Quinazolinone Compounds

Abstract

Novel quinazolinone compounds, as well as pharmaceutical compositions comprising quinazolinones, and methods for the treatment of diseases and conditions associated with mitochondrial dysfunction, are disclosed.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 811,471, filed February 27, 2019, which is incorporated by reference in its entirety. [Background technology]

[0002] 2. Background of the Invention Mitochondrial dysfunction can affect cellular function in several ways. First, mitochondria are the main source of ATP as cellular power plants. Mitochondrial dysfunction leads to a lack of cellular energy and compromises the maintenance of cellular vitality. Second, mitochondria possess the electron transport chain involved in oxidative phosphorylation. This process generates reactive oxygen species (ROS) that can perform some signaling functions under basal conditions, but defective mitochondria are inefficient in the electron transfer process, leading to elevated ROS production, which can cause damage to various macromolecules (proteins, nucleic acids, lipids, etc.). This oxidative damage is widely associated with diseases, especially age-related diseases. Third, mitochondria are important organelles in maintaining cellular calcium homeostasis. Mitochondria import calcium released from intracellular stores, especially the ER, or calcium generated by excitation. Mitochondrial dysfunction can alter cellular calcium homeostasis and lead to conditions such as ER stress, which is associated with several disease states. In addition, mitochondrial calcium is essential for the activity of certain enzymes in the TCA cycle and the electron transport chain. Thus, alterations in mitochondrial calcium homeostasis can result in mitochondrial energy insufficiency. Finally, mitochondria act as gatekeepers of cell life and death, controlling both apoptotic and necrotic cell death. Thus, at the cell's end, impairments in these pathways can induce premature cell death, leading to degenerative diseases. Conversely, lack of proper cell death can lead to inappropriate tissue growth and cancer development, which are often characterized by alterations in mitochondrial metabolism.

[0003] A number of major human diseases, many of which represent urgent unmet medical needs, are associated with mitochondrial dysfunction, ranging from cancer and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and ALS, to brain injuries such as stroke, seizures, neuropathic pain, traumatic brain injury, spinal cord injury, aneurysm, and subarachnoid hemorrhage) to certain non-neurological disorders (e.g., sepsis, acute kidney injury, cardiorenal syndrome, cardiac ischemia-reperfusion injury, pulmonary arterial hypertension, chronic obstructive pulmonary disease, and vasoconstriction). Summary of the Invention

[0004] BRIEF SUMMARY OF THE INVETION Provided herein are compounds of formula I, and pharma- ceutically acceptable salts thereof: TIFF0007597722000001.tif28128In formula, R 1 , R 2 , and R 3 is independently C 1~6 Alkyl, C 1~6 alkoxy, and halogen, where R 1 ~R 3 at least one of which is a halogen; R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , and -N(R b )2 is selected from the group consisting of; Each R a are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~7 Acyl, -C(O)OR a1 , and -C(O)N(R a2 )2, wherein Each R a1 is C 1~6 Alkyl, C3~8 Cycloalkyl, and C 6~10 aryl; Each R a2 are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~7 Acyl, -SO2R b1 , -C(O)OR b1 , and -C(O)N(R a2 )2, wherein Each R b1 is C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R b2 are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; However, R 1 , R 2 , and R 3 is a halogen, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methyl and R 2 is chloro and R 3 When is methoxy, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 If is chloro, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2is chloro and R 3 is chloro and R 5 is methyl or chloro, R 4 , R 6 , and R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 is chloro and R 6 If is chloro, R 4 , R 5 , and R 7 At least one of is other than hydrogen.

[0005] Also provided herein is a method for treating the disease or condition associated with mitochondrial dysfunction.The method comprises administering to a subject in need thereof an effective amount of the compound or pharmaceutical composition described herein.In some embodiments, the disease / condition is cancer, neurodegenerative disease, non-neurological disorder, or aging. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] Detailed Description of the Invention I. Definition As used herein, the term "alkyl" by itself or as part of another substituent means a straight or branched chain saturated aliphatic group having the designated number of carbon atoms. Alkyl can be any number of carbons, e.g., C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6For example, C 1~6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl may also refer to alkyl groups having up to 20 carbons, such as, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups may be substituted or unsubstituted. For example, a "substituted alkyl" group may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0007] The term "alkoxy," as used herein, by itself or as part of another substituent, refers to a group having the formula --OR, where R is alkyl.

[0008] The terms "halo" and "halogen," as used herein, by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0009] The term "cycloalkyl," as used herein, by itself or as part of another substituent, means a saturated or partially unsaturated monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing three to twelve ring atoms, or the indicated number of atoms. Cycloalkyl can include any number of carbons, e.g., C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , C 6~8 , C 3~9 , C 3~10 , C 3~11 , and C 3~12Examples of saturated monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Examples of saturated bicyclic and polycyclic cycloalkyl rings include norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group may be partially unsaturated and have one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Examples of saturated monocyclic cycloalkyl rings include norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. 3~8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3~6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted. For example, a "substituted cycloalkyl" group can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0010] The term "alkenyl" as used herein, by itself or as part of another substituent, means a straight or branched chain hydrocarbon of 2 to 6 carbon atoms having at least one double bond. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, or hexadienyl. Alkenyl groups can be substituted or unsubstituted. For example, a "substituted alkenyl" group can be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0011] The term "aryl" as used herein, by itself or as part of another substituent, refers to an aromatic ring system having any suitable number of carbon ring atoms and any suitable number of rings. An aryl group can have any suitable number of carbon ring atoms, e.g., C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C31, C32, C33, C34, C35, C36, C37, C38, C39, C40, C41, C42, C43, C44, C45, C46, ​​C47, C48, C49, C50, C51, C52, C53, C54, C55, C56, C57, C58, C59, C60, C61, C62, 10 , C 11 , C 12 , C 13 , C 14 , C 15 , or C 16 , and C 6~10 , C 6~12 , or C 6~14 Aryl groups may be monocyclic, fused to form bicyclic (e.g., benzocyclohexyl) or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups, such as phenyl, naphthyl, or biphenyl, have 6-12 ring members. Other aryl groups, such as phenyl or naphthyl, have 6-10 ring members. Some other aryl groups, such as phenyl, have 6 ring members. Aryl groups may be substituted or unsubstituted. For example, a "substituted aryl" group may be substituted with one or more groups selected from halo, hydroxy, amino, alkylamino, amido, acyl, nitro, cyano, and alkoxy.

[0012] The term "carbonyl," as used herein, by itself or as part of another substituent, means -C(O)-, i.e., a carbon atom that is double bonded to an oxygen and is bonded to two other groups in the moiety containing the carbonyl.

[0013] As used herein, the term "amino" refers to a -NR2 moiety, where each R group is hydrogen or alkyl. The amino moiety may be ionized to form the corresponding ammonium cation.

[0014] As used herein, the term "sulfonyl" refers to a -SO2R moiety where the R group is alkyl, haloalkyl, or aryl. The amino moiety may be ionized to form the corresponding ammonium cation. "Alkylsulfonyl" refers to an amino moiety where the R group is alkyl.

[0015] As used herein, the term "hydroxy" means an --OH moiety.

[0016] The term "cyano" as used herein means a carbon atom triple bonded to a nitrogen atom (ie, a -C≡N moiety).

[0017] As used herein, the term "carboxy" refers to a -C(O)OH moiety. The carboxy moiety can be ionized to form the corresponding carboxylate anion.

[0018] As used herein, the term "amide" refers to a -NRC(O)R or -C(O)NR2 moiety, where each R group is hydrogen or alkyl.

[0019] As used herein, the term "acyl" refers to a -C(O)R moiety, where each R is alkyl.

[0020] As used herein, the term "nitro" refers to a -NO2 moiety.

[0021] The term "oxo" as used herein means an oxygen atom that is double bonded to a compound (ie, O=).

[0022] The term "treatment" as used herein refers to the medical management of a patient with the intention of curing, ameliorating, stabilizing, or preventing a disease, pathological condition, or disorder. This term includes active treatment, i.e., treatment that specifically aims to improve a disease, pathological condition, or disorder, and also includes causative treatment, i.e., treatment that aims to eliminate the cause of the associated disease, pathological condition, or disorder. In addition, this term includes symptomatic treatment, i.e., treatment designed to relieve symptoms rather than cure the disease, pathological condition, or disorder; preventive treatment, i.e., treatment that aims to minimize or partially or completely inhibit the occurrence of the associated disease, pathological condition, or disorder; and supportive treatment, i.e., treatment used to complement another specific treatment that aims to improve the associated disease, pathological condition, or disorder. In various aspects, this term covers all treatments of subjects, including mammals (e.g., humans), including (i) preventing the onset of disease in subjects who may be susceptible to disease but have not yet been diagnosed with the disease; (ii) inhibiting disease, i.e., stopping its onset; or (iii) relieving disease, i.e., causing disease regression. In one aspect, the subject is a mammal, such as a primate, and in a further aspect, the subject is a human. The term "subject" also includes domestic animals (e.g., cats, dogs, etc.), livestock animals (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, fruit flies, etc.).

[0023] The term "prevent" or "preventing" as used herein means to prevent, avert, render unnecessary, forestall, stop, or impede something from happening, especially by taking a proactive measure. Where "reduce," "inhibit," or "prevent" are used herein, it will be understood that the use of the other two words is also expressly disclosed, unless specifically indicated otherwise.

[0024] The term "diagnosed" as used herein means that upon examination by a person of ordinary skill in the art, e.g., a physician, the individual is determined to have a condition that can be diagnosed or treated with the compounds, compositions, or methods disclosed herein.

[0025] As used herein, the phrase "identified as needing treatment of disorder" refers to the selection of a subject based on the need for treatment of disorder.For example, a subject can be identified as needing treatment of disorder (e.g., Alzheimer's disease-related disorder) based on early diagnosis by a person skilled in the art, and then be treated for said disorder.In one aspect, it is assumed that the person who made the diagnosis may perform the identification.In a further aspect, it is assumed that the person who made the administration can perform the administration subsequently.

[0026] The terms "administering" and "administration" as used herein refer to any method of providing a pharmaceutical formulation to a subject. These methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injection administration, such as intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, the formulation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various aspects, the formulation can be administered prophylactically, i.e., administered for the prevention of a disease or condition.

[0027] As used herein, the term "contacting" refers to the association of a disclosed compound with a cell, target receptor, or other biological entity such that the compound can affect the activity of the target (e.g., receptor, transcription factor, cell, etc.) either directly, i.e., by interacting with the target itself, or indirectly, i.e., by interacting with another molecule, cofactor, factor, or protein on which the activity of the target depends.

[0028] The terms "effective amount" and "amount effective" as used herein refer to an amount sufficient to obtain a desired result or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to obtain a desired therapeutic effect or to have an effect on an undesired symptom, but generally insufficient to cause adverse side effects. The specific therapeutically effective amount level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the particular composition being used; the age, weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the particular compound being used; the duration of treatment; drugs used in combination or concomitantly with the particular compound being used, and similar factors well known in the medical field. For example, it is well within the skill of the art to begin administering a compound at a level lower than that required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained. If desired, the effective daily amount may be divided into multiple doses for administration purposes. Thus, a single dose of the composition may contain an amount that constitutes a daily dose, or a fraction thereof. In the event of any contraindications, the dosage may be adjusted by the individual physician. Dosage can vary and can be administered in one or more doses daily for one or several days. Guidance regarding appropriate dosages for a given class of pharmaceutical agent can be found in the literature. In various further aspects, the formulation can be administered in a "prophylactically effective amount", i.e., an amount effective for the prevention of a disease or condition.

[0029] The term "pharmaceutical acceptable excipient" as used herein refers to a substance that is useful for administering an active agent to a subject. "Pharmaceutically acceptable" means that the excipient is compatible with other components of the formulation and is not harmful to the recipient. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, glidants, coatings, sweeteners, flavors, and colorants.

[0030] The term "salt" used herein refers to the acid salt or base salt of the compound of the present invention.The examples of pharmaceutically acceptable salts include the salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), the salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) and the salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.).It is understood that pharmaceutically acceptable salts are non-toxic.

[0031] Pharmaceutically acceptable salts of acidic compounds of the invention include salts formed with bases, i.e., cationic salts, such as alkali metal and alkaline earth metal salts (e.g., sodium, lithium, potassium, calcium, and magnesium salts), and ammonium salts (e.g., ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl-ammonium salts).

[0032] Similarly, acid addition salts, such as salts of mineral acids, organic carboxylic acids, and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible, provided that a basic group, such as pyridyl, forms part of the structure.

[0033] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms with respect to certain physical properties, such as solubility in polar solvents, but otherwise the salts are identical to the parent forms of the compounds of this invention.

[0034] As used herein, the term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0035] II. Quinazolinone Compounds Provided herein are compounds of formula I, and pharma- ceutically acceptable salts thereof: TIFF0007597722000002.tif28128In formula, R 1 , R 2 , and R 3 is independently C 1~6 Alkyl, C 1~6 alkoxy, and halogen, where R 1 ~R 3 at least one of which is a halogen; R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , and -N(R b )2 is selected from the group consisting of; Each R a are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~7 Acyl, -C(O)OR a1 , and -C(O)N(R a2 )2, wherein Each R a1 is C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R a2 are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, and C6~10 aryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~7 Acyl, -SO2R b1 , -C(O)OR b1 , and -C(O)N(R a2 )2, wherein Each R b1 is C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R b2 are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; However, R 1 , R 2 , and R 3 is a halogen, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methyl and R 2 is chloro and R 3 When is methoxy, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 If is chloro, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 is chloro and R 5 is methyl or chloro, R 4 , R 6 , and R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 is chloro and R 6 If is chloro, R 4 , R 5 , and R 7 At least one of is other than hydrogen.

[0036] R in the compound of formula I 1 ~R 3 At least one of R is a halogen. For example, R 1 , R 2 , and R 3 may each independently be fluoro (F), chloro (Cl), bromo (Br), or iodo (I). In some embodiments, R 2 is a halogen. In some embodiments, R 2 and R 3 is a halogen. In some embodiments, R 2 and R 3 In some embodiments, R 2 is fluoro and R 3 In some embodiments, R 1 , R 2 , and R 3 is a halogen. In some embodiments, R 1 is fluoro and R 2 and R 3 is chloro.

[0037] In some embodiments, R 1 ~R 3 At least one of them is C 1~6 For example, R 1 , R 2 , R 3 may each independently be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, branched pentyloxy, n-hexyloxy, or branched hexyloxy. 1 and R2 is C 1~6 In some embodiments, R 1 and R 3 is C 1~6 In some embodiments, R 2 and R 3 is C 1~6 In some embodiments, R 1 is C 1~6 alkoxy (e.g., methoxy), and R 2 is halogen (e.g., fluoro, chloro, or bromo) or C 1~6 Alkoxy (eg methoxy).

[0038] In some embodiments, R 1 ~R 3 At least one of them is C 1~6 For example, R 1 , R 2 , R 3 may each independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, branched pentyl, n-hexyl, or branched hexyl. 1 is C 1~6 In some embodiments, R 2 is C 1~6 In some embodiments, R 3 is C 1~6 In some embodiments, R 1 is C 1~6 alkoxy (e.g., methoxy), and R 2 is halogen (e.g., fluoro, chloro, or bromo) or C 1~6 alkoxy (e.g., methoxy), and R 3 is C 1~6 It is alkyl (eg, methyl).

[0039] R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, C 1~6Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , and -N(R b For example, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , or -N(R b )2. In some embodiments, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, or C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , or -N(R b )2. In some embodiments, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, or C 1~6 Alkyl, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , or -N(R b )2. In some embodiments, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, or C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkenyl, -OR a , or -N(R b )2. In some embodiments, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, or C1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, -OR a , or -N(R b )2. In some embodiments, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, or C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 alkenyl, or -N(R b )2. In some embodiments, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, or C 1~6 Alkyl, C 1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, or -OR a In any of these embodiments, R 1 , R 2 , and R 3 can be defined according to any combination described above.

[0040] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is hydrogen, and R 7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, or C 1~6 Alkenyl. 7 can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, branched pentyl, n-hexyl, branched hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl. 7 is hydrogen, C 3~8cycloalkyl (e.g., cyclopropyl), or C 1~6 It is alkenyl (eg, vinyl).

[0041] In some embodiments, R 6 is C 1~6 For example, R 6 can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, branched pentyloxy, n-hexyloxy, or branched hexyloxy. 6 is C 1~6 Alkoxy, R 5 is hydrogen, halogen, -OR a , and -N(R b )2; in some of these embodiments, R 4 is hydrogen. In some embodiments, R 5 and R 6 is independently C 1~6 Alkoxy, C 3~8 Cycloalkyl, -OR a , and -N(R b )2; in some of these embodiments, R 4 is hydrogen. In some embodiments, R 6 is C 1~6 Alkoxy, R 5 is selected from hydrogen, halogen, -OH, and -NH; in some of these embodiments, R 4 is hydrogen. In any of these embodiments, R 7 can be defined according to any combination described above. In some embodiments, R 7 is hydrogen. In some embodiments, R 4 and R 7 is hydrogen.

[0042] In some embodiments, R 1 C 1~6 is alkoxy; R 2 and R3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 C 1~6 Alkoxy, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , -N(R b )2, and hydrogen; R 6 C 1~6 is an alkoxy; Provided are compounds of formula I and pharma- ceutically acceptable salts thereof:

[0043] In some embodiments, R 1 is C 1~6 Alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 is other than halogen; R 6 is C 1~6 In some embodiments, R 1 is C 1~6 Alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 is other than chloro; R 6 is C 1~6 It is an alkoxy.

[0044] In some embodiments, R 1 C 1~6 is alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 is a halogen; R 6 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , -N(R b 2, halogen, and hydrogen; Provided are compounds of formula I and pharma- ceutically acceptable salts thereof:

[0045] In some embodiments, R 1 is C 1~6 Alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 is a halogen; R 6 is C 1~6 In some of these embodiments, R is other than alkoxy. 1 is C 1~6 Alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 is a halogen; R 6 is other than methoxy.

[0046] Compounds of formula I may be further substituted. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. In general, the combination of substituents is one that allows the formation of a stable compound or a chemically viable compound. The term "stable" as used herein means a compound that is substantially unaltered when subjected to conditions that allow its production, detection, and in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein. In general, "substituted" as used herein does not encompass the replacement and / or modification of the primary functional group by which the molecule is identified, for example, such that the "substituted" functional group becomes a different functional group through substitution. For example, a "substituted phenyl" group must still contain a phenyl moiety and, under this definition, cannot be altered by substitution to, for example, a cyclohexyl group.

[0047] Examples of suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2) 0~4 R α ; -(CH2) 0~4 OR α -O(CH2) 0~4 R α , -O-(CH2) 0~4 C(O)OR α ; -(CH2) 0~4 CH(OR α )2; -(CH2) 0~4 S.R. α ; -(CH2) 0~4 Ph, where Ph is R α phenyl, optionally substituted with -(CH2) 0~4 O(CH2)0~1 Phenyl, where phenyl is R α -CH=CHPh, where Ph is R α phenyl, optionally substituted with -(CH2) 0~4 O(CH2) 0~1 -Py, where Py is R α -N3; -(CH2) 0~4 N(R α )2; -(CH2) 0~4 N(R α )C(O)R α ; -N(R α )C(S)R α ; -(CH2) 0~4 N(R α )C(O)NR α 2; -N(R α )C(S)NR α 2; -(CH2) 0~4 N(R α )C(O)OR α ; -N(R α )N(R α )C(O)R α ; -N(R α )N(R α )C(O)NR α 2; -N(R α )N(R α )C(O)OR α ; -(CH2) 0~4 C(O)R α ;-C(S)R α ; -(CH2) 0~4 C(O)OR α ; -(CH2) 0~4 C(O)SR α ; -(CH2) 0~4 C(O)OSiR α 3; -(CH2) 0~4 O.C.(O)R α -OC(O)(CH2) 0~4 SR-SC(S)SR α ; -(CH2) 0~4 SC(O)R α ; -(CH2) 0~4 C(O)NRα 2; -C(S)NR α 2. -C(S)SR α ;-SC(S)SR α , -(CH2) 0~4 OC(O)NR α 2; -C(O)N(OR α )R α ; -C(O)C(O)R α -C(O)CH2C(O)R α ; -C(NOR α )R α ; -(CH2) 0~4 SSR α ; -(CH2) 0~4 S(O)2R α ; -(CH2) 0~4 S(O)2OR α ; -(CH2) 0~4 OS(O)2R α -S(O)2NR α 2; -(CH2) 0~4 S(O)R α ; -N(R α )S(O)NR α 2; -N(R α )S(O)2R α ; -N(OR α )R α -C(NH)NR α 2; -P(O)2R α ;-P(O)R α 2;-OP(O)R α 2; -OP(O)(OR α )2; SiR α 3; -(C 1~4 Linear or branched alkylene)-ON(R α )2; or -(C 1~4 (linear or branched) alkylene) C(O) ON (R α )2. Each R α are independently hydrogen; C 1~6 Alkyl; -CH2Ph, -O(CH2) 0~1 Ph; -CH2-(5-6 membered heteroaryl); C 3~8 Cycloalkyl; C 6~10aryl; 4-10 membered heterocyclyl; or 6-10 membered heteroaryl; each R α may be further substituted as described below.

[0048] R α Examples of suitable monovalent substituents above are independently halogen, -(CH2) 0~2 R β ; -(CH2) 0~2 OH; -(CH2) 0~2 OR β ; -(CH2) 0~2 CH(OR β )2; -CN; -N3; ​​-(CH2) 0~2 C(O)R β ; -(CH2) 0~2 C(O)OH; -(CH2) 0~2 C(O)OR β ; -(CH2) 0~2 S.R. β ; -(CH2) 0~2 SH; -(CH2) 0~2 NH2; -(CH2) 0~2 NHR β ; -(CH2) 0~2 NR β 2; -NO2; SiR β 3;-OSiR β 3; -C(O)SR β ; -(C 1~4 Linear or branched alkylene)C(O)OR β ; or -SSR β where each R β is independently C 1~4 Alkyl; -CH2Ph; -O(CH2) 0~1 Ph;C 3~8 Cycloalkyl; C 6~10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl. R α Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0049] Examples of suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: =O; =S; =NNR γ 2; =NNHC(O)R γ ; =NNHC(O)OR γ ; =NNHS(O)2R γ ;=NR γ ;=NOR γ ; -O(C(R γ 2)) 2~3 O-; or -S(C(R γ 2)) 2~3 S-, where each independently occurring R γ is hydrogen; C, which may be substituted as defined below 1~6 Alkyl; C 3~8 Cycloalkyl; C 6~10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl. Preferred divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR β 2) 2~3 O-, where each independently occurring R β is hydrogen; C, which may be substituted as defined below 1~6 Alkyl; C 3~8 Cycloalkyl; C 6~10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.

[0050] R γ Examples of suitable substituents on the alkyl group of -R include halogen; δ -OH; -OR δ -CN; -C(O)OH; -C(O)OR δ -NH2; -NHR δ ;-NR δ 2; or -NO2, where each R δ is independently C 1~4 Alkyl; -CH2Ph; -O(CH2) 0~1 Ph; a 4- to 10-membered heterocyclyl; or a 6- to 10-membered heteroaryl.

[0051] Examples of suitable substituents on the substitutable nitrogen of the "optionally substituted" group include -R ε ;-NR ε 2;-C(O)R ε ; -C(O)OR ε ; -C(O)C(O)R ε -C(O)CH2C(O)R ε ;-S(O)2R ε -S(O)2NR ε 2; -C(S)NR ε 2; -C(NH)NR ε 2; or -N(R ε )S(O)2R ε where each R ε are independently hydrogen; C, which may be substituted as defined below 1~6 Alkyl; C 3~8 Cycloalkyl; C 6~10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.

[0052] R ε Examples of suitable substituents on the alkyl group of -R are independently halogen; δ -OH; -OR δ -CN; -C(O)OH; -C(O)OR δ -NH2; -NHR δ ;-NR δ 2; or -NO2, where each R δ is independently C 1~4 Alkyl; -CH2Ph; -O(CH2) 0~1 Ph;C 6~10 aryl; 4- to 10-membered heterocyclyl; or 6- to 10-membered heteroaryl.

[0053] In some embodiments, the compound is the following compound: TIFF0007597722000003.tif124128TIFF0007597722000004.tif62128 and pharma- ceutically acceptable salts thereof.

[0054] The starting materials and reagents used in preparing the compounds of the invention are available from commercial suppliers or are described in detail in Fieser and Fieser's Reagents for Organic Synthesis, Vol. 1-28 (Wiley, 2016); March's Advanced Organic Chemistry, 7 th Ed. (Wiley, 2013); and Larock's Comprehensive Organic Transformations, 2 nd They are prepared by methods known to those skilled in the art according to procedures described in references such as The Journal of Chemical Substances and Their Applications, Vol. 13, No. 1, 1999, Ed. (Wiley, 1999). If desired, the starting materials and reaction intermediates can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. These materials can be characterized using conventional means, including measurement of physical constants and acquisition of spectral data.

[0055] In some embodiments, the compound of formula I is combined with an isothiocyanate of formula II: TIFF0007597722000005.tif16128 and an aminobenzoic acid of formula III: and maintaining the resulting mixture under conditions sufficient to form the quinazolinone of formula I. Isothiocyanates of formula II can be prepared from the corresponding anilines by reaction with thiophosgene. Aminobenzoic acids of formula III can be prepared from commercially available anthranilic acid and its substituted analogs as described below.

[0056] Unless otherwise specified, the reactions described herein are carried out at atmospheric pressure over a temperature range of about -78°C to about 250°C. For example, the reactions can be carried out at about 0°C to about 125°C, or at about room temperature (or ambient temperature), e.g., about 20°C. In some embodiments, the reactions are carried out at about 0°C, 20°C, 25°C, 90°C, 100°C, 110°C, 125°C, 150°C, 175°C, or 200°C. In some embodiments, the reactions are carried out starting at a first temperature (e.g., about -78°C or about 0°C) and increasing the temperature to a higher second temperature (e.g., about 20°C or about 25°C). One of skill in the art will recognize that various modifications can be made to the procedures described herein.

[0057] III. Pharmaceutical Compositions Also provided herein is a pharmaceutical composition comprising one or more of the compounds described above and one or more pharma- ceutically acceptable carriers or other excipients. Pharmaceutical compositions can be prepared by any method known in the art of pharmacy and drug delivery. In general, the method of preparing the composition comprises combining an active ingredient with a carrier containing one or more accessory ingredients. Usually, pharmaceutical compositions are prepared by uniformly and intimately combining an active ingredient with a liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into desired formulation. The composition can be conveniently prepared and / or packaged in unit dosage form.

[0058] The pharmaceutical composition can be in the form of sterile injectable aqueous or oily solution and suspension.Sterile injectable preparations can be formulated using non-toxic parenterally acceptable vehicles, including water, Ringer's solution, and isotonic saline, and acceptable solvents such as 1,3-butanediol.In addition, sterile non-volatile oils are usually used as solvents or suspension media.For this purpose, any non-irritating non-volatile oils can be used, including synthetic monoglycerides or diglycerides.In addition, fatty acids such as oleic acid are used in the preparation of injectable solutions.

[0059] Aqueous suspensions contain a mixture of the active ingredient and excipients suitable for the manufacture of aqueous suspensions.These excipients include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, oily propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth, and gum arabic; dispersing or wetting agents such as lecithin, polyoxyethylene stearate, and polyethylene sorbitan monooleate; and preservatives such as ethyl, n-propyl, and p-hydroxybenzoates.

[0060] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions can contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[0061] Dispersible powders and granules (suitable for preparation of an aqueous suspension by the addition of water) may contain a mixture of the active ingredient with a dispersing agent, wetting agent, suspending agent, or combinations thereof. Additional excipients may also be present.

[0062] The pharmaceutical composition of the present invention may be in the form of oil-in-water emulsion.The oil phase may be vegetable oil, such as olive oil or arachis oil, or mineral oil, such as liquid paraffin, or mixtures thereof.Suitable emulsifiers may be natural gums, such as gum arabic or gum tragacanth; natural phospholipids, such as soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0063] Pharmaceutical compositions containing the compounds of the present disclosure may be in a form suitable for oral administration. Compositions suitable for oral administration include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions for oral administration can be formulated according to any method known to those skilled in the art. These compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorings, antioxidants, and preservatives to obtain pharma- ceutically elegant and palatable formulations.

[0064] In general, tablets contain a mixture of active ingredients and non-toxic pharma- ceutically acceptable excipients, including inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents such as corn starch and alginic acid; binders such as polyvinylpyrrolidone (PVP), cellulose, polyethylene glycol (PEG), starch, gelatin, and gum arabic; and lubricants such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated or may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby achieving a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Tablets may be coated with a semipermeable membrane and an optional polymeric osmogen according to known techniques to form an osmotic pump composition for controlled release.

[0065] Compositions for oral administration can be formulated as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin) or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0066] The transdermal delivery of the compounds of the present disclosure can be achieved by iontophoretic patches and the like.The compounds may also be administered in the form of suppositories for rectal administration of the drug.These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.These materials include cocoa butter and polyethylene glycol.

[0067] In some embodiments, the pharmaceutical composition comprises one or more of the compounds described above and one or more additional active agents. In some embodiments, pharmaceutical compositions are provided that comprise one or more additional active agents for the treatment of neurological disorders. Examples of these active agents include cholinesterase inhibitors (e.g., donepezil, donepezil / memantine, galantamine, rivastigmine, tacrine, etc.), alpha-7 nicotinic receptor modulators (e.g., alpha-7 agonists such as encenicline and APN1125), serotonin modulators (e.g., idalopirdine, RVT-101, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, etc.), NMDA modulators (e.g., NMDA receptor antagonists such as memantine, etc.), and the like. agonists), Aβ targeted therapies (e.g., pioglitazone, begacestat, atorvastatin, simvastatin, etazolate, tramiprosate, etc.), ApoE targeted therapies (e.g., retinoid X receptor agonists), tau targeted therapies (e.g., methylthioninium, leucomethylthioninium, etc.), and anti-inflammatory agents (e.g., NSAIDs such as apazone, diclofenac, ibuprofen, indomethacin, ketoprofen, nabumetone, naproxen, piroxicam, or sulindac).

[0068] In some embodiments, pharmaceutical compositions are provided that include one or more compounds of the present disclosure and one or more additional active agents for the treatment of cancer.Examples of these active agents include, but are not limited to, angiogenesis inhibitors (e.g., bevacizumab, ranibizumab, etc.), immune checkpoint inhibitors (e.g., CTLA-4 antibody, OX40 antibody, PD-L1 antibody, PD1 antibody, or BY55 antibody), anthracyclines (e.g., doxorubicin, daunorubicin, etc.), platins (e.g., cisplatin, oxaliplatin, carboplatin, etc.), antimetabolites (e.g., 5-fluorouracil, methotrexate, etc.), kinase inhibitors (e.g., erlotinib, gefitinib, etc.), nucleoside analogs (e.g., gemcitabine, cytarabine, etc.), and taxanes (e.g., paclitaxel, docetaxel, etc.).

[0069] IV. Treatment Methods The compounds and pharmaceutical compositions of the present disclosure are useful for treating diseases and conditions associated with mitochondrial dysfunction, including, but not limited to, cancer, neurodegenerative diseases, brain conditions, and non-neurological disorders.

[0070] In some embodiments, the method is provided, wherein the disease or condition is a neurodegenerative disease. Examples of neurodegenerative diseases include, but are not limited to, tauopathies (e.g., Josephs; Mayo Clinic Proceedings, 2017, 92(8) 1291-1303), synucleinopathies (e.g., Savica, et al.; Mayo Clinic Proceedings, 2019, 94(9), 1825-1831), Parkinson's disease, Alzheimer's disease, Gaucher's disease, amyotrophic lateral sclerosis, and Huntington's disease. In some embodiments, the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or Huntington's disease.

[0071] In some embodiments, the method is provided, wherein the disease or condition is a brain condition.Examples of brain conditions include, but are not limited to, stroke, epileptic seizures, neuropsychiatric conditions (including but not limited to depression, schizophrenia, autism spectrum disorder, fragile X syndrome, and bipolar disorder), neuropathic pain, traumatic brain injury, spinal cord injury, aneurysm, and subarachnoid hemorrhage.In some embodiments, the brain condition is stroke, epileptic seizures, neuropathic pain, traumatic brain injury, spinal cord injury, aneurysm, or subarachnoid hemorrhage.

[0072] In some embodiments, the method is provided, wherein the disease or condition is a non-neurological disorder, such as diabetes, acute kidney injury, renal fibrosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, idiopathic pulmonary fibrosis, cardiac fibrosis, scleroderma, myelofibrosis, pancreatic fibrosis, mitochondrial myopathies (including but not limited to myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); myoclonus, epilepsy, and ragged red fibers (MERRF); and ataxic neuropathy syndrome (ANS) as described in Pfeffer and Chinery; Annals of Medicine, 2013 45:1, 4-16), age-related macular degeneration (AMD; For example, dry (atrophic) AMD), congenital mitochondrial disease (including but not limited to Leber's hereditary optic neuropathy (LHON), Leigh syndrome, and Barth syndrome), sepsis, cardiorenal syndrome, cardiac ischemia-reperfusion injury, pulmonary arterial hypertension, chronic obstructive pulmonary disease, and vasoconstriction. In some embodiments, the non-neurological disorder is sepsis, acute kidney injury, cardiorenal syndrome, cardiac ischemia-reperfusion injury, pulmonary arterial hypertension, chronic obstructive pulmonary disease, or vasoconstriction. In some embodiments, the condition is human aging caused by mitochondrial dysfunction.

[0073] Also provided are methods and compositions for reducing cancer cell proliferation, for example, in individuals with cancer, for example, to treat the cancer. Cancer refers to a group of diseases involving uncontrolled cell proliferation. In cancer, cells grow or divide uncontrollably, forming malignant tumors and invading nearby parts of the body. Cancer can also metastasize or spread to more distant parts of the body through the lymphatic system or bloodstream. Treatment can be preventive in terms of complete or partial prevention of cancer or its symptoms, and / or therapeutic in terms of partial or complete cure of cancer and / or the adverse effects that may result from the cancer.

[0074] Treating cancer may include (a) preventing the development of cancer in a subject who may be susceptible to cancer but has not yet been diagnosed with cancer; (b) inhibiting cancer, i.e., halting the development of cancer; or (c) alleviating cancer, i.e., causing regression of cancer. Therapeutic agents can be administered before, during, or after the onset of cancer. Treating ongoing cancer is of particular interest if the treatment stabilizes or reduces undesirable clinical symptoms in the patient. This treatment is desirably performed before complete loss of function of the affected tissue. The therapeutic agent is desirably administered during, and in some cases after, the symptomatic stage of cancer. The terms "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any mammalian subject, particularly a human, for whom diagnosis, treatment, or therapy is desired. In some cases, the methods and compositions reduce, e.g., inhibit, the growth of cancer. In some cases, the methods and compositions reduce, e.g., inhibit, the metastasis of cancer.

[0075] In some embodiments, the cancer is a Notch-associated cancer, i.e., associated with or at least partially caused by active Notch signaling. By "Notch" is meant an evolutionarily conserved single-pass transmembrane receptor that influences numerous cell fate decisions through short-range cell-cell interactions (Artavanis-Tsakonas and Muskavitch 2010). Notch proteins (cLIN-12 and cGLP-1 in C. elegans, Notch in Drosophila, Notch1-4 in mammals) consist of a ligand-binding extracellular domain (NECD) with 29-36 epidermal growth factor (EGF) repeats, a transmembrane domain, and a transcriptionally active intracellular domain (NICD). By "active Notch signaling" is meant that the Notch protein is active in the cancer cells, e.g., the Notch protein is activated Notch or constitutively active Notch, e.g., the Notch protein is mutated such that the Notch protein or one of its domains is always active. Examples of Notch-associated cancers include hematological malignancies, such as acute lymphoblastic leukemia (T-ALL); breast tumors, such as breast cancer; brain tumors, such as glioblastoma multiforme (GBM); lung cancer; and intestinal cancer (Artavanis-Tsakonas and Muskavitch 2010). Cancers can be easily identified as Notch-associated cancers by detecting Notch mutations in cancerous cells, such as in tumor biopsy tissue or cell smears, that result in constitutively active Notch. Several mutations that result in constitutively active Notch signaling have been identified, which can be detected, for example, by chromosomal dispersion or PCR, as known in the art. Alternatively, cancers can be identified as Notch-associated cancers by detecting upregulation of the activity of downstream effectors of Notch signaling, such as upregulation of the activity of non-canonical Notch signaling proteins, such as increased PINK1 expression, increased mTORC2 signaling (increased Akt phosphorylation), and increased assembly of respiratory chain complexes, compared to non-cancerous cells.

[0076] Notch proteins regulate cellular activities through canonical and non-canonical pathways. In canonical Notch pathway signaling, Notch ligands (transmembrane proteins containing three motifs, DSL (Delta, Serrate, LAG-2), DOS (Delta and OSM-11-like), and EGF repeats) bind to the EGF repeats of the Notch extracellular domain in neighboring cells. Ligand-Notch interaction leads to cleavage of the Notch extracellular domain by members of the α-secretase / metalloprotease family (ADAM10 / Kuzmanian, ADAM17 / TACE), followed by cytoplasmic cleavage of the Notch intracellular domain by γ-secretase (a multisubunit protease complex composed of presenilin (PS), nicastrin (NCT), Aph-1, Pen-2, etc.). The released intracellular domain translocates to the nucleus, where it interacts with the DNA-binding transcription factor CSL (CBF1 / RBPjk in vertebrates, Suppressor of Hairless in Drosophila, Lag-1 in C. elegans) through its RAM domain and transcriptionally activates Notch target genes by acting as a coactivator for other cofactors such as CSL, Mastermind-like protein (MAML1 in vertebrates, Mastermind in Drosophila, Lag-3 in C. elegans), and CBP / p300 (Kopan and Ilagan 2009). In the absence of the released intracellular domain Notch, CSL functions as a sequence-specific repressor. Thus, genes that mediate canonical Notch signaling (i.e., "canonical Notch signaling genes") would include genes encoding polypeptides of the γ-secretase complex, CSL ("CBF1 / RBPjk" in vertebrates, "Suppressor of Hairless" in Drosophila, "Lag-1" in C. elegans), Mastermind-like proteins ("MAML1" in vertebrates, "Mastermind" in Drosophila, "Lag-3" in C. elegans), and the CBP / p300 gene.

[0077] Notch can also signal through non-canonical pathways. Non-canonical Notch signaling is CSL-independent and can be ligand-dependent or ligand-independent (Kopan and Ilagan 2009). Although several genes are affected by non-canonical Notch function, in most cases, the mediators of non-canonical Notch signaling are unknown. The most well-studied and conserved effect of non-canonical Notch function is the regulation of Wnt / β-catenin signaling. In this non-canonical Notch signaling pathway, Notch binds to and determines the levels of active β-catenin, an essential Wnt signaling component (Takebe et al. 2011). Thus, active β-catenin activity can serve as a useful readout of non-canonical Notch signaling. Other investigated non-canonical Notch signaling pathways include signaling through NF-κB, signaling through the JNK pathway, and signaling through HES1 and MCK (Andersen et al. 2012).

[0078] Recently, mTORC2, Akt, and proteins that promote mitochondrial biogenesis or function, such as PINK1, mitochondrial respiratory chain complex proteins, mitochondrial fission proteins, and mitochondrial biogenesis proteins, have been discovered to mediate non-canonical Notch signaling (Lee et al. 2013). For example, polypeptides of mitochondrial respiratory chain complex I (e.g., 75 kDa subunit ND-75), mitochondrial fission protein Dynamin-1-like protein (Drp1), and mitochondrial biogenesis protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha). Importantly, many of these genes in the non-canonical Notch signaling pathway code for proteins that control mitochondrial function (Lee et al. 2013). The compounds of the present disclosure can be used to target Notch-promoted cancer cell proliferation, such as the proliferation of T-ALL (Molt-4, Jurkat cell lines) and glioblastoma (T98G, U118MG cell lines).

[0079] Notch signaling, as a key regulator of neuronal development and function, is deeply involved in many aspects of brain development, function, and maintenance. Dysregulation of Notch signaling is involved in the pathogenesis of brain tumors, stroke, neurodegeneration, neuropathic pain, traumatic brain injury, depression, and neuropsychiatric disorders (Mathieu et al., 2013; Zhang et al., 2018; Alfred and Vaccari, 2018). The fact that the outcome of Notch signaling is highly context-dependent suggests that non-canonical Notch function may be the rule rather than the exception. The fact that efficient inhibition of canonical Notch signaling has proven too toxic for clinical use, mainly due to unwanted on-target effects (Andersson and Lendahl, 2014), suggests that extending methods for modulating the Notch signaling pathway beyond the canonical pathway will broaden the available range of therapeutic options. Compounds of the present disclosure can be used to inhibit aberrant Notch activation through non-canonical pathways and treat a wide range of brain disorders and conditions.

[0080] In some embodiments, methods are provided for the treatment of T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCL), glioblastoma, cholangiocarcinoma, non-alcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC), colorectal cancer, breast cancer, and / or ovarian cancer.

[0081] The compounds of the present disclosure can be administered in any suitable dose in the methods provided herein.Generally, the compounds are administered in a dose range of about 0.1 milligrams to about 1000 milligrams per kilogram of subject body weight (i.e., about 0.1-1000 mg / kg). The dose of the compound can be, for example, about 0.1-1000 mg / kg, or about 1-500 mg / kg, or about 25-250 mg / kg, or about 50-125 mg / kg. The dose of the compound is about 0.1 to 1 mg / kg, or about 1 to 50 mg / kg, or about 50 to 100 mg / kg, or about 100 to 150 mg / kg, or about 150 to 200 mg / kg, or about 200 to 250 mg / kg, or about 250 to 300 mg / kg, or about 350 to 400 mg / kg, or about 450 to 500 mg / kg, or about 500 to 550 mg / kg. g / kg, or about 550-600 mg / kg, or about 600-650 mg / kg, or about 650-700 mg / kg, or about 700-750 mg / kg, or about 750-800 mg / kg, or about 800-850 mg / kg, or about 850-900 mg / kg, or about 900-950 mg / kg, or about 950-1000 mg / kg. The dose of the compound can be about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg / kg.The compound and the composition, including any of the above compositions, can be administered orally, topically, parenterally, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally, subcutaneously, or intrathecally using a suitable vehicle.Alternatively, the compound and the composition can be administered by suppository or by implanting a slow release device, such as a mini osmotic pump.

[0082] Dosage may vary depending on the patient's requirements, the severity of the disease or condition being treated, and the specific formulation being administered. The dosage administered to a patient should be sufficient to obtain a beneficial therapeutic response in the patient. The size of the dosage is also determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the drug in a particular patient. Determining the dosage that is appropriate for a particular situation is within the skill of a typical medical practitioner. The total dosage can be divided and administered in portions over a suitable time period to treat the disease or condition.

[0083] The administration of the compounds and compositions of the present disclosure can be carried out over a period of time that varies depending on the nature of the particular disorder, its severity, and the general condition of the patient. Administration can be carried out twice a day, including, for example, every hour, every 2 hours, every 3 hours, every 4 hours, every 6 hours, every 8 hours, or every 12 hours, or at intermediate intervals therebetween. Administration can be carried out once a day, once every 36 hours or every 48 hours, or once every month or several months. After treatment, the patient can be monitored for changes in his or her condition and relief of symptoms of the disorder. If the patient does not respond significantly to a particular dosage level, the dosage of the particular compound can be increased, and if relief of symptoms is observed or if unacceptable side effects are seen at a particular dosage, the dosage can be reduced. The administration regimen can consist of two or more different interval sets. For example, the first part of the administration regimen can be carried out to the subject multiple times a day, once a day, once every two days, or once every three days. The dosing regimen may begin by administering the drug to the subject once every 2 days, once every 3 days, once a week, once every 2 weeks, or once a month. The first portion of the dosing regimen may be administered for up to 30 days, for example, 7 days, 14 days, 21 days, or 30 days. A subsequent second portion of the dosing regimen with a different interval of administration may follow, administered once a week, once every 14 days, or once a month, lasting from 4 weeks up to 2 years or more, for example, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, 26 weeks, 32 weeks, 40 weeks, 52 weeks, 63 weeks, 68 weeks, 78 weeks, or 104 weeks. Alternatively, if symptoms go into remission or gradually improve, the dosage may be maintained or kept below the maximum amount. If the condition or symptoms worsen, the first dosing regimen may be resumed until improvement is observed, and the second dosing regimen may be administered again. This cycle may be repeated multiple times as necessary. EXAMPLES

[0084] V. Working Examples Example 1 Synthesis of 6-chloro-3-(2-chloro-4,5-dimethoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (1) TIFF0007597722000007.tif20128To a solution of compound 1.1 (5 g, 31.53 mmol) and K2CO3 (13 g, 94.59 mmol) in DMF (100 mL) was added CH3I (22.4 g, 157.77 mmol) at room temperature and stirred at room temperature for 16 h (monitored by TLC). The reaction was poured into water (100 mL) and the solution was extracted with EA (3x100 mL). The combined organic fractions were evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA = 10:1 to 3:1 to give compound 1.2 as a light yellow liquid (5.4 g, 99% yield).

[0085] TIFF0007597722000008.tif21128Compound 1.2 (4.3 g, 24.91 mmol) was dissolved in 50 mL of acetic anhydride. Nitric acid (60%, 5 mL) was added dropwise to the solution at 15° C., and the mixture was then stirred at 15° C. for 30 min. The reaction solution was poured into ice water. The precipitated crystals were collected by filtration. The collected crystals were washed with water and dried under reduced pressure to give compound 1.3 as a light yellow solid (4.9 g, 90% yield).

[0086] TIFF0007597722000009.tif20128To a stirred solution of compound 1.3 (1 g, 4.61 mmol) in water (12 mL), SnCl2 (4.28 g, 18.43 mmol) was added, followed by slow addition of concentrated HCl and stirring at room temperature for 3 h. TLC showed the compound was completely reacted. The reaction was cooled to 0°C, quenched with ice, neutralized with 1N KOH, and the solution was extracted with EA (3x50 mL). The organic layer was washed with brine and dried over Na2SO4. Filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=10:1-3:1 to give compound 1.4 as a light yellow solid (550 mg, 63% yield). ESI LC-MS: R t =1.230 minutes, 188.1[M+1] + .

[0087] TIFF0007597722000010.tif20128 Thiophosgene (0.22 mL, 2.72 mmol) was added to a solution of compound 1.4 (300 mg, 1.60 mmol) in dioxane (3 mL) and the solution was heated to reflux for 2 h. TLC showed the compound had reacted completely. The reaction mixture was concentrated to give the crude product as a yellow solid (360 mg, 98% yield). The crude product 1.5 was used without purification as described below.

[0088] TIFF0007597722000011.tif27128A mixture of compound 1.7 (4 g, 18.55 mmol) in a solution of NaOH (1.48 g, 37.1 mmol) in water (12 mL) was stirred at room temperature overnight. TLC showed the compound was completely reacted. The solution was acidified with 2N HCl and filtered. The filter cake was washed with water and dried to give product 1.8 as a white solid (3 g, 80% yield). ESI LC-MS: Rt=1.321 min, 202.1 [M+1] + .

[0089] TIFF0007597722000012.tif29128 To a mixture of compound 1.5 (323 mg, 1.6 mmol) and compound 1.8 (367 mg, 1.6 mmol) in 2-propanol (6 mL) was added NaOMe (4 mg, 0.08 mmol) and stirred at reflux temperature overnight. The mixture was concentrated and the resulting residue was suspended in DCM (20 ml) and filtered. The filter cake was washed with DCM (5 mL) to give product 1 as a white solid (60 mg, 10% yield). ESI / LC-MS: R t =1.948 minutes, 413.1[M+1] + . TIFF0007597722000013.tif20155

[0090] Example 2 Synthesis of 6-chloro-3-(2-chloro-4-fluoro-5-methoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (2) TIFF0007597722000014.tif28128 Compound 2.2 (4.44 g, 40.94 mmol) was added to a solution of compound 2.1 (5 g, 34.12 mmol) and TEA (10.6 g, 104.26 mmol) in DCM (20 mL) at 0° C. and stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=10:1 to 3:1 to give compound 2.3 as a light yellow solid (6.17 g, 82% yield). ESI LC-MS: R t =1.316 minutes, 219.2[M+1] + .

[0091] TIFF0007597722000015.tif18128 Compound 2.3 (6.17 g, 28.22 mmol) was dissolved in concentrated H2SO4 (60 mL). Nitric acid (60%, 50 mL) was added dropwise to the solution at 10°C, and the mixture was stirred at 10°C for 2 h. The reaction solution was poured into ice water. The precipitated crystals were collected by filtration. The collected crystals were washed with water and dried under reduced pressure to give compound 2.4 as a yellow solid (7.43 g, 99% yield). ESI LC-MS: R t =1.456 minutes, 264.0[M+1] + .

[0092] TIFF0007597722000016.tif20128 To a stirred solution of compound 2.4 (7.43 g, 28.19 mmol) in MeOH (100 mL) was added NaHCO3 (5.92 g, 70.48 mmol) and the solution was stirred at 60 °C for 16 h. TLC showed the compound was completely reacted. The reaction was neutralized with 1N HCl and the solution was concentrated to give the crude product. The residue was extracted with EA. The organic layer was washed with brine and dried over Na2SO4. Filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=10:1 to 5:1 to give compound 2.5 as a light yellow solid (5.23 g, 96% yield). ESI LC-MS: Rt=1.256 min, 191.9[M+1] + .

[0093] TIFF0007597722000017.tif20128 To a solution of compound 2.5 (5.23 g, 27.31 mmol) in DMF, CH3I (5 g, 35.1 mmol) was added at room temperature and stirred at room temperature for 16 hours. The reaction solution was poured into H2O. The precipitated crystals were collected by filtration. The collected crystals were washed with water and dried under reduced pressure to give compound 2.6 as a whitish yellow solid (5 g, 89% yield).

[0094] TIFF0007597722000018.tif20128To a solution of compound 2.6 (4.1 g, 19.94 mmol) in AcOH, Fe powder (4.47 g, 79.76 mmol) was added at room temperature and stirred at 40 °C for 16 h. TLC showed that compound 2.6 was completely reacted. The mixture was extracted with EA. The organic layer was washed with brine and dried over Na2SO4. Filtered. The filtrate was evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=10:1 to 5:1 to give compound 2.7 as a light yellow solid (3.15 g, 90% yield). ESI LC-MS: R t =1.306 minutes, 176.0[M+1] + .

[0095] TIFF0007597722000019.tif18128 To a solution of compound 2.7 (3.15 g, 16.79 mmol) in dioxane (30 mL) was added thiophosgene (2.31 mL, 28.54 mmol) and the solution was heated to reflux for 2 h. TLC showed the compound had reacted completely. The reaction was concentrated to give crude product 2.8 as a yellow solid (3.85 g, 100% yield). The crude product was used directly in the next step.

[0096] TIFF0007597722000020.tif44128 To a mixture of compound 2.8 (500 mg, 2.30 mmol) and compound 1.8 (464 mg, 2.3 mmol) in 2-propanol (6 mL) was added NaOMe (6 mg, 0.12 mmol) and the solution was stirred at reflux temperature overnight. Concentrated, the residue was suspended in DCM (20 ml), filtered and the filter cake was washed with DCM (5 mL) to give product 2 as a white solid (120 mg, 13% yield). ESI LC-MS: Rt =1.656 minutes, 401.0[M+1] + . TIFF0007597722000021.tif20151.

[0097] Example 3 Synthesis of 6-chloro-3-(4-chloro-2,5-dimethoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (3) TIFF0007597722000022.tif31128 To a solution of compound 3.1 (2 g, 10.66 mmol) in dioxane (22 mL) was added thiophosgene (1.4 mL, 18.12 mmol) and the solution was stirred at reflux temperature for 2 h. The solvent was concentrated to give crude product 3.2 as a yellow solid (468 mg). The crude product was used directly in the next step.

[0098] TIFF0007597722000023.tif32128To a mixture of compound 3.2 (294 mg, 1.28 mmol) and compound 1.8 (300 mg, 1.28 mmol) in 2-propanol (5 mL), NaOMe (4 mg, 0.1 mmol) was added and the solution was stirred at reflux temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give compound 3 (56 mg, 2% yield). ESI LC-MS: R t =1.704 minutes, 413.0[M+1] + . TIFF0007597722000024.tif12131

[0099] Example 4 Synthesis of 6-chloro-3-(2,4-dichloro-5-fluorophenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (4) TIFF0007597722000025.tif18128 Thiophosgene (0.73 mL, 9.44 mmol) was added to a solution of compound 4.1 (1 g, 5.56 mmol) in dioxane (11.2 mL) and the solution was stirred at reflux temperature for 2 h. TLC showed that the compound had reacted completely. The reaction was concentrated to give crude product 4.2 as a yellow solid (1.12 g, 100% yield). The crude product was used directly in the next step.

[0100] TIFF0007597722000026.tif37128 To a mixture of compound 4.2 (617 mg, 2.78 mmol) and compound 1.8 (560 mg, 2.78 mmol) in 2-propanol (10 mL) was added NaOMe (8 mg, 0.14 mmol) and the solution was stirred at reflux overnight. Concentrated, the residue was suspended in DCM (10 ml), filtered and the filter cake was washed with DCM (5 mL) to give product 4 as a white solid (130 mg, 11% yield). ESI LC-MS: R t =1.929 minutes, 402.8[M-1] - . TIFF0007597722000027.tif20151

[0101] Example 5 Synthesis of 3-(2,4-dichloro-5-methoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (5) TIFF0007597722000028.tif21128 Thiophosgene (0.68 mL, 8.84 mmol) was added to a solution of compound 5.1 (1 g, 5.2 mmol) in dioxane (12 mL) and the solution was stirred at reflux temperature for 2 h. The solvent was removed under reduced pressure to give crude product 5.2 as a yellow solid (1.1 g, crude). The crude product was used directly in the next step.

[0102] TIFF0007597722000029.tif36128 To a mixture of compound 5.2 (500 mg, 2.14 mmol) and compound 3 (357 mg, 2.14 mmol) in 2-propanol (10 mL) was added NaOMe (6 mg, 0.1 mmol) and the solution was stirred at reflux overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give compound 5 (128 mg, 14% yield for two steps). ESI LC-MS: R t =1.717 minutes, 381.0[M-1] - . TIFF0007597722000030.tif20154

[0103] Example 6 Synthesis of 3-(2,4-dichloro-5-methoxyphenyl)-2-mercapto-6,7-dimethoxyquinazolin-4(3H)-one (6) TIFF0007597722000031.tif40128 To a mixture of compound 5.2 (500 mg, 2.14 mmol) and compound 6.1 (422 mg, 2.14 mmol) in 2-propanol (10 mL) was added NaOMe (6 mg, 0.1 mmol) and the solution was stirred at reflux overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give compound 6 (45 mg, 4.6% yield for two steps). ESI LC-MS: R t =1.639 minutes, 412.9[M+1] + . TIFF0007597722000032.tif12128

[0104] Example 7 Synthesis of 3-(2,4-dichloro-5-methoxyphenyl)-6-hydroxy-2-mercapto-7-methoxyquinazolin-4(3H)-one (7) TIFF0007597722000033.tif36128To a mixture of compound 7.1 (3 g, 16.47 mmol) and K2CO3 (6.8 g, 49.41 mmol) in DMF (20 mL) in an ice bath, BnBr (2 mL, 16.37 mmol) was added and stirred at room temperature overnight. TLC showed that compound 7.1 was consumed. The mixture was extracted with EtOAc (3x50 mL). The combined organic fractions were evaporated under reduced pressure to give product 7.2 as a light yellow solid (3.9 g, 88% yield). ESI LC-MS: R t =1.859 minutes, 273.0[M+1] + .

[0105] TIFF0007597722000034.tif31128To a mixture of compound 7.2 (3.9 g, 14.32 mmol) in Ac2O (80 mL) was added HNO3 (1.56 mL, 21.48 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. The solution was poured into ice water and the solution was extracted with EtOAc (3x50 mL). The combined organic fractions were evaporated under reduced pressure to give product 7.3 as a yellow solid (4.02 g, 88% yield).

[0106] TIFF0007597722000035.tif31128To a solution of compound 7.3 (4.02 g, 12.68 mmol) in water (33 ml) was added concentrated HCl (27 mL) and SnCl2·2H2O (11.45 g, 50.72 mmol). The mixture was stirred at room temperature for 2 h. The mixture was extracted with EA (3x50 mL). The combined organic fractions were evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=0%-30% to give compound 7.4 as a white solid (440 mg, 12% yield). ESI LC-MS: R t =1.788 minutes, 288.1[M+1] + .

[0107] TIFF0007597722000036.tif31128 A mixture of compound 7.4 (400 mg, 1.39 mmol) and NaOH (223 mg, 5.57 mmol) in water (2.5 mL) and THF (10 mL) was stirred at 100° C. overnight. The solution was acidified with 2N HCl and filtered. The filter cake was washed with water and dried to give product 7.5 as a black solid (340 mg, 89% yield, confirmed by LCMS). ESI LC-MS: R t =1.479 minutes, 274.0[M+1] + .

[0108] TIFF0007597722000037.tif31128 A mixture of compound 7.5 (340 mg, 1.39 mmol) and Pd / C (136 mg, 50% water) in MeOH (15 ml) was stirred overnight at 50° C. under H2 atmosphere. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give crude product 7.6 as a black solid (220 mg, 96% yield, confirmed by LCMS). ESI LC-MS: R t =0.464 minutes, 184.0[M+1] + The crude product was used directly in the next step.

[0109] TIFF0007597722000038.tif38144 To a mixture of compound 7.6 (220 mg, 1.2 mmol) and compound 5.2 (337 mg, 1.44 mmol) in 2-propanol (10 mL) was added NaOMe (5 mg, 0.1 mmol) and the solution was stirred at reflux temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give product 7 (55 mg, 9% yield). ESI LC-MS: R t =1.290 minutes, 399.0[M+1] + . TIFF0007597722000039.tif12131

[0110] Example 8 Synthesis of 6-amino-3-(2,4-dichloro-5-methoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (8) TIFF0007597722000040.tif28128To a stirred solution of compound 8.1 (1 g, 5.98 mmol) in CH2Cl2 (12 ml), AcCl (563 mg, 7.18 mmol) was added dropwise at 0°C and stirred at room temperature for 2 h. TLC showed the compound was completely reacted. The solvent was removed under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=10:1 to 3:1 to give compound 8.2 as a white solid (1.1 g, 87% yield). ESI LC-MS: R t =1.043 minutes, 210.0[M+1] + .

[0111] TIFF0007597722000041.tif28128To a stirred solution of compound 8.2 (600 mg, 2.87 mmol) in CH3CN (12 ml) was added NO2BF4 (457 mg, 3.45 mmol) at room temperature. The solution was stirred at room temperature for 3 h. TLC showed that the compound was completely reacted. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography eluting with 0% to 10% EtOAc in PE to give compound 8.3 as a white solid (520 mg, 71% yield). ESI LC-MS: R t =1.183 minutes, 255.1[M+1] + .

[0112] TIFF0007597722000042.tif32128 A mixture of compound 8.3 (520 mg, 2.05 mmol) and Pd / C (52 mg) in CH3OH (12 mL) was stirred under H2 at room temperature for 16 h. TLC showed that the compound had reacted completely. The solvent was removed under reduced pressure to give crude compound 8.4 as a white solid (425 mg, 91% yield). ESI LC-MS: R t =0.905 minutes, 225.0[M+1] + The crude product was used directly in the next step.

[0113] TIFF0007597722000043.tif35129 To a mixture of compound 8.4 (425 mg, 1.87 mmol) and compound 5.2 (438 mg, 1.87 mmol) in 2-propanol (6 mL) was added NaOMe (5 mg, 0.09 mmol) and the solution was stirred at reflux temperature overnight. Concentrated, the residue was suspended in DCM (20 ml), filtered and the filter cake was washed with DCM (5 mL) to give product 8.5 as a white solid (400 mg, 50% yield). ESI LC-MS: R t =1.580 minutes, 440.0[M+1] + .

[0114] TIFF0007597722000044.tif27133 To a stirred solution of compound 8.5 (400 mg, 0.94 mmol) in H2O (5 ml) was added concentrated HCl (5 ml) and the solution was stirred at 100° C. for 16 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give product 8 as a light yellow solid (50.54 mg, 14% yield). ESI LC-MS: Rt=1.318 min, 398.1 [M+1] + . TIFF0007597722000045.tif20159

[0115] Example 9 Synthesis of 6-cyclopropyl-3-(2,4-dichloro-5-methoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (9) TIFF0007597722000046.tif25128To a solution of compound 9.1 (8 g, 48 mmol) in DMF (60 mL) was added NBS (2.5 g, 56 mmol) in an ice bath and the solution was stirred at reflux temperature for 2 h. The solution was poured into 200 mL of water and the solution was extracted with EtOAc (3x200 mL). The combined organic fractions were evaporated under reduced pressure to give the crude product as a brown solid (10 g, 85% yield). ESI LC-MS: R t =1.357 minutes, 247.9[M+1] + The crude product 9.2 was used directly in the next step.

[0116] TIFF0007597722000047.tif23128To a solution of compound 9.2 (8.4 g, 34.15 mmol) in DMF (40 mL) was added K2CO3 (14.1 g, 102.44 mmol) and CH3I (2.7 mL, 44 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. It was poured into 100 mL of water. The mixture was extracted with EtOAc (3x200 mL). The combined organic fractions were evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=20:1 to 5:1 to give compound 9.3 as a yellow solid (4.12 g, 46% yield). ESI LC-MS: R t =1.658 minutes, 261.9[M+1] + .

[0117] TIFF0007597722000048.tif25128To a stirred solution of compound 9.3 (1.6 g, 6.16 mmol) in toluene / H2O (50 mL / 5 mL), P(cy)3 (259 mg, 0.93 mmol), K3PO4 (2.58 g, 12.32 mmol), Pd2(dba)3 (282 mg, 0.31 mmol) were added, followed by slow addition of compound 9.4 (794 mg, 9.24 mmol), and the mixture was stirred at 100 °C for 16 h. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the crude product. The residue was purified by silica column chromatography eluting with EA:PE=0%~20% to give compound 9.5 as a light yellow solid (709 mg, 52% yield). ESI LC-MS: R t =1.743 minutes, 222.1[M+1] + .

[0118] TIFF0007597722000049.tif24128 A mixture of compound 9.5 (709 mg, 3.21 mmol) and LiOH (588 mg, 14.7 mmol) in water (10 mL) and THF (40 mL) was stirred at room temperature overnight. The solution was acidified with 2N HCl and filtered. The filter cake was washed with water and dried to give product 9.6 as a yellow solid (508 mg, 76% yield). ESI LC-MS: R t =1.452 minutes, 208.1[M+1] + .

[0119] To a mixture of TIFF0007597722000050.tif281289.6 (100 mg, 0.48 mmol) and compound 5.2 (113 mg, 0.48 mmol) in 2-propanol (4 mL) was added NaOMe (5 mg, 0.1 mmol) and the solution was stirred at reflux temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give product 9 (45 mg, 22% yield). ESI LC-MS: R t =1.966 minutes, 423.0[M+1] + . TIFF0007597722000051.tif19157

[0120] Example 10 Synthesis of 6-chloro-3-(2,4-dichloro-5-methylphenyl)-2-mercaptoquinazolin-4(3H)-one (10) TIFF0007597722000052.tif40128 To a mixture of compound 5.2 (342 mg, 1.56 mmol) and compound 10.1 (268 mg, 1.56 mmol) in 2-propanol (5 mL) was added NaOMe (4 mg, 0.08 mmol) and the solution was stirred at reflux overnight. Concentrated, the residue was suspended in DCM (10 ml), filtered, and the filter cake was washed with DCM (5 mL) to give product 10 as a white solid (79 mg, 13% yield). ESI LC-MS: R t =1.853 minutes, 386.9[M+1] + . TIFF0007597722000053.tif20158

[0121] Example 11 Synthesis of 6-chloro-7-cyclopropyl-3-(2,4-dichloro-5-methoxyphenyl)-2-mercaptoquinazolin-4(3H)-one (11) TIFF0007597722000054.tif25128To a stirred solution of compound 11.1 (600 mg, 2.27 mmol) in toluene / H2O (20 mL / 2 mL) was added P(cy)3 (95 mg, 0.34 mmol), K3PO4 (950 mg, 4.54 mmol), Pd2(dba)3 (104 mg, 0.11 mmol), followed by slow addition of compound 9.4 (293 mg, 3.41 mmol) and the mixture was stirred at 100 °C for 16 h. Filtered through Celite. The filtrate was concentrated under reduced pressure to give crude product 11.2 as a light yellow oil (695 mg). ESI LC-MS: R t =1.930 minutes, 226.0[M+1] + The crude product was used directly in the next step.

[0122] TIFF0007597722000055.tif26128 A mixture of compound 11.2 (695 mg, 3.28 mmol) and NaOH (525 mg, 13.13 mmol) in water (5 mL) and THF (20 mL) was stirred at room temperature overnight. The solution was acidified with 2N HCl and the solution was extracted with EA (3x40 mL). The organic layer was concentrated under reduced pressure. The residue was purified by reverse phase to give product 11.3 as a yellow solid (243 mg, 35% yield). ESI LC-MS: R t =1.615 minutes, 212.0[M+1] + .

[0123] TIFF0007597722000056.tif28135 To a mixture of compound 11.3 (243 mg, 1.15 mmol) and compound 5.2 (269 mg, 1.15 mmol) in 2-propanol (4 mL) was added NaOMe (5 mg, 0.1 mmol) and the solution was stirred at reflux temperature overnight. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to give product 12 (74 mg, 15% yield). ESI LC-MS: R t =2.065 minutes, 427.1[M+1] + . TIFF0007597722000057.tif20157

[0124] Example 12 Synthesis of 6-chloro-3-(2,4-dichloro-5-methoxyphenyl)-2-mercapto-7-methoxy-8-vinylquinazolin-4(3H)-one (12) TIFF0007597722000058.tif33128 A mixture of compound 12.1 (750 mg, 2.20 mmol), Pd(dppf)Cl2 (225 mg, 0.3 mmol), compound 12.2 (510 mg, 3.3 mmol), and K2CO3 (915 mg, 6.6 mmol) in dioxane (18 mL) and H2O (3 mL) was stirred at 100 °C for 16 h. The solution was poured into water (100 mL). The solution was extracted with EA (3x30 mL). The combined organic fractions were evaporated under reduced pressure. The residue was purified by silica column chromatography eluting with EA 0%-20% in PE to give compound 12.3 as a light yellow liquid (280 mg, 52% yield). ESI LC-MS: R t =1.761 minutes, 242.0[M+1] + .

[0125] TIFF0007597722000059.tif28128 A mixture of compound 12.3 (280 mg, 1.16 mmol) and NaOH (186 mg, 4.64 mmol) in THF / H2O (6 mL / 6 mL) was stirred at room temperature overnight. The reaction solution was acidified with 2N HCl. Filtered. The filter cake was washed with water and dried to give product 12.4 as a white solid (224 mg, 84% yield). ESI LC-MS: R t =1.471 minutes, 228.0[M+1] + .

[0126] TIFF0007597722000060.tif34128 To a mixture of compound 12.4 (224 mg, 0.98 mmol) and compound 5.2 (230 mg, 0.98 mmol) in 2-propanol (10 mL) was added NaOMe (4 mg, 0.08 mmol). The solution was stirred at reflux overnight. Concentrated, the residue was suspended in DCM (20 ml), filtered, and the filter cake was washed with DCM (5 mL) to give product 13 as a white solid (41 mg, 9.43% yield, confirmed by 1H NMR and LCMS). ESI LC-MS: R t=2.113 minutes, 443.0[M+1] + . TIFF0007597722000061.tif20152

[0127] Example 13 Synthesis of 6-chloro-8-cyclopropyl-3-(2,4-dichloro-5-methoxyphenyl)-2-mercapto-7-methoxyquinazolin-4(3H)-one (13) TIFF0007597722000062.tif22128To a solution of compound 1.7a (5 g, 27.6 mmol) in CHCl3 (600 ml) in an ice bath, SO2Cl2 (2.6 mL, 33.1 mmol) was added and the solution was stirred at reflux temperature for 4 h. The solvent was removed under reduced pressure. The residue was purified by trituration with PE / EA = 1:1 (200 mL) to give product 1.7 as a white solid (3.5 g, 60% yield). ESI LC-MS: R t =1.705 minutes, 216.0[M+1] + .

[0128] TIFF0007597722000063.tif25128To a solution of compound 1.7 (3.5 g, 16.23 mmol) in DMF, H2SO4 was added at room temperature, followed by the addition of N-iodosuccinimide (NIS) in several portions at room temperature. After 4 h, the solution was poured onto crushed ice. The precipitated crystals were collected by filtration. The collected crystals were washed with water and dried under vacuum to give compound 13.1 as a light yellow solid (4.5 g, 81% yield). ESI LC-MS: R t =2.017 minutes, 341.9[M+1] + .

[0129] TIFF0007597722000064.tif35128To a stirred solution of compound 13.1 (550 mg, 1.61 mmol) in toluene / H2O (6 mL / 6 mL), P(Cy)3 (66 mg, 0.23 mmol), K3PO4 (682 mg, 3.21 mmol), Pd2(dba)3 (77 mg, 0.077 mmol) were added, followed by slow addition of compound 9.4 (209 mg, 2.41 mmol) and the mixture was stirred at 100 °C for 16 h. The solution was concentrated under reduced pressure. The residue was extracted with EA. The organic layer was washed with saturated NaCl and dried over Na2SO4. Filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography eluting with PE:EA=10:1 to 3:1 to give compound 13.2 as a light yellow solid (230 mg, 55% yield). ESI LC-MS: R t =1.768 minutes, 256.0[M+1] + .

[0130] TIFF0007597722000065.tif34128 A solution of compound 13.2 (230 mg, 0.89 mmol) and NaOH (72 mg, 1.8 mmol) in THF / H2O (3 mL / 3 mL) was stirred at room temperature overnight. The solution was acidified with 2N HCl. Filtered. The filter cake was washed with water and dried to give the product 13.3 as a white solid (200 mg, 92% yield). ESI LC-MS: R t =1.348 minutes, 242.0[M+1] + .

[0131] TIFF0007597722000066.tif37128 To a mixture of compound 13.3 (200 mg, 0.82 mmol) and compound 5.2 (194 mg, 0.82 mmol) in 2-propanol (5 mL) was added NaOMe (3 mg, 0.06 mmol) and the solution was stirred at reflux temperature overnight. Concentrated, the residue was suspended in DCM (20 ml), filtered and the filter cake was washed with DCM (5 mL) to give product 13 as a white solid (28 mg, 7% yield). ESI LC-MS: R t =1.666 minutes, 454.9[M-1] - . TIFF0007597722000067.tif20153

[0132] Example 14 Evaluation of the anticancer activity of quinazolinones CellTiter-Glo Luminescent Cell Viability Assay Kit was obtained from Promega. RPMI 1640 was obtained from Invitrogen. Fetal Bovine Serum (FBS) was obtained from Corning. L-Glutamine was obtained from Invitrogen. 100X Penicillin-Streptomycin was obtained from HyClone. 0.05% Trypsin-EDTA (TE) was obtained from Invitrogen. DPBS was obtained from Corning. DMSO was obtained from Sigma. Black 384-well plates were obtained from Greiner. 96-well V-bottom plates were obtained from Axygen.

[0133] At cell seeding on day "-1", the density of Molt-4 cells was adjusted according to the supplier's recommended information. 50 μL of cells were seeded into four 384-well plates and 50 μL of DPBS was added to the edge wells. On day 0, test compounds were dissolved in DMSO and stored in a nitrogen cabinet. The stock concentration of test compounds was 120 mM. The stock concentration of reference compounds was 10 mM. Test compounds (125 nL in DMSO) were added to the wells and serially diluted 3-fold to obtain 10 doses per series with a maximum concentration of 300 μM. An equal volume of DMSO without test compound was transferred to the control row in the well plate. Using this procedure, the DMSO concentration throughout the well plate was 0.25% (v / v). On day 3 (after cells were treated with compounds for 72 hours), the plates were equilibrated at room temperature for approximately 30 minutes. 25 μL of CellTiter Glo reagent was added to each well and luminescence in each well was measured after 10 minutes using an ENVISION fluorescent plate reader (PerkinElmer).

[0134] The formula used for data analysis was: % inhibition = (max-sample value) / max*100. Curves were fitted to a sigmoidal dose-response (variable slope) model by Prism and generated by a 4-parameter logistic model or a sigmoidal dose-response model Y=lower+(upper-lower) / (1+10^((logEC50-x)*Hill slope)).

[0135] To evaluate the antitumor activity of the compounds, the growth inhibitory effect of the compounds was measured in various human cancer cell lines after 72 hours of incubation. In the assay, the viability of Molt-4 cells during the initial cell plating was greater than 85%. All cell plates met the criteria of a coefficient of variation (CV) of less than 10%. The IC 50 The observed values ​​were compared with the IC 50 Summarize with observations. TIFF0007597722000068.tif91128

[0136] VI. ILLUSTRATIVE EMBODIMENTS Exemplary embodiments provided in accordance with the subject matter disclosed herein include, but are not limited to, the following embodiments and the claims. 1. A compound of formula I or a pharma- ceutically acceptable salt thereof: TIFF0007597722000069.tif28128In formula, R 1 , R 2 , and R 3 is independent, C 1~6 Alkyl, C 1~6 alkoxy, and halogen, where R 1 ~R 3 at least one of which is a halogen; R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, C 1~6 Alkyl, C1~6 Alkoxy, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , and -N(R b )2 is selected from the group consisting of; Each R a are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~7 Acyl, -C(O)OR a1 , and -C(O)N(R a2 )2, wherein Each R a1 is C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R a2 are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 2~7 Acyl, -SO2R b1 , -C(O)OR b1 , and -C(O)N(R a2 )2, wherein Each R b1 is C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; Each R b2 are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, and C 6~10 aryl; However, R 1 , R 2 , and R 3 is a halogen, R 4 ~R 7 at least one of which is other than hydrogen; R1 is methyl and R 2 is chloro and R 3 When is methoxy, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 If is chloro, R 4 ~R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 is chloro and R 5 is methyl or chloro, R 4 , R 6 , and R 7 at least one of which is other than hydrogen; R 1 is methoxy or isopropoxy, and R 2 is chloro and R 3 is chloro and R 6 If is chloro, R 4 , R 5 , and R 7 At least one of is other than hydrogen. 2. R 1 ~R 3 At least one of them is C 1~6 The compound of embodiment 1, or a pharma- ceutically acceptable salt thereof, wherein: R is alkoxy; 3. R 1 C 1~6 Alkoxy, R 2 The compound of embodiment 1 or embodiment 2, or a pharma- ceutically acceptable salt thereof, wherein is halogen. 4. R 1 C 1~6 Alkoxy, R 2 C 1~6 The compound of embodiment 1 or embodiment 2, or a pharma- ceutically acceptable salt thereof, wherein: R is alkoxy; 5. R 5 and R 6 became independent, C 1~6 Alkoxy, C 3~8 Cycloalkyl, -OR a , and -N(R b 5. The compound of any one of embodiments 1 to 4, wherein the compound is selected from the group consisting of: 6. R 4 and R 7 The compound of any one of embodiments 1-5, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. 7. R 1 C 1~6 is alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 But, C 1~6 Alkoxy, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 1~6 Alkenyl, -OR a , -N(R b )2, and hydrogen; R 6 C 1~6 is an alkoxy; A compound of embodiment 1 or a pharma- ceutically acceptable salt thereof. 8. R 1 C 1~6 is alkoxy; R 2 and R 3 are independently selected halogens; R 4 and R 7 is hydrogen; R 5 is a halogen; R 6 But, C 1~6 Alkyl, C 3~8Cycloalkyl, C 1~6 Alkenyl, -OR a , -N(R b 2, halogen, and hydrogen; A compound of embodiment 1 or a pharma- ceutically acceptable salt thereof. 9. The compound of embodiment 1 is selected from the group consisting of: TIFF0007597722000070.tif124128TIFF0007597722000071.tif62128 and pharma- ceutically acceptable salts thereof. 10. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 9, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. 11. A method for treating a disease or condition associated with mitochondrial dysfunction, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-9 or a pharma- ceutically acceptable salt thereof, or an effective amount of the composition of embodiment 10. 12. The method of embodiment 11, wherein the disease is cancer. 13. The method of embodiment 12, wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCL), glioblastoma, cholangiocarcinoma, non-alcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC), colorectal cancer, breast cancer, or ovarian cancer. 14. The method of embodiment 11, wherein the disease is a neurodegenerative disease. 15. The method of embodiment 14, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Gaucher's disease, amyotrophic lateral sclerosis, or Huntington's disease. 16. The method of embodiment 11, wherein the condition is a brain condition. 17. The method of embodiment 16, wherein the brain condition is stroke, epileptic seizure, a neuropsychiatric condition, neuropathic pain, traumatic brain injury, spinal cord injury, aneurysm, or subarachnoid hemorrhage. 18. The method of embodiment 11, wherein the disease or condition is a non-neurological disorder. 19. The method of embodiment 18, wherein the non-neurological disorder is diabetes, acute kidney injury, renal fibrosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, idiopathic pulmonary fibrosis, cardiac fibrosis, scleroderma, myelofibrosis, pancreatic fibrosis, mitochondrial myopathy, age-related macular degeneration (AMD), congenital mitochondrial disease, sepsis, cardiorenal syndrome, cardiac ischemia-reperfusion injury, pulmonary arterial hypertension, chronic obstructive pulmonary disease, or vasoconstriction. 20. The method of embodiment 11, wherein the condition is human aging caused by mitochondrial dysfunction.

[0137] Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications can be made within the scope of the appended claims.Furthermore, each reference cited herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference.In the event of any inconsistency between this application and a reference cited herein, this application shall control.

Claims

1. A compound selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

2. 13. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

3. 13. A pharmaceutical composition for treating a disease or condition associated with mitochondrial dysfunction comprising the compound of claim 1.

4. 4. The pharmaceutical composition of claim 3, wherein the disease is cancer.

5. 5. The pharmaceutical composition of claim 4, wherein the cancer is T-cell acute lymphoblastic leukemia (T-ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCL), glioblastoma, cholangiocarcinoma, non-alcoholic steatohepatitis (NASH)-induced hepatocellular carcinoma (HCC), colorectal cancer, breast cancer, or ovarian cancer.

6. 4. The pharmaceutical composition of claim 3, wherein the disease is a neurodegenerative disease.

7. 7. The pharmaceutical composition of claim 6, wherein the neurodegenerative disease is Parkinson's disease, Alzheimer's disease, Gaucher's disease, amyotrophic lateral sclerosis, or Huntington's disease.

8. 4. The pharmaceutical composition of claim 3, wherein the condition is a brain condition.

9. 9. The pharmaceutical composition of claim 8, wherein the brain condition is stroke, epileptic seizure, neuropathic pain, neuropsychiatric condition, traumatic brain injury, spinal cord injury, aneurysm, or subarachnoid hemorrhage.

10. 4. The pharmaceutical composition of claim 3, wherein the disease or condition is a non-neurological disorder.

11. 11. The pharmaceutical composition of claim 10, wherein the non-neurological disorder is diabetes, acute kidney injury, renal fibrosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, idiopathic pulmonary fibrosis, cardiac fibrosis, scleroderma, myelofibrosis, pancreatic fibrosis, mitochondrial myopathy, age-related macular degeneration (AMD), congenital mitochondrial disease, sepsis, cardiorenal syndrome, cardiac ischemia-reperfusion injury, pulmonary arterial hypertension, chronic obstructive pulmonary disease, or vasoconstriction.

12. 4. The pharmaceutical composition of claim 3, wherein the condition is human aging caused by mitochondrial dysfunction.

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