] [ka] wherein ring A is a 5- or 6-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms; ring B is a 5- or 6-membered heteroaryl ring containing at least one nitrogen atom; ring C is an optionally substituted aryl ring; 1 , A 2 , A 3 , A 4 are independently =N-, -C(=O)-, -C(R a )=, =C(R b )-, -C(R c )(R d )-N(R e )-, -C(R c )(R d )-O-, or -[C(R c )(R d )] n -, where n is 1 or 2; X 1 ~X 2 is (R 6 )CN, NC(R 6 ), NN, NO, 0-N, NS, or SN; X 3 is (R 7 )C=C(R 8 ), O, S, or N(R 9 and Z is O, NH or R 5 is a bond to; R a and R bis independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido, or carboxy, with the proviso that R a and R b may also be joined to form a ring of up to six atoms; R c and R d is independently selected from the group consisting of hydrogen, alkyl, aryl, or heteroaryl, with the proviso that R c and R d may also be joined to form a ring of up to six atoms; R e is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R 2 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R 5 is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; R 9 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylanomicyl, or a pharma- ceutically acceptable salt thereof.

[0045] In any embodiment of the present disclosure, the 20-hydroxyecdysone analog has the formula (IV):

[0046] [ka] [wherein V is a carbon-carbon single bond, Y is a hydroxyl group or hydrogen, or V is a C=C ethylene bond; X is oxygen, Q is a carbonyl group; R 1 are selected from the group (C1-C6)W(C1-C6); the group (C1-C6)W(C1-C6)W(C1-C6); the group (C1-C6)W(C1-C6)CO2(C1-C6); the group (C1-C6)A (wherein A represents a heterocycle, optionally substituted by groups of the type OH, OMe, (C1-C6), N(C1-C6), CO2(C1-C6))CH2Br; where W is a heteroatom selected from N, O and S.

[0047] In any embodiment of the disclosure, the angiotensin(1-7) analog is a sequence of at least three consecutive amino acids of the R1-R8 groups in a sequence of the general formula (i) R1-R2-R3-R4-R5-R6-R7-R8, where R1 and R2 taken together are of the formula XR A -R B - group, X is H or 1 to 3 peptide groups; R A is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2), Suc, and glycosylated forms thereof; R B R is selected from the group consisting of Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg, D-Lys, His, and glycosylated forms thereof; R is selected from the group consisting of Val, Ala, Leu, Nle, Ile, Gly, Pro, Aib, Acpc, Lys, Tyr, and glycosylated forms thereof; R 4is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ser, Hse, Ala, azaTyr, Tyr, Phe, and glycosylated forms thereof; R5 is selected from the group consisting of Ile, Ala, Leu, Nle, Val, Gly, and glycosylated forms thereof; R6 is His, Arg, 6-NH2-Phe, Lys, and glycosylated forms thereof; R7 is Pro, Ala, Gly, Ser, or glycosylated forms thereof; and R8 is selected from the group consisting of Phe, Phe(Br), Ile, Tyr, Ser, Thr, Hyp, and glycosylated forms thereof. In some embodiments of formula (i), formula (i) excludes sequences that include R4 as a terminal Tyr group.

[0048] In any embodiment of the present disclosure, an analog of angiotensin(1-7) may also comprise a sequence of the general formula (ii) Ala1-R2-R3-R4-R5-R6-R7, where R2 is selected from Arg, Lys, Ala, Cit, Orn, Ser(Ac), Sar, D-Arg, and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, Nle, Ile, Gly, Pro, Aib, Acpc, Lys, and Tyr; R4 is Ser or forms a cyclic thioether with R7; R5 is selected from the group consisting of Ile, Ala, Leu, Nle, Val, and Gly; R6 is His, Arg, 6-NH2-Phe, Lys, and glycosylated forms thereof; and R7 is Cys or forms a cyclic thioether with R4.

[0049] In any embodiment of the present disclosure, the disease can be a disease associated with having above-normal levels of mitophagy. In any embodiment of the present disclosure, the disease is a disease associated with having below-normal levels of mitochondrial biogenesis. [Brief description of the drawings]

[0050] Exemplary embodiments of the present disclosure will be better understood and readily apparent to those skilled in the art from the following written description, by way of example only, taken in conjunction with the drawings in which: [Figure 1-1] FIG. 1 is an exemplary schematic diagram of the role of the MAS receptor in the angiotensin cell signaling pathway. [Figure 1-2] FIG. 1 is an exemplary schematic diagram of the canonical renin-angiotensin-aldosterone system (RAAS). [Figure 2-1] FIG. 1 is a cell signaling schematic of conventional pharmacological intervention strategies in the RAAS system, for example, using ACE inhibitors or angiotensin II receptor blockers. [Figure 2-2] FIG. 1 is a schematic diagram of the cell signaling pathway of angiotensin(1-7) affecting the MAS receptor. [Figure 3-1] FIG. 1 shows the chemical structure of a small molecule defined herein as “Compound 7.” [Figure 3-2] FIG. 1 shows the chemical structure of the heptapeptide angiotensin(1-7). [Figure 3-3] FIG. 1 shows the chemical structure of the synthetic peptide Nle3-A(1-7), also known as aclerastide. [Diagram 3-4] FIG. 1 shows the chemical structure of the small molecule 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole. [Figure 4] FIG. 1 is a schematic diagram of the biomolecular causes of mitophagy and some exemplary downstream pathogens therefrom. [Diagram 5] FIG. 2 shows a fluorescent probe assay for mitophagy in eukaryotic cells. [Figure 6-1] FIG. 1 shows the rate of mitophagy after three treatment periods with various test compounds, including dimethyl sulfoxide (DMSO) negative control and 50 nM angiotensin(1-7), Nle3-A(1-7), and compound 7. [Figure 6-2]FIG. 1 shows the rate of mitophagy after 8 hours of treatment with DMSO negative control and MAS receptor agonists Angiotensin(1-7), Nle3-A(1-7) and Compound 7 at four different dose levels. [Figure 6-3] Figure 1 shows the mitophagy response to MAS receptor activation and chemical knockdown of the MAS receptor. Cells were treated with DMSO negative control, 1 μM MAS receptor inhibitor (antagonist) A779, angiotensin (1-7), angiotensin (1-7) + A779, Nle3-A (1-7), Nle3-A (1-7) + A779, compound 7, and compound 7 + A779. The results of the experiments provide strong evidence that MAS receptor activity directly affects mitochondrial turnover. [Figure 7-1] Figure 7 shows the oxygen consumption rate (OCR) in cells treated with DMSO negative control, no mitochondria control, and three different concentrations of MAS receptor agonists Nle3-A(1-7) (Figure 7A), angiotensin(1-7) (Figure 7B), and compound 7 (Figure 7C). CCCP is carbonyl cyanide m-chlorophenylhydrazone, a chemical inhibitor of OXPHOS, which acts in these experiments as a negative control for mitochondrial activity. [Figure 7-2] Figure 7 shows the oxygen consumption rate (OCR) in cells treated with DMSO negative control, no mitochondria control, and three different concentrations of MAS receptor agonists Nle3-A(1-7) (Figure 7A), angiotensin(1-7) (Figure 7B), and compound 7 (Figure 7C). CCCP is carbonyl cyanide m-chlorophenylhydrazone, a chemical inhibitor of OXPHOS, which acts in these experiments as a negative control for mitochondrial activity. [Figure 7-3]Figure 7 shows the oxygen consumption rate (OCR) in cells treated with DMSO negative control, no mitochondria control, and three different concentrations of MAS receptor agonists Nle3-A(1-7) (Figure 7A), angiotensin(1-7) (Figure 7B), and compound 7 (Figure 7C). CCCP is carbonyl cyanide m-chlorophenylhydrazone, a chemical inhibitor of OXPHOS, which acts in these experiments as a negative control for mitochondrial activity. [Figure 8-1] Figure 8 shows the extracellular acidification rate (ECAR) in negative control, no mitochondrial control, and cells treated with three different concentrations of MAS receptor agonists Nle3-A(1-7) (Figure 8A), angiotensin(1-7) (Figure 8B), and compound 7 (Figure 8C). CCCP serves in these experiments as a negative control for mitochondrial activity. [Figure 8-2] Figure 8 shows the extracellular acidification rate (ECAR) in negative control, no mitochondrial control, and cells treated with three different concentrations of MAS receptor agonists Nle3-A(1-7) (Figure 8A), angiotensin(1-7) (Figure 8B), and compound 7 (Figure 8C). CCCP serves in these experiments as a negative control for mitochondrial activity. [Figure 8-3] Figure 8 shows the extracellular acidification rate (ECAR) in negative control, no mitochondrial control, and cells treated with three different concentrations of MAS receptor agonists Nle3-A(1-7) (Figure 8A), angiotensin(1-7) (Figure 8B), and compound 7 (Figure 8C). CCCP serves in these experiments as a negative control for mitochondrial activity. [Figure 9]Figure 1 shows cellular mitochondrial mass after various durations, concentrations, and treatments of test compounds. Cells were treated with DMSO negative control, Nle3-A(1-7), angiotensin(1-7), and compound 7 at three concentrations for 8, 24, and 72 hours. Stable cellular mitochondrial content is strong evidence that mitotic mitochondria are replaced by new mitochondria via biogenesis. [Figure 10-1] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-2] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-3] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-4] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-5] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-6] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-7] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-8] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-9] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-10] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-11] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-12] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 10-13] Super-resolution micrographs after treatment with DMSO negative control and angiotensin(1-7), Nle3-A(1-7), and compound 7 at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. [Figure 11-1] FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-2]FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-3] FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-4] FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-5] FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-6] FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-7] FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 11-8]FIG. 1 shows super-resolution micrographs of cells after treatment with DMSO negative control, A779 (MAS receptor inhibitor), Angiotensin(1-7), Angiotensin(1-7)+A779, Nle3-A(1-7), Nle3-A(1-7)+A779, Compound 7, and Compound 7+A779. [Figure 12] FIG. 1 shows a table briefly illustrating cellular mitochondrial morphology in cells following treatment with Angiotensin(1-7), Nle3-A(1-7), or Compound 7 for 8 hours, 24 hours, and 72 hours. [Figure 13] FIG. 1 shows mitochondrial co-localized LC3 in certain cell lines as indicated. [Figure 14] FIG. 14 demonstrates that the MAS agonists tested induced mitophagy in U2-OS cells. UT=untreated, UA=urolithin A, DFP=deferiprone, FCCP+oligo=carbonyl cyanide-4(trifluoromethoxy)phenylhydrazone+oligomycin; and A(1-7)=angiotensin(1-7). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] The present subject matter may be more readily understood by reference to the following detailed description, which forms a part of this disclosure: It is to be understood that the present disclosure is not limited to the specific products, methods, conditions or parameters described and / or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only, and is not intended to limit the disclosure as claimed.

[0052] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0053] As employed above, and throughout this disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

[0054] In this disclosure, the singular forms "a," "an," and "the" include plural references, and reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" is a reference to one or more of such compounds and equivalents thereof known to those of skill in the art. The term "plurality," as used herein, means two or more. When a range of values ​​is expressed, another embodiment includes the one particular value and / or the other particular value.

[0055] Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable. In the context of this disclosure, "about" a particular amount means that the amount is within ±20% of the stated amount, or within ±10% of the stated amount, or within ±5% of the stated amount.

[0056] As used herein, the terms "treat", "treatment" or "therapy" (as well as its various forms) refer to therapeutic treatment, including prophylactic or preventative measures, where the objective is to prevent or slow down (alleviate) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or alleviation of a disease or condition, and remission (whether partial or total) of a disease or condition. Those in need of treatment include those already with the disease or condition, those prone to have the disease or condition, or those in whom the disease or condition is to be prevented.

[0057] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to an animal, e.g., a human, to which treatment with a composition or formulation according to the present disclosure is provided. As used herein, the term "subject" refers to human and non-human animals. A human can be any human of any age. In one embodiment, a human is an adult. In another embodiment, a human is a child. A human can be male, female, pregnant, middle-aged, adolescent, or elderly.

[0058] The conditions and disorders for which a particular drug, compound, composition, formulation (or combination thereof) is said to be "indicated" herein are not limited to those conditions and disorders for which the drug or compound or composition or formulation has been expressly approved by a regulatory agency, but also include other conditions and disorders that are known or reasonably believed by a physician or other health or nutritional professional to be suitable for treatment with that drug or compound or composition or formulation, or combination thereof.

[0059] An "analog" (or "analog") will be readily understood by one of skill in the art as a compound that has substantially the same chemical structure as a reference compound, but differs in the substitution of atoms and / or functional groups and / or substructures. If a chemical structural definition of an analog of a particular compound is not otherwise provided in the present disclosure, the general definition provided in this paragraph shall apply.

[0060] It should be readily apparent to one of skill in the art that a disease may have multiple interchangeable names (i.e., amyotrophic lateral sclerosis (ALS) is the same condition as Lou Gehrig's disease, Charcot's disease, and motor neurone disease (MND)).

[0061] "Mitochondrial turnover" refers to the process by which new mitochondria are biogenic and grow while defective mitochondria are eliminated. Mitochondria divide and proliferate by fission, while older defective mitochondria are primarily eliminated by mitophagy (i.e., autophagy / macroautophagy). In general, a higher rate of mitochondrial turnover is associated with having a population of younger, healthier mitochondria. Conversely, a lower rate of mitochondrial turnover is associated with having a population of older, defective mitochondria, resulting in reduced cellular function. Mitophagy impairment disrupts the mitochondrial turnover process and is associated with numerous pathologies. (Bakula & Scheibye-Knudsen, Front. Cell. Dev. Biol. 2020, 8:239; Killackey et al., J. Cell Biol., 2020, 219:11.)

[0062] Recently, it was discovered that certain compounds that modulate the G protein-coupled receptor MAS cause an increase in mitochondrial turnover rate. The MAS receptor had never been previously thought to be related to mitochondrial function. It is best known for playing an essential signaling role in the renin-angiotensin-aldosterone system (RAAS), an endocrine signaling system traditionally understood to regulate kidney function and blood pressure. The discovery of the role of the MAS receptor in mitochondrial turnover was exciting and unexpected, as the MAS receptor may provide a new avenue for ameliorating numerous diseases resulting from mitochondrial dysfunction.

[0063] The present disclosure relates to medical intervention methods and agents, namely, methods and agents for stimulating mitochondrial turnover for the treatment of disease in a mammal.

[0064] For example, the mitochondrial turnover rate in cells can be increased by increasing MAS receptor signaling by (1) activating the MAS receptor, (2) increasing the sensitivity of the MAS receptor, (3) increasing the steric availability of the MAS receptor, (4) increasing the membrane surface presentation and / or amount of the MAS receptor, (5) other means, or any combination thereof.

[0065] MAS agonists or substances that induce the endogenous production of MAS receptor agonists. The agent that causes an increase in MAS receptor signaling can be a small molecule drug, a peptide, a protein, or any other biomolecule. The agent can act directly on the MAS receptor or can be upstream of another effectuator. For example, the ACE enzyme is known to catalyze the production of angiotensin (1-7), which is also a MAS receptor agonist.

[0066] The MAS receptor (also referred to as MAS1 or MASR) is a G-protein-coupled receptor (GPCR) encoded by Mas1 that has a well-characterized role in the renin-angiotensin-aldosterone system (RAAS) cardiovascular endocrine pathway outlined in Figure 1B. The RAAS (sometimes abbreviated as RAS) is a hormonal system that acts on the heart, kidneys, liver, lungs, pituitary gland, arteries, and the sympathetic nervous system, which regulates systemic blood pressure, fluid retention and volume, ion / electrolyte balance, and systemic vascular resistance. The canonical MAS signaling pathway for the RAAS is shown in Figure 1A. Angiotensin-converting enzyme 2 (ACE2) is an enzyme that catalyzes the conversion of angiotensin II protein to angiotensin (1-7) heptapeptide. Human recombinant ACE2 GSK2586881 is an example of a synthetic ACE2 agent that can stimulate MAS receptor activity in vivo. ACE2 activators are a class of compounds that promote or enhance ACE2 activity. Examples of ACE2 activators include xanthenone (XNT) and diminazene aceturate (DIZE). ACE inhibitors (ACEI) are any of a class of drugs that inhibit angiotensin-converting enzyme (ACE), which in turn reduces the formation of angiotensin II. Examples of ACEIs include enazepril (Lotensin™), captopril (Capoten™), enalapril (Vasotec™, Epaned™, Lexxel™), fosinopril (Monopril™), lisinopril (Prinivil™, Zestril™, Qbrelis™), moexipril (Univasc™), perindopril (Aceon™), quinapril (Accupril™), ramipril (Altace™), and trandolapril (Mavik™).

[0067] For purposes of this disclosure, "MAS receptor modulator" means an agent that alters the biochemical activity of the MAS receptor, for example, by increasing its binding affinity to an agonist or antagonist, decreasing its binding affinity to an agonist or antagonist, increasing the steric availability of the MAS receptor to binding agents, increasing or decreasing the cell surface availability of the MAS receptor, decreasing the steric availability of the MAS receptor to binding agents, or any combination thereof.

[0068] As used herein, "MAS receptor agonist" or "MAS agonist" refers to an agent that activates the biochemical activity of the MAS receptor. Non-limiting examples of MAS receptor agonists are described herein.

[0069] "C u~v " or "C u ~C v " prefix indicates that the following group has u to v carbon atoms. For example, "C 1~6 The terms "alkyl" or "C1-C6 alkyl" or "(C1-C6)-alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0070] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to an alkyl group having 1 to 20 carbon atoms (i.e., C 1~20 alkyl), 1 to 12 carbon atoms (i.e., C 1~12 alkyl), 1 to 8 carbon atoms (i.e., C 1~8 alkyl), 1 to 6 carbon atoms (i.e., C 1~6 alkyl), or 1 to 4 carbon atoms (i.e., C 1~4Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a particular number of carbons is designated by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons can be included, thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0071] "Alkenyl" refers to an alkyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 12 carbon atoms (i.e., C 2~12 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 Alkenyl refers to an alkyl group having the substituents 1,2-, 1,3-, or 2-alkyl. Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0072] "Alkynyl" refers to an alkynyl group containing at least one (e.g., 1 to 3, or 1) carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 12 carbon atoms (i.e., C 2~12 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 The term "alkynyl" also includes groups having one triple bond and one double bond.

[0073] "Alkoxy" refers to the group "alkyl-O-." Example alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0074] "Acyl" means -C(O)R y R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0075] An "amide" is a group -C(O)NR y R z refers to the "C-amide" group and the group -NR y C(O)R z and "N-amide" groups, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein, or R y and R z taken together form a cycloalkyl or heterocyclyl; each of which may be optionally substituted as defined herein.

[0076] "Amino" means -NR y R z Ry and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0077] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl refers to an aromatic carbocyclic group having 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap in any way with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused to a heterocyclyl ring, the resulting ring system is a heterocyclyl, regardless of the point of attachment. When one or more aryl groups are fused to a cycloalkyl ring, the resulting ring system is a cycloalkyl, regardless of the point of attachment.

[0078] "Aryloxy" refers to "aryl-O-".

[0079] "Carboxy" refers to -CO2H.

[0080] "Carboxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced by a carboxy group.

[0081] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" refers to cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3 As used herein, cycloalkyl includes carbocyclic fused ring systems having 3 to 20 ring carbon atoms (i.e., at least one non-aromatic ring). 3~20 cycloalkyl), 3 to 14 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3~6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of the attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when there are two positions for substitution on the same carbon atom, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0082] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to an aromatic group having 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C3~12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3~8Heteroaryl) and 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. In certain cases, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindo. canyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, and the heteroaryl can be bonded through any ring of the fused system. Any aromatic ring containing at least one heteroatom and having single or multiple fused rings is considered heteroaryl, regardless of the bond to the rest of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0083] "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. A heterocyclyl may be monocyclic or polycyclic, where the polycyclic rings may be fused, bridged, or spiro, and may include one or more (e.g., 1-3) oxo (=O) or N-oxide (-O) groups. - ) moieties. Any non-aromatic ring containing at least one heteroatom, regardless of attachment, is considered a heterocyclyl (i.e., it can be attached via a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring, regardless of attachment to the remainder of the molecule, may be fused to a cycloalkyl, aryl, or heteroaryl ring. As used herein, heterocyclyl refers to a ring having 2 to 20 ring carbon atoms (i.e., C 2~20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C 2~12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C 2~10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C 2~8 heterocyclyl), 3 to 12 ring carbon atoms (i.e., C 3~12 heterocyclyl), 3 to 8 ring carbon atoms (i.e., C 3~8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C 3~6Heterocyclyl) having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoquinol ... These include isoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic systems such as, for example, oxabicyclo[2.2.2]octanyl, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be attached via either ring of the fused system.

[0084] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro, chloro, bromo, or iodo.

[0085] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (eg, 1 to 6 or 1 to 3) hydrogen atoms are replaced with a hydroxy group.

[0086] The following compounds and pharmaceutical compositions thereof are useful for the purposes described herein.

[0087] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole is the chemical compound having the following formula:

[0088] [ka]

[0089] The 1-(p-thienylbenzyl)imidazole analogues have the formula (I):

[0090] [ka] [wherein R(1) is (1) halogen, (2) hydroxyl, (3) (C1-C4)-alkoxy, (4) (C1-C8)-alkoxy (wherein 1 to 6 carbon atoms are replaced by heteroatoms O, S, or NH), (5) (C1-C4)-alkoxy substituted by saturated cyclic ethers, (6) O-(C1-C4)-alkenyl, (7) O-(C1-C4)-alkylaryl, or (8) phenoxy which is unsubstituted or substituted by a substituent selected from halogen, (C1-C3)-alkyl, (C1-C3)-alkoxy, and trifluoromethyl; and R( or (3) (C1-C4)-alkyl; X is (1) oxygen or (2) sulfur; Y is (1) oxygen or (2) -NH-; and R(5) is (1) hydrogen, (2) (C1-C6)-alkyl or (3) (C1-C4)-alkylaryl, where R(5) may be hydrogen only if Y has the meaning stated in (2); and R(6) is (1) (C1-C5)-alkyl, or a physiologically acceptable salt thereof.

[0091] The analogues of 1-(p-thienylbenzyl)imidazole also have the formula (II) in all its stereoisomers and mixtures thereof in all ratios:

[0092] [ka] [In the formula, R(1) is 1. (C1-C5)-alkyl which is unsubstituted or substituted with a radical selected from NH2, halogen, O-(C1-C3)-alkyl, CO-O-(C1-C3)-alkyl, and CO2H; 2. (C3-C8)-cycloalkyl; 3. (C1-C3)-alkyl-(C3-C8)-cycloalkyl; 4. (C6-C7)-alkyl which is unsubstituted or substituted with a radical selected from halogen and O-(C1-C3-alkyl; 10)-aryl, 5.(C1-C3)-alkyl-(C6-C 10 )-aryl, where the aryl radical is unsubstituted or substituted by a radical selected from halogen and O-(C1-C3)-alkyl, 6. (C3-C5)-heteroaryl, and 7. (C1-C3)-alkyl-(C1-C5)-heteroaryl, where R(2) is selected from hydrogen, 2. (C1-C6)-alkyl, which is unsubstituted or substituted by a radical selected from halogen and O-(C1-C3-alkyl, 3. (C3-C8)-cycloalkyl, 4. (C1-C3)-alkyl-(C3-C8)-cycloalkyl, 5. (C6-C6)-alkyl, which is unsubstituted or substituted by a radical selected from halogen, O-(C1-C3)-alkyl and CO-O-(C1-C3)-alkyl, 10 )-aryl, and 6. (C1-C3)-alkyl-(C6-C8) which is unsubstituted or substituted by a radical selected from halogen and O-(C1-C3)-alkyl. 10)-aryl, R(3) is selected from among 1. hydrogen, 2. COOH, and 3. COO-(C1-C4)-alkyl, R(4) is selected from among 1. hydrogen, 2. halogen, and 3. (C1-C4)-alkyl, R(5) is selected from among 1. hydrogen, 2. (C1-C6)-alkyl, R(6) is selected from among 1. hydrogen, 2. (C1-C6)-alkyl, 3. (C1-C3)-alkyl-(C3-C8)-cycloalkyl, and 4. (C2-C6)-alkenyl, X is selected from among 1. oxygen, and 2. NH, and physiologically tolerated salts thereof. In some embodiments, the 1-(p-thienylbenzyl)imidazole analog is a compound, in any stereoisomeric form or mixture thereof in any ratio, in which R(1) is (1) chlorine, (2) hydroxyl, (3) methoxy, ethoxy, or propyloxy, (4) methoxyethoxy or methoxypropoxy, (5) allyloxy, or (6) phenoxy; R(4) is (1) hydrogen or (2) chlorine; R(5) is (1) hydrogen or (2) (C1-C4)-alkyl; and R(6) is (1) n-propyl or 2-isobutyl, and the other radicals are as defined above, or a physiologically tolerable salt thereof.

[0093] In some embodiments, the analog of 1-(p-thienylbenzyl)imidazole has the formula (α):

[0094] [ka] wherein the radical R(1) is (1) chlorine, (2) hydroxyl, (3) methoxy, ethoxy, or propyloxy, (4) methoxyethoxy or methoxypropoxy, (5) allyloxy, or (6) phenoxy; R(4) is (1) hydrogen or (2) chlorine; R(5) is (1) hydrogen or (2) (C1-C4)-alkyl; R(6) is (1) n-propyl or 2-isobutyl; and Y is oxygen or -NH-.

[0095] Exemplary 1-(p-thienylbenzyl)imidazole analogs can include, but are not limited to, 4-chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, the structure of which is provided below:

[0096] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole:

[0097] [ka] 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-propyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, the structure of which is provided below:

[0098] [ka] 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole:

[0099] [ka] 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole:

[0100] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole:

[0101] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[ 4 -[2-(methylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole:

[0102] [ka] 5-formyl-4-methoxyethoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole:

[0103] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole:

[0104] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]-2-chlorophenyl]methyl]imidazole:

[0105] [ka] 4-Chloro-5-formyl-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole:

[0106] [ka] 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butyloxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole:

[0107] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methoxycarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole:

[0108] [ka] 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(n-butylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole:

[0109] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(methylaminocarbonylsulfonamido)-5-n-propyl-3-thienyl]phenyl]methyl]imidazole:

[0110] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole sodium salt:

[0111] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole L-lysine salt:

[0112] [ka] 5-Formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole tris(hydroxymethyl)aminomethane salt:

[0113] [ka] Compound 7 is a heterocyclic non-peptidic compound of the formula:

[0114] [ka] The heterocyclic non-peptidic angiotensin (1-7) mimetic compound has the formula (III):

[0115] [ka] wherein ring A is a 5- or 6-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms; ring B is a 5- or 6-membered heteroaryl ring containing at least one nitrogen atom; ring C is an optionally substituted aryl ring; 1 , A 2 , A 3 , A 4 are independently =N-, -C(=O)-, -C(R a )=, =C(R b )-, -C(R c )(R d )-N(R e )-, -C(R c )(R d )-O-, or -[C(R c )(R d )] n -, where n is 1 or 2; X 1 ~X 2 is (R 6 )CN, NC(R 6 ), NN, NO, ON, NS, or SN; X 3 is (R 7 )C=C(R 8 ), O, S, or N(R 9 ) and Z is O, NH or R 5 is a bond to; R a and R b is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido, or carboxy, with the proviso that R a and R b may also be joined to form a ring of up to six atoms; R c and R d is independently selected from the group consisting of hydrogen, alkyl, aryl, or heteroaryl, with the proviso that R c and R dmay also be joined to form a ring of up to six atoms; R e is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; R 1 , R 3 , R 4 , R 6 , R 7 , and R 8 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R 2 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R 5 is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; R 9 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl, or a pharma- ceutically acceptable salt thereof.

[0116] In some embodiments of Formula (III), R 2 is trifluoromethoxy. In some embodiments, Z is O or NH. In an exemplary embodiment, ring A is

[0117] [ka] wherein R 10 and R 11is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido, or carboxy, with the proviso that R 10 and R 11 may also be linked to form a carbocyclic, heterocyclic, aryl or hetoaryl ring; R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; R 13 is hydrogen, alkyl, aryl or heteroaryl; R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; R f , R g , R h , and R i is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl.

[0118] In another exemplary embodiment, Ring B is

[0119] [ka] wherein the group R 6 , R 7 , R 8 , and R 9 is as defined in general formula (III) in the paragraph above.

[0120] In some exemplary embodiments, the compounds provided are:

[0121] [ka]

[0122] [ka] [In the formula, the group R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , A 1 , A 2 , A 3 , A 4 and Z is as defined in general formula (III) in the paragraph above.

[0123] In other exemplary embodiments, the compounds provided are:

[0124] [ka]

[0125] [ka]

[0126] [ka] [In the ceremony base R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , Ra , R b , R c , R d and Z is as defined in the paragraph above in general formula (III), R 10 and R 11 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido, or carboxy, with the proviso that R 10 and R 11 may also be linked to form a carbocyclic, heterocyclic, aryl, or hetoaryl ring; R 12 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; R 13 is hydrogen, alkyl, aryl or heteroaryl; R 14 is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, thalkylaminoacyl, or dialkylaminoacyl; R f , R g , R h , and R i are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl.

[0127] Additional heterocyclic non-peptidic angiotensin(1-7) mimetic analogs can be found in U.S. Pat. No. 10,301,298 (B2), which is incorporated herein by reference in its entirety.

[0128] Compound 10 is a heterocyclic non-peptidic compound of the formula:

[0129] [ka]

[0130] Nle 3 -A(1-7) (also called aclerastide, which may alternatively be called Nle3-A(1-7)) is a peptide consisting of the amino acid sequence Asp-Arg-Nle-Tyr-Ile-His-Pro of the following formula:

[0131] [ka]

[0132] 20-hydroxyecdysone (also commonly referred to as ecdysterone, hydroxyecdysone, or "20E") is a chemical compound of the following formula:

[0133] [ka]

[0134] An analog of 20-hydroxyecdysone has the formula (IV):

[0135] [ka] [wherein V is a carbon-carbon single bond, Y is a hydroxyl group or hydrogen, or V is a C=C ethylene bond; X is oxygen, Q is a carbonyl group; R 1is selected from the group (C1-C6)W(C1-C6), the group (C1-C6)W(C1-C6)W(C1-C6), the group (C1-C6)W(C1-C6)CO2(C1-C6), the group (C1-C6)A (wherein A represents a heterocycle optionally substituted by groups of the type OH, OMe, (C1-C6), N(C1-C6), CO2(C1-C6)), the group CH2Br; where W is a heteroatom selected from N, O and S.

[0136] Angiotensin(1-7) is a seven amino acid peptide (i.e., heptapeptide) fragment of the protein angiotensin, consisting of the amino acid sequence Asp-Arg-Val-Tyr-Ile-His-Pro of the following formula:

[0137] [ka]

[0138] Angiotensin (1-7) (also referred to as "A(1-7)") comprises the amino acid sequence: H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH. An analog of Angiotensin (1-7) is any peptide having a sequence of at least three consecutive amino acids of the R1-R8 groups in a sequence of the general formula (i) R1-R2-R3-R4-R5-R6-R7-R8, where R1 and R2 together represent the formula XR A -R B - group, X is H or 1 to 3 peptide groups; R A is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2) and Suc, and glycosylated forms thereof; R BR is selected from the group consisting of Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg, D-Lys, His, and glycosylated forms thereof; R3 is selected from the group consisting of Val, Ala, Leu, Nle, Ile, Gly, Pro, Aib, Acpc, Lys, Tyr, and glycosylated forms thereof; R4 is selected from the group consisting of Tyr, Tyr(PO3)2, Thr, Ser, Hse, Ala, and azaTyr, Tyr, Phe, and glycosylated forms thereof. R5 is selected from the group consisting of Ile, Ala, Leu, Nle, Val, Gly, and glycosylated forms thereof; R6 is His, Arg or 6-NH2-Phe, Lys, and glycosylated forms thereof; R7 is Pro, Ala, Gly, Ser, and glycosylated forms thereof; and R8 is selected from the group consisting of Phe, Phe(Br), Ile, Tyr, Ser, Tr, Hyp, and glycosylated forms thereof. In some embodiments of formula (i), formula (i) sequences comprising R4 as a terminal Tyr group are excluded.

[0139] In some embodiments, analogs of angiotensin(1-7) can include peptide and non-peptide agents (i.e., peptidomimetics) that possess the required biological activity. A and R Bare Asp-Arg, Asp-Lys, Glu-Arg and Glu-Lys. Some embodiments of this class include: Arg-Val-Tyr-Ile-His-Pro-Phe, Val-Tyr-Ile-His-Pro-Phe, Asp-Arg-Val-Tyr-Ile-His-Pro, Arg-Val-Tyr-Ile-His-Pro, Val-Tyr-Ile-His-Pro, Ile-His-Pro-Phe, Asp-Arg-Val-Tyr-Ile-His, Asp-Arg-Val-Tyr-Ile, Asp-Arg-Val-Tyr and Asp-Arg-Val. Some embodiments include Arg-Nle-Tyr-Ile-His-Pro-Phe and Arg-Val-Tyr-Nle-His-Pro-Phe. In some embodiments peptides having the sequences Asp-Arg-Pro-Tyr-Ile-His-Pro-Phe, His-Pro-Phe, and Tyr-Ile-His-Pro-Phe are provided.

[0140] A class of analogs of Angiotensin(1-7) may have the following general structure: R1-Arg-R2-R3-R4-His-Pro-R5, where R1 is selected from the group consisting of H and Asp, R2 is selected from the group consisting of Val and Pro, R3 is selected from the group consisting of Tyr and Tyr(PO3)2, R4 is selected from the group consisting of Ala, Ile, Leu, and Nle, and R5 is Phe, Ile, or absent.

[0141] In any embodiment of the present disclosure, an analog of angiotensin(1-7) may also comprise a sequence of the general formula (ii) Ala1-R2-R3-R4-R5-R6-R7, where R2 is selected from Arg, Lys, Ala, Cit, Orn, Ser(Ac), Sar, D-Arg, and D-Lys, R3 is selected from the group consisting of Val, Ala, Leu, Nle, Ile, Gly, Pro, Aib, Acpc, Lys, and Tyr, R4 is Ser or forms a cyclic thioether with R7, R5 is selected from the group consisting of Ile, Ala, Leu, Nle, Val, and Gly, R6 is His, Arg, 6-NH2-Phe, Lys, and glycosylated forms thereof, and R7 is Cys or forms a cyclic thioether with R4.

[0142] A779 is a peptide MAS receptor antagonist (i.e., inhibitor) of the amino acid sequence Asp-Arg-Val-Tyr-Ile-His-D-Ala, where D-Ala is the D-enantiomer of alanine. A779 may be used in MAS receptor inhibition experiments, competitive binding assays, or other purposes.

[0143] The abbreviations used herein for standard proteinogenic amino acids conform to industry standards and should be readily understood by one of ordinary skill in the art. Amino acids abbreviated with the prefix D refer to the D-enantiomer, but without any prefix, they shall be understood to refer to the L-enantiomer unless otherwise indicated by the context. As used herein, modified unusual non-proteinogenic amino acids and other groups are abbreviated as follows: Aad = 2-aminoadipic acid; bAad = 3-aminoadipic acid; Acpc = 1-aminocyclopropanecarboxylic acid; bAla = β-alanine (i.e., β-aminopropionic acid); Abu = 2-aminobutyric acid; 4Abu = 4-aminobutyric acid (i.e., piperidine acid); Acp = 6-aminocaproic acid; Ahe = 2-aminoheptanoic acid; Aib = 2-aminoisobutyric acid; bAib = 3-aminoisobutyric acid; Bet = 1-carboxy-N,N,N-trimethylmethanaminium hydroxide inner salt (betaine); Apm = 2-aminopimelic acid; Dbu = 2,4-diaminobutyric acid; Des = desmosine; Dpm = 2,2' -diaminopropionic acid;Dpr=2,3-diaminopropionic acid;EtGly=N-ethylglycine;EtAsn=N-ethylasparagine;Hse=homoserine (i.e., isothreonine);Hyl=hydroxylysine;aHyl=allo-hydroxylysine;3Hyp=3-hydroxyproline;4Hyp=4-hydroxyproline;Ide=isodesmosine;alle=allo-isoleucine;MeGly=N-methylglycine (i.e., sarcosine);Me2Gly=dimethylglycine;MeIle=N-methylisoleucine;MeLys=6-N-methyllysine;MeVal=N-methylvaline;Nva=norvaline;Nle=norleucine;Orn=ornithine;Sar=sarcosine;Suc=succinic acid. In addition, some alternative abbreviations for less common amino acids may be known to those of skill in the art and may be readily understood from their context. For example, norleucine may sometimes be abbreviated as "norLeu" and homoserine may be abbreviated as "homoSer."

[0144] In some embodiments, the analog of angiotensin(1-7) is A-1317 (wherein the amino acid L-arginine is to the N-terminus of Ang(1-7)).

[0145] In some embodiments, the MAS receptor agonist is a compound of formula (III).

[0146] In some embodiments, the MAS receptor agonist is Heterocyclic non-peptidic angiotensin (1-7) mimetics or analogs thereof, angiotensin(1-7) or an analogue thereof, Nle 3 -A(1-7) or an analogue thereof, 1-(p-thienylbenzyl)imidazole analogues, and 20-hydroxyecdysone or an analog thereof.

[0147] In some embodiments, the MAS receptor agonist is compound 7, compound 10, Nle 3 -A(1-7), Angiotensin(1-7), Ang-1-6-Ser-0-glycosylated analogs of angiotensin(1-7), and 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole.

[0148] In some embodiments, the MAS receptor agonist is compound 7. In some embodiments, the MAS receptor agonist is compound 10. In some embodiments, the MAS receptor agonist is Nle 3-A(1-7). In some embodiments, the MAS receptor agonist is angiotensin(1-7). In some embodiments, the MAS receptor agonist is 20-hydroxyecdysone or an analog thereof. In some embodiments, the MAS receptor agonist is 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole.

[0149] Pharmaceutical Compositions Provided herein is a pharmaceutical composition comprising the compound described herein. In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable carriers, excipients, and / or diluents.

[0150] In some embodiments, the phrase "pharmacologically acceptable" is employed herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio.

[0151] The present disclosure also includes "pharmaceutically acceptable salts" of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, where the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts of the compounds of the present disclosure include conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the compounds of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or free base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, and acetonitrile can be used.

[0152] Pharmaceutically acceptable salts of the compounds of the present disclosure can also be obtained by converting derivatives bearing tertiary amino groups into corresponding quaternary ammonium salts using quaternizing agents in a manner known per se.Examples of suitable quaternizing agents are alkyl halides, such as methyl iodide, ethyl bromide, and n-propyl chloride, and also aryl alkyl halides, such as benzyl chloride or 2-phenylethyl bromide.In some embodiments, salts can be formed by conventional means, such as by reacting the free base form or free acid form of the product with one or more equivalents of a suitable acid or base in a solvent or medium in which the salt is insoluble, or in a solvent such as water that is removed in vacuum, or by lyophilization, or by exchanging the ions of existing salts with another ion or suitable ion exchange resin.

[0153] Possible pharma- ceutically acceptable salts are well known in the art.For example, SM Berge et al. describe pharma- ceutically acceptable salts in detail in J. Pharmaceutical Sciences 66:1-19, 1977, which is incorporated herein by reference.

[0154] Typically, pharma- ceutically acceptable salt forms of compounds can be prepared in situ during the final isolation and purification of the compounds or separately by reacting the free base function with a suitable organic or inorganic acid.Examples of typical pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange.

[0155] Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethoxybenzoate ... Examples of suitable salts include benzenesulfonate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0156] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and quaternary ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0157] The present disclosure further includes derivatives of the compounds of the present disclosure. The term "derivatives" includes, but is not limited to, ether derivatives, acid derivatives, amide derivatives, ester derivatives, and the like. In addition, the present disclosure further includes hydrates or solvates of the compounds of the present disclosure. The term "hydrate" includes, but is not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, and the like.

[0158] The present disclosure further includes metabolites of the compounds of the present disclosure. The term "metabolite" means any substance produced from another substance by metabolism or a metabolic process.

[0159] "Pharmaceutically acceptable excipient" generally means an excipient that is safe, non-toxic, and not biologically or otherwise undesirable, useful for preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0160] A "pharmaceutical acceptable carrier" includes any excipient that is non-toxic to a cell or subject exposed to it at the dosage and concentration employed. The pharmaceutical composition may include one or additional therapeutic agents.

[0161] Pharmaceutically acceptable carriers include solvents, dispersion media, buffers, coatings, antibacterial and antifungal agents, wetting agents, preservatives, buggers, chelating agents, antioxidants, isotonic agents, and absorption delaying agents.

[0162] Pharmaceutically acceptable carriers include water, saline, phosphate buffer salts, dextrose, glycerol, alcohols such as ethanol and isopropanol, phosphates, citrates, and other organic acids, ascorbic acid, low molecular weight (less than about 10 residues) polypeptides, proteins such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine, or lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin, EDTA, salts forming counterions such as sodium, and / or non-ionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®, isotonicity agents such as sugars, polyhydric alcohols such as mannitol and sorbitol, and sodium chloride, and combinations thereof. Antibacterial and antifungal agents include parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal.

[0163] The present disclosure further includes pharmaceutical compositions and pharmaceutical products of the compounds of the present disclosure. The terms "pharmaceutical composition" and "pharmaceutical product" as defined herein refer to compositions suitable for pharmaceutical use (pharmaceutical composition). In some embodiments, as used herein, "pharmaceutical composition" also refers to a therapeutically effective amount of the compounds of the present disclosure with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers.

[0164] In practice, the compounds of the present disclosure, for example those represented by formula (I), formula (III), and other compounds or compounds described herein, or pharma- ceutically acceptable salts thereof, can be combined as active ingredients in an intimate mixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms, depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil emulsion.

[0165] In addition to the above common dosage forms, the compounds described herein, such as the compounds represented by formula (I) or (III) or other formulas described herein, or pharma- ceutically acceptable salts thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired form.

[0166] Solid pharmaceutical forms can include inert components and carrier substances such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talc, highly dispersed silicic acid, silicone oils, high molecular weight fatty acids, (such as stearic acid), gelatin, agar, or vegetable or animal fats or oils, or solid high molecular weight polymers (such as polyethylene glycol), and preparations suitable for oral administration can contain additional flavorings and / or sweeteners as required.

[0167] Liquid pharmaceutical forms may be sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting agents, osmotic agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, and / or viscosity regulators, for adjusting or buffering osmotic pressure. Examples of such additives are tartrate and citrate buffers, ethanol, and sequestering agents, such as ethylenediaminetetraacetic acid and its non-toxic salts. High molecular weight polymers, such as liquid polyethylene oxide, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, dextran or gelatin, are suitable for adjusting the viscosity. Examples of solid carrier materials are starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.

[0168] Oily suspensions for parenteral or topical application may be based on vegetable synthetic or semi-synthetic oils, such as liquid fatty acid esters in each case having 8 to 22 C atoms in the fatty acid chain, such as, for example, palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassicic acid, erucic acid or oleic acid, which are esterified with mono- to trihydric alcohols having 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are, inter alia, commercially available Miglyol, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG6-capric acid, caprylic / capric esters of saturated fatty alcohols, polyoxyethylene glycerol trioleate, ethyl oleate, waxy fatty acid esters such as artificial ducktail gland fat, coconut fatty acid isopropyl esters, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, etc. Silicone oils of different viscosities, or fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids such as oleic acid, etc. Furthermore, it is possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil.

[0169] Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholine, dioxane, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

[0170] Mixtures of gelling agents and film-forming agents are also entirely possible. In this case, in particular, ionic polymers such as sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as sodium salt, gum arabic, xanthan gum, guar gum or carrageenan are used. As additional formulation auxiliary, glycerol, paraffin of different viscosity, triethanolamine, collagen, allantoin and novantisolic acid can be used. The use of surfactants, emulsifiers or wetting agents, such as sodium lauryl sulfate, fatty alcohol ether sulfates, di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g., Tween®), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride, or mono- / dialkyl polyglycol ether orthophosphate monoethanolamine salts, may also be required in the formulation. Stabilizers such as montmorillonite or colloidal silicic acid to stabilize emulsions or to prevent the degradation of active substances, such as antioxidants, for example, tocopherol or butylhydroxyanisole, or preservatives such as p-hydroxybenzoic acid esters, may also be used to prepare the desired formulation.

[0171] The preparation for parenteral administration can be in the form of separate dosage units, such as ampoules or vials.The solution of active compound, such as aqueous solution, and in some embodiments, isotonic solution and suspension are also used.These injection forms can be available as ready-to-use preparations, or can be prepared only immediately before use, by mixing the active compound, for example lyophilized, with desired solvent or suspending agent, which appropriately contains other solid carrier material.

[0172] Intranasal preparations may be in the form of aqueous or oily solutions or suspensions. They can also be in the form of lyophilisates prepared before use with suitable solvents or suspending agents.

[0173] Inhalable preparations can be present as powders, solutions or suspensions, in some embodiments, the inhalable preparations are in the form of a powder, e.g., a mixture of the active ingredient with suitable formulation auxiliaries, such as lactose.

[0174] The preparation is produced under customary antimicrobial and aseptic conditions, aliquoted and sealed.

[0175] Accordingly, the present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0176] The term "carrier" refers to any chemical entity that can be incorporated into a composition containing an active agent (e.g., a compound described herein, such as a compound of Formula (I) or Formula (III)) without interfering with the stability and / or activity of the agent. In some embodiments, the term "carrier" refers to a pharma- ceutically acceptable carrier. An exemplary carrier herein is water.

[0177] Particulate compositions coated with polymers (e.g., poloxamers or poloxamines) are also encompassed by the present disclosure. Other embodiments of the compositions of the present disclosure incorporate protective coatings, protease inhibitors, or permeation enhancers in particulate form for various routes of administration, including parenteral, pulmonary, nasal, and oral. In some embodiments, pharmaceutical compositions are administered parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intravaginally, intracranially, and intratumorally.

[0178] The present disclosure further includes prodrugs of the compounds of the present disclosure. The compounds of the present disclosure can also be prepared as prodrugs, for example, pharma- ceutically acceptable prodrugs. The terms "pro-drug" and "prodrug" are used interchangeably herein and can refer to any compound that releases an active parent drug in vivo. Since prodrugs are known to enhance many desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacture, etc.), the compounds of the present disclosure can be delivered in prodrug form. The term "prodrug" or "prodrug" refers to a substance that can be converted into a biologically active drug in vivo by reactions such as hydrolysis, esterification, deesterification, activation, salt formation, etc.

[0179] The present disclosure further includes crystals of the compounds of the present disclosure. In addition, the present disclosure provides polymorphs of the compounds of the present disclosure. "Crystal" refers to a substance in a crystalline state. The term "polymorph" refers to a specific crystalline state of a substance that has specific physical properties such as X-ray diffraction, IR spectrum, melting point, etc.

[0180] The pharmaceutical compositions of the present disclosure may be formulated in a variety of ways, including, for example, solid, semi-solid (e.g., creams, ointments, and gels), and liquid dosage forms, such as liquid solutions (e.g., topical lotions or sprays), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. In some embodiments, the compositions are in the form of an injectable or infusible solution. The compositions are in a form suitable for oral, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, transdermal, or topical administration. The compositions may be formulated as immediate release, controlled release, extended release, or delayed release compositions.

[0181] Pharmaceutical compositions suitable for use include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile solutions or dispersions. It should be stable under the conditions of manufacture and storage, and can be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Suitable formulations for use in the therapeutic methods disclosed herein are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., 16th ed. (1980).

[0182] In some embodiments, the composition contains an isotonic agent, such as sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride, etc. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0183] Sterile solution can be prepared by incorporating the molecule, alone or in combination with other active agents, in the required amount in a suitable solvent with one or a combination of the components listed herein, and then sterilizing by filtration as necessary.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other required components from those listed above.In the case of sterile powder for preparing sterile injectable solution, one preparation method is vacuum drying and freeze-drying, which results in a powder of active ingredient plus any additional desired components from a solution that has been previously sterile filtered.Injectable preparation is processed and filled into containers such as ampoules, bags, bottles, syringes or vials, and sealed under aseptic conditions according to methods known in the art.

[0184] Further, the preparations may be packaged and sold in the form of a kit. Such articles of manufacture may bear a label or package insert indicating that the associated composition is useful for treating a subject suffering from a disease or condition described herein.

[0185] Treatment Methods and Uses The effective dose of the compositions of the present disclosure for the treatment of the conditions or diseases described herein will vary depending on many different factors, including the means of administration, the target site, the physiological condition of the patient, whether the patient is human or animal, other drugs administered, and whether the treatment is prophylactic or therapeutic. Typically, the patient is a human, but non-human organisms, including non-human mammals and birds, and transgenic organisms, can also be treated. Therapeutic dosages can be titrated using routine methods known to those skilled in the art to optimize safety and efficacy.

[0186] The pharmaceutical compositions of the present disclosure may comprise a "therapeutically effective amount". A "therapeutically effective amount" refers to an amount effective to achieve a desired therapeutic result at the dosage and duration required. A therapeutically effective amount of a molecule may vary depending on factors such as the disease state of the individual, the species, age, sex, and weight of the individual, and the ability of the molecule to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.

[0187] Also, as used herein, in some embodiments, the terms "therapeutically effective amount" and "effective amount" of an agent refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, disorder, or condition, e.g., an amount sufficient to delay or minimize the onset (e.g., reduce the incidence, frequency, and / or magnitude) of one or more symptoms associated with the disease, disorder, or condition being treated. One of skill in the art will understand that a composition may be said to contain a "therapeutically effective amount" of an agent if the composition contains an amount that is effective when administered as a single dose within the context of a treatment regimen. In some embodiments, a therapeutically effective amount is an amount that, when administered as part of a dosing regimen, is statistically likely to delay or minimize the onset (reduce the incidence and / or magnitude) of one or more symptoms or side effects of a disease, disorder, or condition. In some embodiments, a "therapeutically effective amount" is an amount that enhances the therapeutic effectiveness of another agent administered in combination with the composition.

[0188] In some embodiments, the therapeutically effective amount for administration to a human corresponds to a reference amount (e.g., a therapeutically effective amount in an animal model, such as a mouse model) adjusted for human body surface area compared to the body surface area of ​​the animal model, as known in the art (see, e.g., Reagan-Shaw et al., "Dose translation from animal to human studies revisited," The FASEB Journal 22:659-661 (2007), which is incorporated herein by reference in its entirety). In some embodiments, the reference therapeutically effective amount is an amount that is therapeutically effective in an animal model (e.g., a mouse model). In some embodiments, the reference therapeutically effective amount is in the range of about 0.01 mg / kg to about 500 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 0.01 mg / kg to about 0.1 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 0.1 mg / kg to about 0.5 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 0.5 mg / kg to about 1 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 1 mg / kg to about 2.5 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 2.5 mg / kg to about 10 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 10 mg / kg to about 50 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 50 mg / kg to about 100 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 100 mg / kg to about 250 mg / kg. In some embodiments, the reference therapeutically effective amount is in the range of about 250 mg / kg to about 500 mg / kg.

[0189] As used herein, "modulating" refers to "stimulating" or "inhibiting" the activity of a molecular target or pathway. For example, a composition modulates the activity of a molecular target or pathway if it stimulates or inhibits the activity of the molecular target or pathway by at least 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or about 99% or more, compared to the activity of the molecular target or pathway under the same conditions but lacking only the presence of the composition. In another example, a composition modulates the activity of a molecular target or pathway if it stimulates or inhibits the activity of the molecular target or pathway by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, or at least 100-fold, compared to the activity of the molecular target or pathway under the same conditions but lacking only the presence of the composition. The activity of a molecular target or pathway can be measured by any reproducible means. The activity of a molecular target or pathway can be measured in vitro or in vivo. For example, the activity of a molecular target or pathway can be measured in vitro or in vivo by a suitable assay known in the art for measuring activity. A control sample (untreated with the composition) can be assigned a relative activity value of 100%. The change in activity caused by the composition can be measured in an assay.

[0190] As used herein, the terms "treat" and "treatment" refer to therapeutic procedures, including prophylactic or preventative measures, where the objective is to prevent or slow down (alleviate) undesirable physiological changes associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delaying or slowing the progression of a disease or condition, amelioration or alleviation of a disease or condition, and remission (whether partial or total) of a disease or condition. "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Those in need of treatment include those already with the disease or condition, as well as those prone to have the disease or condition or those in whom the disease or condition is to be prevented.

[0191] In one example, a single bolus may be administered. In another example, several divided doses may be administered over time. In yet another example, the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form, as used herein, refers to physically discrete units suitable as unitary dosages for treating mammalian subjects. Each unit may contain a predetermined amount of active compound calculated to produce the desired therapeutic effect. In some embodiments, the dosage unit forms of the present disclosure are determined by and directly depend on the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved.

[0192] The compositions of the present disclosure may be administered only once or multiple times. In the case of multiple doses, the compositions may be administered, for example, three times a day, twice a day, once a day, every other day, twice a week, once a week, once every two weeks, or once a month.

[0193] As used herein, a compound "activates" an activity if it reduces the desired activity by at least 10% compared to the activity under the same conditions but only lacking the presence of the compound. Activity can be measured by any reproducible means. Activity can be measured in vitro or in vivo. In some embodiments, the compounds used in the methods described herein activate MAS receptor activity by at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, about 95%, about 98%, or about 99% or more.

[0194] In some embodiments, "stimulating mitophagy" refers to increasing mitophagy by at least 5%, at least 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or about 99% or more relative to the amount of mitophagy prior to administration of an active agent (including but not limited to a MAS agonist) to a subject in need thereof.

[0195] As used herein, a "mitophagy stimulating amount" refers to an amount of an active agent (including, but not limited to, a MAS agonist) that increases mitophagy in a subject compared to the amount of mitophagy in the subject prior to administration of the active agent to the subject. In some embodiments, mitophagy is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, or more than about 50% compared to the level of mitophagy in the subject prior to administration of the active agent to the subject.

[0196] It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated. It should be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0197] "Administering" to a subject is not limited to any particular delivery system and may include, but is not limited to, topical, transdermal, oral (e.g., in capsules, suspensions, or tablets), parenteral (including subcutaneous, intravenous, intramedullary, intraarticular, intramuscular, or intraperitoneal injection), or rectal. Administration to a subject may be in a single dose or multiple doses, and in any of a variety of physiologically acceptable salt forms, and / or with acceptable pharmaceutical carriers and / or excipients as part of a pharmaceutical composition (described above). Again, physiologically acceptable salt forms and standard pharmaceutical formulation techniques are well known to those of skill in the art (see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co.).

[0198] The term "subject" includes mammals, such as humans, companion animals (e.g., dogs, cats, birds, etc.), farm animals (e.g., cows, sheep, pigs, horses, poultry, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, birds, etc.). In some embodiments, the subject is a human patient. In some embodiments, the subject is a human male or human female.

[0199] The present disclosure further provides a method of preventing, treating, or intervening in a subject the recurrence of a disease or condition described herein, comprising administering to the subject a compound of the present disclosure described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0200] The treatment of a human or mammalian subject with the compound of the present disclosure for any one of the conditions or diseases described herein is typically achieved by administering the compound in a pharmaceutical composition.The present disclosure also encompasses a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier.Some embodiments provide a pharmaceutical composition comprising a compound of formula (III) and a pharmaceutically acceptable carrier.

[0201] Exemplary diseases that can be treated by stimulating mitochondrial turnover include mitochondrial and non-mitochondrial diseases, vascular diseases, inflammatory diseases, renal diseases, ophthalmic diseases, neurological diseases, and neurodegenerative diseases.

[0202] Exemplary diseases that have been shown to have a direct pathogenic link to mitochondrial turnover include Alzheimer's disease, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, cardiovascular disease, Parkinson's disease, hematopoietic disorders, primary biliary cirrhosis / cholangitis (PBC), sepsis, and renal trauma / injury.

[0203] Some embodiments provide for treating a disease or condition in a subject in need thereof, where the disease or condition manifests itself in defective mitochondrial function (including, but not limited to, accumulation of mitochondrial damage or impaired biogenesis) or defective mitophagy (such as blocked mitophagy or impaired mitophagy).

[0204] In some embodiments, the disease or condition (e.g., a disease or condition exhibiting defective mitochondrial function or defective mitophagy) is MELAS, MERRF, Leigh syndrome, progeria, Werner syndrome, early-onset Parkinson's, late-onset Parkinson's disease, early-onset Parkinson's disease, or Rett syndrome.

[0205] Some embodiments provide for treating a disease or condition in a subject in need thereof, where the disease or condition is a primary mitochondrial disease.

[0206] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising administering to the subject an effective amount of a MAS receptor agonist, or an agent that induces the endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0207] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising administering to the subject an effective amount of a MAS receptor agonist, or an agent that induces the endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, wherein the MAS receptor agonist is a compound of formula (III).

[0208] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising administering to the subject an effective amount of a MAS receptor agonist, or an agent that induces the endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, MAS receptor agonists include Compound 7, Compound 10, and Nle 3-A(1-7), and angiotensin(1-7).

[0209] Some embodiments herein provide methods of treating a disease or condition in a subject in need thereof, comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist.

[0210] It is believed that stimulation of mitophagy can improve mitochondrial function and integrity. To evaluate mitochondrial function and integrity, multiple parameters can be evaluated, such as morphological changes and total mass, mtDNA copy number and heteroplasmic shift, ROS production, electron chain function, and ATP synthase hydrolysis capacity.

[0211] Mitochondrial morphology may change due to accumulation of damage and induction of mitophagy. Specifically, when persistent depolarization of mitochondrial membrane potential occurs, mitochondrial fission is required to isolate damaged mitochondria for degradation. Conversely, maintaining membrane potential does not allow this degradation, and in healthy cells, elongated morphology is observed. Thus, mitochondrial morphology is an important parameter for evaluating mitochondrial integrity. Morphology is evaluated by confocal microscopy, and images are quantified to measure mitochondrial size and shape (i.e., aspect ratio and circularity) according to methods known in the art. Similarly, mitochondrial mass can be evaluated by total volume or total area, although complementary methods can also be used. To that end, the total amount of integrated protein in cell lysates by Western blotting and mtDNA copy number measurable by RT-PCR can be used to determine mitochondrial mass.

[0212] In cells with mtDNA mutations and deletions with variable heteroplasmy levels, the shift from disease-causing alterations to wild-type DNA can be used to assess clearance by mitophagy. To that end, assessment of heteroplasmy % can be performed by methods known in the art, such as NGS sequencing, single-cell droplet digital PCR, or random mutation capture assays, depending on the sensitivity required to detect heteroplasmy levels and the type of alteration (point mutation or deletion). Mitochondrial dysfunction can also increase ROS levels, creating a more structural and optimal environment for mtDNA damage. In some embodiments, assessment of ROS levels by imaging cells loaded with mitochondrial-targeted fluorescent tools, such as mitosox or a probe proportional to the applied voltage, can be performed according to methods known in the art using microscopy.

[0213] Mitochondrial damage and mitophagy can also affect ETC function, and respirometry or specific complex activity can be assessed in certain disease scenarios. More specifically, the ability of ATP synthase to produce ATP is a way to assess how healthy a mitochondrial population is. Under certain conditions, when the electrochemical proton gradient begins to fall, ATP synthase reverses direction and rotates counterclockwise, hydrolyzing ATP to actively transport protons from the mitochondrial matrix to the intermembrane space, thereby maintaining a proton gradient across the inner mitochondrial membrane and preventing depolarization. As a result of ATP hydrolysis by CV, less ATP is available for other cellular processes, and preventing depolarization also blocks mitophagy.

[0214] Some embodiments herein provide a method of treating a disease or condition in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist, where the MAS receptor agonist is a compound of formula (III).

[0215] Some embodiments herein provide a method of treating a disease or condition in a subject in need thereof, comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist; wherein the MAS receptor agonist is selected from the group consisting of Compound 7, Compound 10, Nle 3 -A(1-7), and angiotensin(1-7).

[0216] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0217] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, wherein the MAS receptor agonist is a compound of formula (III).

[0218] Some embodiments provide for treating a disease or condition in a subject in need thereof comprising stimulating mitophagy in said subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic limb paralysis and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, MAS receptor agonists include Compound 7, Compound 10, and Nle 3-A(1-7), and angiotensin(1-7).

[0219] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with intracerebral iron deposition (neurodege2.2neration) 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof.

[0220] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with intracerebral iron deposition (neurodege2.2neration) 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, wherein the MAS receptor agonist is a compound of formula (III).

[0221] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist, wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) );Leigh syndrome;Mental retardation, X-linked, syndromic, Turner type (MRXST);Maternally inherited diabetes and deafness syndrome (MIDD);Microcephaly 18 (MCPH18);Microphthalmia syndrome 7;Mitochondrial DNA depletion syndrome (MDDS);Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS);Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE);Mitochondrial recessive ataxia syndrome (MIRAS);mtDNA heteroplasmy;Methylmalonic acidemia (MMA);Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with intracerebral iron deposition (neurodege2.2neration) 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, MAS receptor agonists include Compound 7, Compound 10, and Nle 3-A(1-7), and angiotensin(1-7).

[0222] Some embodiments provide a method of treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist, wherein the subject exhibits a C9orf72 mutation, an Optineurin mutation, or a TBK1 mutation.

[0223] Some embodiments provide a method of treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist, wherein the subject exhibits a C9orf72 mutation, an Optn (optineurin) mutation, or a TBK1 mutation, and the MAS receptor agonist is a compound of formula (III).

[0224] Some embodiments provide a method of treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist, wherein the subject exhibits a C9orf72 mutation, an Optineurin (Optn) mutation, or a TBK1 mutation, and the MAS receptor agonist is selected from the group consisting of Compound 7, Compound 10, Nle 3 -A(1-7), and angiotensin(1-7).

[0225] Some embodiments provide a method of treating Parkinson's disease in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist; wherein the subject exhibits an LRRK2 mutation, a GBA mutation, a Pink1 mutation, or a Prkn2 mutation.

[0226] Some embodiments provide a method of treating Parkinson's disease in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist; wherein the subject exhibits an LRRK2 mutation, a GBA mutation, a Pink1 mutation, or a Prkn2 mutation, and the MAS receptor agonist is a compound of Formula (III).

[0227] Some embodiments provide a method of treating Parkinson's disease in a subject in need thereof, comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist; wherein the subject exhibits an LRRK2 mutation, a GBA mutation, a Pink1 mutation, or a Prkn2 mutation, and the MAS receptor agonist is Compound 7, Compound 10, Nle 3 -A(1-7), and angiotensin(1-7).

[0228] Some embodiments provide a method of treating a disease or condition in a subject in need thereof, the method comprising: Stimulating mitophagy in a subject; and administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist or a substance that induces endogenous production of a MAS receptor agonist; administering to the subject an effective amount of an agent that stimulates mitochondrial biogenesis; stimulating mitophagy in a subject by Here, the disease or condition is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); cardiovascular disease; frontotemporal dementia; hematopoietic disorders; Parkinson's disease; primary biliary cirrhosis / cholangitis (PBC); sepsis; renal trauma / injury, hypertension, cancer, or any combination thereof.

[0229] In some embodiments, the disease or condition is Alzheimer's disease. In some embodiments, the disease or condition is ALS. In some embodiments, the disease or condition is hypertension. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is osteosarcoma.

[0230] Some embodiments further comprise administering to the subject an effective amount of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is urolithin A.

[0231] Some embodiments further include administering to the subject an effective amount of an agent that stimulates mitochondrial biogenesis. Non-limiting examples of agents that stimulate mitochondrial biogenesis include AMPK activators (such as AICAR), SIRT1 activators (such as resveratrol, SRT1720, SRT1460, SRT2104, and SRT2379), β2-adrenergic agonists (such as formoterol), 5HT agonists (such as LY344, 864, and DOI), CB1 agonists (such as rimonabant), PPARα agonists (such as fibrates and thiazolidinediones), PPARγ agonists (such as rimonabant), and mitochondrial activators (such as rimonabant). These include agonists (such as GW501516), glucocorticoid agonists (such as dexamethasone), PDE inhibitors (such as sildenafil or vardenafil), nitric oxide mimetics (DETA-NO), GC activators (such as BAY-41-2272, cinaciguat, riociguat), natural peptides (ANP or BNP), natural products (such as green tea polyphenols, lipoamide, isoflavones, quercetin), and genetic modulators (such as recombinant TFAM or donor mtDNA).

[0232] Some embodiments provide a method of treating a disease or condition in a subject in need thereof comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist; wherein the disease or condition is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); cardiovascular disease; frontotemporal dementia; hematopoietic disorders; Parkinson's disease; primary biliary cirrhosis / cholangitis (PBC); sepsis; renal trauma / injury, hypertension, cancer, or any combination thereof; Here, the subject is administered, prior to administration of a MAS receptor agonist or a substance that induces endogenous production of a MAS receptor agonist, These include one or more of the following: elevated lactate levels; impaired phosphocreatine salvage; reduced levels of mitochondrial respiratory complex proteins and activity; downregulated mitochondrial genes; elevated plasma acylcarnitine levels; elevated mitochondrial DNA (mtDNA) deletion mutation frequency; elevated creatine levels; elevated levels of fibroblast growth factor 21 (FGF21); elevated levels of growth / differentiation factor 15 (GDF-15); elevated levels of cell-free circulating mtDNA (ccf-mtDNA); elevated levels of neurofilament light chain (NF-L); elevated levels of depolarized mitochondria or mitochondria with oxidized content, damaged content, or structural disturbances; elevated mitochondrial heterogeneity; or elevated levels of mtDNA released into the cytosol or plasma.

[0233] Also provided herein is a method of treating a disease or condition caused by dysfunctional macrophages, monocytes, microglial cells, or neutrophils in a subject in need thereof, comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist. A non-limiting example of a disease or condition caused by dysfunctional macrophages, monocytes, microglial cells, or neutrophils may be a disease or condition caused by aged and exhausted macrophages, monocytes, and microglial cells that have limited phagocytic activity and antigen-presenting capacity. EXAMPLES

[0234] method The following examples are provided to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as the present disclosure. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, quantities, temperatures, concentrations, etc.), but some experimental error and deviation should be allowed for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0235] The following methods were used for the studies described herein, which were performed with INS1 or U2OS cell lines. The data described in Examples 1-5 were generated in the INS1 cell line, unless otherwise noted.

[0236] Viral transduction Cells were seeded and cultured on pre-placed cover slips in 24-well plates. There is no need to coat the cover slips. Cells were transduced with 1 mL of working stock of mCherry-GFP-Fis1101-152 adenovirus. The working stock was prepared by first injecting 1 μL of stock mCherry-GFP-Fis1101-152 virus (1 × 10 12vp / mL; Welgen™) was prepared by diluting in 500 μL of 5 mM RPMI solution ("Roswell Park Memorial Institute" solution) (Solution A) and then further diluted by transferring 0.75 μL / well of Solution A to 24 mL of 5 mM RPMI. Virus incubation was performed for 24 hours at 37° C. in a 5% CO2 incubator. After 24 hours, treatment was performed. Different compounds were treated for 8 hours, 24 hours, and 72 hours. When treatment was completed, cells were fixed with pre-warmed 4% paraformaldehyde (PFA). PFA was removed by two washes of PBS-0.2% TWEEN® solution.

[0237] Imaging Equipment All imaging was performed on a Zeiss™ LSM880. Super-resolution imaging was performed using a 63x apochromatic oil immersion lens and an AiryScan™ super-resolution detector (Huff et al., 2015). All fluorophores were excited on separate tracks to avoid artifacts due to bleed-through emission. GFP and MitoTrackerGreen™ were excited with a 488 nm, 25 mW argon ion laser and their emission was captured through a 500-550 nm bandpass filter. mCherry was excited with a 543 nm, 1 mW helium-neon laser or a 561 nm, 20 mW diode-pumped solid-state laser and their emission was captured through a 580-650 nm bandpass filter.

[0238] MitoQC Image Analysis All image analysis was performed with CellProfiler™ software (https: / / cellprofiler.org / ) to identify morphological properties and mitochondrial structure in mitophagy events. Individual mitochondrial fluorescence intensity and area were measured in CellProfiler™ and imported into Microsoft Excel®. Mitochondria smaller than 2 pixels in area were not included in the final analysis. Images were subjected to top-hat filtering followed by a global threshold Otsu method to segment mitochondria. This was performed in both red and green channels.

[0239] Mitochondrial respiration measurements Respiratory measurements of INS1 and U2OS cells were performed using the Seahorse Bioscience™ XF96 platform (Agilent Technologies, Santa Clara, CA) as previously described (Ferrick et al., 2008). Oxygen consumption of β-cells in each well was measured by the change in oxygen concentration over time. Mitochondrial glycolysis was also measured as a readout of the extracellular acidification rate (ECAR) measured by the change in pH versus time. INS1 cells were seeded at 22,000 cells / well in 120 μL / well of 5 mM RPMI, XF96 microplates, and treatments were performed 24 hours after overnight seeding. Respiratory measurements were performed after 2 days using the Seahorse™ XF 96.

[0240] Prior to the assay, INS1 or U2OS cells were incubated for 1 h at 37 °C in 150-185 μL / well of Seahorse™ assay medium (XF-based minimal DMEM, pH 7.4, supplemented with 2 mmol / L glucose, 1 mM sodium pyruvate, and 2 mM l-glutamine). For port injections, nutrients / compounds were injected into port A, such as Oligomycin (final concentration 3 μmol / L), carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) diluted in a mixture of 80% sodium pyruvate and 20% 1:1 L-leucine / L-glutamine (final concentration 1.27 μmol / L FCCP and 2.9 mmol / L each of leucine / glutamine in 11.4 mmol / L sodium pyruvate), and port C, such as rotenone and antimycin A (final concentration 2.5 μmol / L). Upon completion of the Seahorse™ run, oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) were exported from the Agilent Wave™ software and normalized by cell number in Microsoft Excel®. Cells were imaged after Seahorse™ experiments using an Operetta high-throughput imager (PerkinElmer) in brightfield mode with a 2x or 10x objective.

[0241] Mitochondrial content Cells were cultured on coverslips in Petri dishes filled with the appropriate culture medium or grown directly in 4-chamber glass-bottom dishes, after which the cells were imaged on the LSM880. At least 30 cells per condition per experiment were collected, and at least three separate experiments were performed to image clonal cells. Image analysis was performed with CellProfiler™ software (https: / / cellprofiler.org / ) to measure mitophagy events. Individual mitochondrial fluorescence intensity and area were measured in CellProfiler™ and imported into Microsoft Excel. Mitochondria with an area smaller than 2 pixels were not included in the final analysis. Images were subjected to top-hat filtering followed by a global threshold Otsu method to segment mitochondria. To assess the amount of mitochondrial content, the green fluorescence intensity of objects identified as mitochondrial structures was quantified. Data were normalized to the control treatment dimethyl sulfoxide (DMSO).

[0242] form All image analysis was performed with CellProfiler software (https: / / cellprofiler.org / ) to identify mitochondrial structures at mitophagy events. Individual mitochondrial fluorescence intensity and area were measured in CellProfiler and imported into Microsoft Excel. Mitochondria with an area smaller than 2 pixels were not included in the final analysis. Images were subjected to top-hat filtering followed by the global threshold OTSU method to segment mitochondria. This was performed in both the red and green channels. The major axis of the ellipse corresponding to the mitochondrion (long axis over the minor axis) was used to calculate the length and the degree of branching was measured by the shape factor (FF; perimeter 2 / 4π * area).

[0243] Mitophagy INS1 cells were seeded at a density of 2 × 104 cells / compartment in 4-compartment CELLVIEW™ glass-bottom cell culture dishes. After 48 h, cells were transduced with an adenoviral construct encoding the fluorescent mitophagy reporter mCherry-GFP-Fis1101-152 for 24 h. Medium changes containing the indicated treatment concentrations or 0.1% DMSO as vehicle control were performed 8 h before the imaging session. Imaging was performed with a 63x Plan Neofluar objective and Airyscan module on a Zeiss LSM880 confocal microscope. In total, 25 fields containing 59–85 cells were imaged per condition. Experiments were repeated three times independently. Image analysis was performed with FIJI ImageJ 1.51p and CellProfiler 2.2.0 rev ac0529e. Briefly, individual cells were cropped and background subtracted using a median filter-aided processing method. The ratio of red / green fluorescence channels was calculated and mitophagy-positive structures were recognized based on a lower cutoff ratio of red to green of 2.5. Mitophagy events per cell were determined by the following formula: mitophagy events per cell / 4, total area of ​​mitophagy-positive structures per cell, average area of ​​one mitophagy structure. Data were normalized to DMSO control to account for daily variations. Statistical analysis was performed using GraphPad Prism 7.02. Significant treatment differences were determined using one-way ANOVA and Tukey post-hoc test. P<0.05 ( * ) values ​​were considered significant.

[0244] Fibroblasts Control and patient skin-derived fibroblasts were fixed (4% paraformaldehyde in phosphate-buffered saline (PBS)), permeabilized (0.1% Triton® X-100 in PBS) and stained with anti-LC3, anti-TOMM20 and secondary antibodies (Invitrogen) in blocking solution (5% goat serum). Confocal image acquisition of 3D Z-stacks was performed using a Zeiss LSM880 with Airyscan equipped with a Zeiss Pla-Apochromat 40x / 1.2 objective. Quantification of mitophagosomes (LC3+TOMM20 colocalization) was performed using Aivia v.10 software (Leica Microsystems). Both channels were used to generate confidence maps using pixel classification machine learning techniques. 3D colocalization was performed to count LC3 vesicles. The graph shows the % of LC3 vesicles colocalized with TOMM20 from the total LC3 count. Approximately 50 cells were obtained from each condition and analyzed randomly. Statistics between control and patient cell lines used one-way ANOVA with Dunnett's multiple comparisons.

[0245] Example 1. Compounds stimulate mitophagy FIG. 6A shows the results of the 50 nM DMSO negative control, angiotensin(1-7), Nle 3 4 shows the rate of mitophagy after three treatment periods with various test compounds, including Compound 7, ...

[0246] FIG. 6B shows the results of the DMSO negative control and four different doses of the MAS receptor agonists angiotensin(1-7), Nle 3 Figure 1 shows the rate of mitophagy after 8 hours of treatment with -A(1-7), and compound 7.

[0247] Figure 6C shows the mitophagy response to MAS receptor activation and chemical knockdown of the MAS receptor. Cells were incubated with DMSO negative control; 1 μM MAS receptor inhibitor A779; angiotensin (1-7); angiotensin (1-7) + A779; Nle 3 -A(1-7);Nle3 -A(1-7)+A779; Compound 7; and Compound 7+A779. The results of the experiments provide strong evidence that MAS receptor activity directly influences mitochondrial turnover.

[0248] FIG. 14 demonstrates that the MAS agonists tested induced mitophagy in U2-OS cells.

[0249] Example 2. Mitochondrial function is normal after compound treatment 7A, 7B, and 7C show the results of a negative control, a no-mitochondrial control, and three different concentrations of the MAS receptor agonist Nle 3 Figure 7 shows the oxygen consumption rate (OCR) in cells treated with OXPHOS-A(1-7) (Figure 7A), angiotensin(1-7) (Figure 7B), and compound 7 (Figure 7C). CCCP is carbonyl cyanide m-chlorophenylhydrazone, a chemical inhibitor of OXPHOS, which acts in these experiments as a negative control for mitochondrial activity.

[0250] Example 3. Extracellular acidification rate is not altered by test compounds 8A, 8B, and 8C show the results of a negative control, a no-mitochondrial control, and three different concentrations of the MAS receptor agonist Nle 3 Figure 8 shows the extracellular acidification rate (ECAR) in cells treated with angiotensin-A(1-7) (Figure 8A), angiotensin(1-7) (Figure 8B), and compound 7 (Figure 8C). CCCP serves as a negative control for mitochondrial activity in these experiments.

[0251] Example 4. Effect of compounds on mitochondrial mass Figure 9 shows the cellular mitochondrial mass after various durations, concentrations, and treatments of test compounds. Cells were treated with DMSO negative control, Nle 3The cells were treated with α-A(1-7), angiotensin(1-7), and compound 7. The stable cellular mitochondrial content is strong evidence that mitotic mitochondria are replaced by new mitochondria via biogenesis.

[0252] Example 5. Mitochondrial morphology after compound treatment 10A, 10B, 10C, 10D, 10E, 10F, 10G, 10H, 10I, 10J, 10K, 10L, and 10M show the results of the DMSO negative control and the treatment with angiotensin(1-7), Nle at concentrations of 5 nM, 50 nM, 500 nM, and 5 μM, respectively. 3 1 shows super-resolution micrographs of cells after treatment with -A(1-7) and compound 7.

[0253] 11A, 11B, 11C, 11D, 11E, 11F, 11G, and 11H show results for DMSO negative control, A779 (MAS receptor inhibitor), angiotensin (1-7), angiotensin (1-7) + A779, Nle 3 -A(1-7), Nle 3 1 shows super-resolution micrographs of cells after treatment with -A(1-7)+A779, compound 7, and compound 7+A779.

[0254] Figure 12 shows the relationship between angiotensin (1-7), Nle 3 FIG. 1 shows a table briefly outlining the morphology of cellular mitochondria in cells after 8 hours, 24 hours, and 72 hours of treatment with -A(1-7), or compound 7.

[0255] A decrease in connectivity and formation of short or round mitochondria occurs under conditions that impair mitochondrial function, such as mtDNA depletion or treatment with mitochondrial toxins. They transition from highly elongated and branched to fragmented morphology. Treatment with MAS agonists does not induce changes in mitochondrial morphology associated with mitochondrial stress, such as global fragmentation, at the doses tested.

[0256] Example 6: Fibroblast studies Mitochondrial inherited mutations that result in defective mitophagy in certain diseases have been identified, as summarized in the table below (see also FIG. 13). In such diseases, it is contemplated that stimulating mitophagy (e.g., by administration of a MAS agonist) may treat patients suffering from such diseases.

[0257] [Table 1]

Claims

1. A composition for use in a method of treating a disease or condition in a subject in need thereof, the method comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of the MAS receptor agonist or a substance that induces the endogenous production of a MAS receptor agonist, and wherein the disease or condition is Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) ); Leigh syndrome; Mental retardation, X-linked, syndromic, Turner type (MRXST); Maternally inherited diabetes and deafness syndrome (MIDD); Microcephaly 18 (MCPH18); Microphthalmia 7; Mitochondrial DNA depletion syndrome (MDDS); Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); Mitochondrial recessive ataxia syndrome (MIRAS); mtDNA heteroplasmy; Methylmalonic acidemia (MMA); Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodegeneration with cerebral iron deposition 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without epileptic seizures (NEDSBAS); neuronal ceroid lipofuscinosis; Niemann-Pick disease; neuropathy, ataxia, and retinitis pigmentosa (NARP); Pearson syndrome; Pompe disease; rhabdomyosarcoma; schizophrenia; spastic paraplegia type 15; spastic paraplegia type 49; spinocerebellar degeneration 4 (SCA4); spinocerebellar degeneration 25 (SCA25); Vici syndrome; Werner syndrome; Wolfram syndrome; xeroderma pigmentosum (XP) group A; Zellweger syndrome; or any combination thereof, The composition.

2. A composition for treating a disease or condition in a subject in need thereof, comprising a mitophagy-stimulating amount of a MAS receptor agonist, or a substance that induces endogenous production of a MAS receptor agonist, wherein the disease or condition is: Sjögren's syndrome, progeria, Rett syndrome, Down syndrome; ataxia-telangiectasia; autosomal dominant optic atrophy; Barth syndrome; Charcot-Marie-Tooth disease; Charlevoix-Saguet spastic ataxia; Cockayne syndrome; Danon disease; Fabry disease; Fanconi anemia; Friedreich's ataxia; Fuchs endothelial dystrophy; Gaucher disease; intellectual developmental disability with short stature and skeletal abnormalities; Kearns-Sayre syndrome; Krabbe disease; lactic acidosis; Lafora disease; Leber's hereditary optic neuropathy (LHON) ); Leigh syndrome; Mental retardation, X-linked, syndromic, Turner type (MRXST); Maternally inherited diabetes and deafness syndrome (MIDD); Microcephaly 18 (MCPH18); Microphthalmia 7; Mitochondrial DNA depletion syndrome (MDDS); Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); Mitochondrial recessive ataxia syndrome (MIRAS); mtDNA heteroplasmy; Methylmalonic acidemia (MMA); Mucolipidosis II (ML II); multiple sulfatase deficiency; neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP); myoclonus epilepsy with ragged red fibers (MERRF); neurodege2.2neration 5 (NBIA5); neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures (NEDSBAS); neuronal ceroid lipofus Zinn's syndrome; Niemann-Pick disease; Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP); Pearson's syndrome; Pompe's disease; Rhabdomyosarcoma; Schizophrenia; Spastic Paraplegia Type 15; Spastic Paraplegia Type 49; Spinocerebellar Degeneration 4 (SCA4); Spinocerebellar Degeneration 25 (SCA25); Vici's syndrome; Werner's syndrome; Wolfram syndrome; Xeroderma pigmentosum (XP) Group A; Zellweger's syndrome; or any combination thereof, The composition.

3. A composition for use in a method of treating amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising an MAS receptor agonist, or a substance that induces endogenous production of an MAS receptor agonist; The method includes stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of the MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist; The subject exhibits a C9orf72 mutation, an Optineurin mutation, or a TBK1 mutation; composition.

4. A composition for use in a method of treating Parkinson's disease in a subject in need thereof, comprising a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist, said method comprising stimulating mitophagy in said subject by administering to said subject a mitophagy-stimulating amount of said MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist; The subject exhibits a LRRK2 mutation, a GBA mutation, a Pink1 mutation, or a Prkn2 mutation. composition.

5. 1. A composition for use in a method of treating a disease or condition in a subject in need thereof, comprising: (i) a MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist, and (ii) an agent that stimulates mitochondrial biogenesis; The method comprises: administering to the subject a mitophagy-stimulating amount of the MAS receptor agonist, or an agent that induces endogenous production of a MAS receptor agonist; administering to the subject the agent that stimulates mitochondrial biogenesis; stimulating mitophagy in the subject by The disease or condition is Alzheimer's disease; amyotrophic lateral sclerosis (ALS); cardiovascular disease; frontotemporal dementia; hematopoietic disorders; Parkinson's disease; primary biliary cirrhosis / cholangitis (PBC); sepsis; renal trauma / injury, hypertension, cancer, or any combination thereof; The composition.

6. A composition for use in a method of treating a disease or condition caused by dysfunctional macrophages, monocytes, microglial cells, or neutrophils in a subject in need thereof, the composition comprising a MAS receptor agonist, or a substance that induces the endogenous production of a MAS receptor agonist, the method comprising stimulating mitophagy in the subject by administering to the subject a mitophagy-stimulating amount of the MAS receptor agonist or the substance that induces the endogenous production of a MAS receptor agonist.

7. A composition described in any one of claims 1 to 4 and 6, characterized in that the composition is administered in combination with an agent that stimulates mitochondrial biogenesis.

8. The composition of claim 5 , wherein the disease or condition is Alzheimer's disease.

9. The composition of claim 5 , wherein the disease or condition is ALS.

10. The composition of claim 5 , wherein the disease or condition is hypertension.

11. The composition of claim 5 , wherein the disease or condition is cancer.

12. The composition of any one of claims 1 to 11, wherein the subject is a human patient.

13. The MAS receptor agonist is heterocyclic non-peptidic angiotensin (1-7) mimetics or analogs thereof; angiotensin(1-7) or an analogue thereof, Nle ３ -A(1-7) or an analogue thereof, 1-(p-thienylbenzyl)imidazole analogues, and 20-hydroxyecdysone or an analogue thereof, The composition according to any one of claims 1 to 12, selected from the group consisting of:

14. The MAS receptor agonist is compound 7, compound 10, Nee ３ -A(1-7) Angiotensin (1-7), Ang-1-6-Ser-0-glycosylated analogs of angiotensin(1-7), and 5-formyl-4-methoxy-2-phenyl-1-[[4-[2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazole, The composition according to any one of claims 1 to 12, selected from the group consisting of:

15. The MAS receptor agonist is compound 7, compound 10, Nle ３ -A (1-7), and Angiotensin (1-7), The composition of claim 14 selected from the group consisting of:

16. The MAS receptor agonist has the formula (I): 【Chemistry 42】 [In the formula: R(1) is (1) halogen, (2) hydroxyl, (3) (C １ ~C ４ )-alkoxy, (4) (C １ ~C ８ )-alkoxy, in which 1 to 6 carbon atoms are replaced by heteroatoms O, S, or NH; (5) saturated cyclic ether-substituted (C １ ~C ４ )-alkoxy, (6) O-(C １ ~C ４ )-alkenyl, (7) O-(C １ ~C ４ )-alkylaryl, or (8) unsubstituted or halogen, (C １ ~C ３ )-alkyl, (C １ ~ C ３ phenoxy, substituted by substituents selected from: alkoxy, and trifluoromethyl; and R(2) is, (1) CHO, and R(3) is (1) (C １ ~C ４ )-alkyl, or (2) aryl, and R(4) is (1) hydrogen, (2) Halogen, or (3) (C １ ~C ４ )-alkyl, and X, (1) Oxygen, or (2) sulfur, and Y, (1) Oxygen, or (2) -NH-, and R(5) is (1) hydrogen, (2) (C １ ~C ６ )-alkyl, or (3) (C １ ~C ４ )-alkylaryl, and wherein R(5) can be hydrogen only if Y has the meaning given in (2); and R(6) is (1) (C １ ~C ５ )-alkyl; is] or a physiologically acceptable salt thereof, The composition according to any one of claims 1 to 12.

17. The MAS receptor agonist has the formula (II): 【Chemistry 43】 [In the formula: R(1) is 1. Unsubstituted or NH ２ , halogen, O-(C １ ~C ３ )-alkyl, CO—O—(C １ ~C ３ )-alkyl, and CO ２ H; (C １ ~C ５ )-alkyl, 2. (C ３ ~C ８ )-cycloalkyl, 3. (C １ ~C ３ )-alkyl-(C ３ ~C ８ )-cycloalkyl, 4. Unsubstituted or containing halogen and O—(C １ ~C ３ )-alkyl; ６ ~C １０ )-aryl, 5. (C １ ~C ３ )-alkyl-(C ６ ~C １０ )-aryl, where the aryl radical is unsubstituted or substituted with halogen and O—(C １ ~C ３ )-alkyl), 6. (C ３ ~C ５ )-heteroaryl, and 7. (C １ ~C ３ )-alkyl-(C １ ~C ５ )-heteroaryl, is selected from among R(2) is, 1. Hydrogen, 2. Unsubstituted or containing halogen and O—(C １ ~C ３ )-alkyl; １ ~C ６ )-alkyl, 3. (C ３ ~C ８ )-cycloalkyl, 4. (C １ ~C ３ )-alkyl-(C ３ ~C ８ )-cycloalkyl, 5. Unsubstituted or halogen, O—(C １ ~C ３ )-alkyl and CO—O—(C １ ~C ３ )-alkyl; ６ ~C １０ )-aryl, and 6. Unsubstituted or containing halogen and O—(C １ ~C ３ )-alkyl; １ ~C ３ )-alkyl-(C ６ ~C １０ )-aryl, is selected from among R(3) is 1. Hydrogen, 2. COOH, and 3. COO-(C １ ~C ４ )-alkyl, is selected from among R(4) is 1. Hydrogen, 2. Halogens, and 3. (C １ ~C ４ )-alkyl, is selected from among R(5) is 1. Hydrogen, and 2. (C １ ~C ６ )-alkyl, is selected from among R(6) is 1. Hydrogen, 2. (C １ ~C ６ )-alkyl, 3. (C １ ~C ３ )-alkyl-(C ３ ~C ８ )-cycloalkyl, and 4. (C ２ ~C ６ )-alkenyl, is selected from among X, 1. Oxygen, and 2. N.H. Selected from among and physiologically tolerated salts thereof, The composition according to any one of claims 1 to 12,

18. The MAS receptor agonist has the formula (III): 【Chemistry 44】 [In the formula: Ring A is a 5- or 6-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms; Ring B is a 5- or 6-membered heteroaryl ring containing at least one nitrogen atom; Ring C is an optionally substituted aryl ring; A １ 、A ２ 、A ３ 、A ４ が、independantして、=N-、-C(=O)-、-C(R ａ )=、=C(R ｂ )-、-C(R ｃ )(R ｄ )-N(R ｅ )-、-C(R ｃ )(R ｄ )-O-、 Or -[C(R ｃ (R ｄ ) ] ｎ - where n is 1 or 2; X １ ~X ２ But (R ６ )C-N, N-C(R ６ ), N-N, N-O, O-N, N-S, or S-N; X ３ But (R ７ ) C=C(R ８ ), O, S, or N(R ９ ) and Z is O, NH or R ５ is a bond to R ａ and R ｂ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido, or carboxy, with the proviso that R ａ and R ｂ may also combine to form a ring of up to six atoms, R ｃ and R ｄ is independently selected from the group consisting of hydrogen, alkyl, aryl, or heteroaryl, with the proviso that R ｃ and R ｄ may also be linked to form a ring of up to six atoms, R ｅ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; R １ , R ３ , R ４ , R ６ , R ７ , and R ８ is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R ２ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; R ５ is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; and R ９ is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; or a pharma- ceutically acceptable salt thereof, The composition according to any one of claims 1 to 12.

19. The MAS receptor agonist is represented by the general formula (i) R １ -R ２ -R ３ -R ４ -R ５ -R ６ -R ７ -R ８ The group R １ ~R ８ comprising a sequence of at least three consecutive amino acids of In the formula, R １ and R ２ But together, the formula: X-R Ａ -R Ｂ - where X is H or 1-3 peptide groups; R Ａ is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu(NH2), Gly, Asp(NH2), Suc, and glycosylated forms thereof; R Ｂ is selected from Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg, D-Lys, His, and glycosylated forms thereof; R ３ is selected from the group consisting of Val, Ala, Leu, Nle, Ile, Gly, Pro, Aib, Acc, Lys, Tyr, and glycosylated forms thereof; R ４ But Tyr, Tyr(PO ３ ) ２ , Thr, Ser, Hse, Ala, azaTyr, Tyr, Phe, and glycosylated forms thereof; R ５ is selected from the group consisting of Ile, Ala, Leu, Nle, Val, Gly, and glycosylated forms thereof; R ６ His, Arg, 6-NH ２ - Phe, Lys and their glycosylated forms, R ７ is Pro, Ala, Gly, Ser, and their glycosylated forms; R ８ is selected from the group consisting of Phe, Phe(Br), He, Tyr, Ser, Thr, Hyp, and glycosylated forms thereof; The composition according to any one of claims 1 to 12.

20. The MAS receptor agonist is represented by the general formula (ii) Ala １ -R ２ -R ３ -R ４ -R ５ -R ６ -R ７ is an array of R ２ is selected from Arg, Lys, Ala, Cit, Orn, Ser(Ac), Sar, D-Arg, and D-Lys; R ３ is selected from the group consisting of Val, Ala, Leu, Nle, Ile, Gly, Pro, Aib, Acc, Lys, and Tyr; R ４ is Ser, or R ７ forms a cyclic thioether, R ５ is selected from the group consisting of Ile, Ala, Leu, Nle, Val, and Gly; R ６ His, Arg, 6-NH ２ - Phe, Lys and their glycosylated forms, and R ７ is Cys or R ４ forming a cyclic thioether with The composition according to any one of claims 1 to 12.

21. The MAS receptor agonist has the formula (IV): 【Chemistry 45】 [In the formula, V-U is a carbon-carbon single bond, Y is a hydroxyl group or hydrogen, or V-U is a C=C ethylene bond; X is oxygen and Q is a carbonyl group; R １ is a group (C １ ~C ６ ) W (C １ ~C ６ ), group (C １ ~C ６ ) W (C １ ~C ６ ) W (C １ ~C ６ ), group (C １ ~C ６ ) W (C １ ~C ６ )CO2(C １ ~C ６ ), group (C １ ~C ６ ) A (A is optionally OH, OMe, (C １ ~C ６ ), N(C １ ~C ６ ), CO ２ (C １ ~C ６ ) type heterocycle, CH ２ Br groups, The composition of any one of claims 1 to 12, wherein W is a heteroatom selected from N, O and S.

22. The composition according to any one of claims 1 to 6, wherein the substance that induces the endogenous production of a MAS receptor agonist is a substance that induces the endogenous production of angiotensin (1-7).

23. The substance that induces the endogenous production of angiotensin (1-7), ACE2 enzyme, ACE2 activator, ACE inhibitors, or any combination thereof, The composition according to claim 22, wherein

24. 24. The composition of claim 23, wherein the ACE2 enzyme is a recombinant human ACE2 enzyme.

25. 24. The composition of claim 23, wherein the ACE2 activator is a xanthenone or a diminazene aceturate.

26. 24. The composition of claim 23, wherein the ACE inhibitor is enazepril, captopril, enalapril, fosinopril, lisinopril; moexipril, perindopril, quinapril, ramipril, trandolapril, or any combination thereof.

27. The composition according to any one of claims 1 to 26, wherein the MAS receptor agonist or a substance that induces the endogenous production of a MAS receptor agonist is administered as a pharmaceutical composition.

28. The composition according to any one of claims 1 to 27, characterized in that the subject is diagnosed using at least a mitophagy assay.

29. 29. The composition of claim 28, wherein the mitophagy assay is used to assess mitochondrial function and is an assay that measures oxygen consumption; the amount of mitochondrial DNA (mtDNA) mutations or deletions, or the amount of mutations and deletions; the mtDNA copy number; or the activity of a mitochondrial enzyme.

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