Sulfonamides active in acute kidney injury and fibrosis

Abstract

Sulfonamide compounds and sulfonamide-containing compositions are provided. These compounds and compositions are useful in methods for treating renal impairment and fibrosis.

Description

[Technical Field]

[0001] Statement regarding federal government funding This invention was made with government support, including grants DK069403 and DK126122 from the National Institutes of Health, and W81XWH-17-1-0610 from DOD ARMY Medical Research. The government has certain rights in this invention.

[0002] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 458,726, filed on 12 April 2023, the disclosure of which is incorporated by reference in its entirety as part of this specification.

[0003] Compounds and compositions active in the treatment of renal impairment and fibrosis are provided. These molecules offer advantages over conventional compounds because they do not require a prodrug for delivery.

[0004] Kidney damage, such as acute kidney injury (AKI), is very common and has an unacceptably high mortality rate, a situation that has remained unchanged for the past 20 years. AKI treatments developed in experimental models have not shown therapeutic effects in humans when administered before the onset of injury. However, the kidney has an innate ability to regenerate epithelium after injury, and it has been suggested that drugs that enhance this regenerative capacity may be more effective when administered after the onset of injury.

[0005] Acute kidney injury (AKI) is a multifactorial disorder affecting approximately 7% of hospitalized patients. AKI is an independent predictor of in-hospital mortality. Severe AKI requiring renal replacement therapy affects 4% of critically ill patients and accounts for 50% of the in-hospital mortality rate. Long-term studies of survivors of severe AKI have shown that approximately 12.5% ​​become dialysis-dependent. There is an urgent need to develop effective treatments that accelerate the rate of recovery after the onset of renal impairment.

[0006] Fibrosis occurs when fibrous connective tissue accumulates excessively in and around inflamed or damaged tissue. Fibrosis can lead to permanent scarring, organ failure, and death in conditions such as end-stage liver disease, cirrhosis, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure. Collagen deposition plays a crucial and reversible role in wound healing during normal tissue repair. However, severe or repeated tissue damage, or dysregulated wound healing responses, can lead to irreversible fibrotic reactions. Many chronic autoimmune diseases, including but not limited to scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus, result in fibrosis. Fibrosis can also influence tumor invasion and metastasis, chronic graft rejection, and the pathogenesis of many progressive myopathy. There are few effective treatments that effectively target fibrosis (for more information on fibrosis, its causes, and related diseases, see, for example, Wynn TA, et al. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012 Jul 6;18(7):1028-40).

[0007] There is a need for compositions and treatments effective for AKI and fibrosis. [Overview of the project]

[0008] A compound is provided. Exemplary structure (I): [ka] (In the formula, A is a (C5-C7)(hetero)aryl ring and / or phenyl bioequivalent; X is a (C1-C7) divalent (hetero)alkyl; Y is either a methylene (-CH2-) or dimethylene (-CH2-CH2-) molecule forming a five-membered or six-membered ring with 0, 1, or 2 double bonds, or is absent; R1 is (C1-C7)(hetero)alkyl, (C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)aryl, (C1-C6)(hetero)alkoxyl, (C3-C7)(hetero)aryl-oxyl, or (hetero)aryl. Here, A, X, or Y are independently, optionally, substituted with one or more (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)(hetero)aryl-oxyl, (C3-C7)(hetero)aryl-amino, (C3-C7)(hetero)aryl-cyano, (C3-C7)(hetero)aryl-nitro, or (C3-C7)(hetero)aryl-halo groups. A compound or a pharmaceutically acceptable salt thereof having the compound. Compositions comprising the compound and a pharmaceutically acceptable excipient are also provided.

[0009] A method for treating renal impairment in a patient is provided. This method comprises administering to the patient a compound described in the preceding paragraph in an amount effective for treating renal impairment. A method for treating fibrosis in a patient is also provided, comprising administering to the patient an amount and dosage regimen effective for treating fibrosis.

[0010] The following numbered sections outline various aspects, embodiments, and / or examples of the present invention.

[0011] Section 1 Structure (I): [ka] (In the formula, A is a (C5-C7)(hetero)aryl ring and / or phenyl bioequivalent; X is a (C1-C7) divalent (hetero)alkyl; Y is methylene (-CH2-) or dimethylene (-CH2-CH2-), or is absent, forming a 5- or 6-membered ring having 0, 1, or 2 double bonds; R1 is (C1-C7)(hetero)alkyl, (C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)aryl, (C1-C6)(hetero)alkoxyl, (C3-C7)(hetero)aryl-oxyl, or (hetero)aryl, where A, X, or Y are each independently optionally substituted with one or more (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)(hetero)aryl-oxyl, (C3-C7)(hetero)aryl-amino, (C3-C7)(hetero)aryl-cyano, (C3-C7)(hetero)aryl-nitro, or (C3-C7)(hetero)aryl-halo groups) a compound having the same or a pharmaceutically acceptable salt thereof.

[0012] Item 2 Structure (II):

Chemical formula

Chemical formula

[0013] Claim 3 The compound according to claim 2, wherein the bicyclic heteroaryl group comprises a thiophene ring or a thiopyran ring and an aryl ring.

[0014] Claim 4 The compound according to claim 3, wherein the bicyclic heteroaryl group is a benzothiophenyl moiety or a benzothiopyranyl moiety.

[0015] Claim 5 B is

Chemical formula

[0016] Claim 6 B is

Chemical formula

[0017] The compound according to paragraph 6, wherein R2 is phenyl and optionally substituted with one or more of the following groups: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo groups, or is a bioequivalent of any of the above.

[0018] Article 8: A compound according to any one of Articles 2 to 7, wherein X is alkyl.

[0019] The compound described in paragraph 1, in which Y is absent.

[0020] Section 10 Structure: [ka] (In the formula, R3 is one or more of the following: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo group) A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0021] Section 11 Structure: [ka] A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0022] Article 12: A compound according to any one of Articles 1 to 11, wherein R1 is methyl.

[0023] Section 13 Structure: [ka] A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0024] Section 14 Structure: [ka] A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0025] Section 15 Structure: [ka] (wherein R1 is ethyl, cyclopropyl, n-propyl, isopropyl, or t-butyl) A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0026] Section 16 Structure: [ka] (wherein R1 is ethyl, cyclopropyl, n-propyl, isopropyl, or t-butyl) A compound as described in paragraph 1, having the following characteristics.

[0027] Article 17 The compound described in Article 1 or Article 2, wherein X is substituted with one or two methyl groups.

[0028] The compound described in paragraph 17, wherein R1 is methyl and R2 is o-methylphenyl.

[0029] Section 19 Structure: [ka] (In the formula, R4 is one or more of H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo group, and R5 is (C1-C7)(hetero)alkyl or optionally substituted (C1-C7)(hetero) (It is an alkyl(hetero)aryl group, or, in some cases, substituted with one or more of the following: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo groups, or a bioequivalent of any of the above.) A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0030] The compound described in paragraph 19, wherein R5 is methylphenyl.

[0031] Article 21: The compound described in Article 19 or Article 20, wherein R4 is one or more of H or methyl.

[0032] Section 22 Structure: [ka] A compound or a mixture thereof, as described in item 19, and / or a pharmaceutically acceptable salt thereof.

[0033] The compound described in paragraph 22, wherein R4 is H.

[0034] Section 24 Structure: [ka] A compound or a pharmaceutically acceptable salt thereof, having the properties of the compound described in paragraph 1.

[0035] A composition comprising a compound described in any one of paragraphs 1 to 24 and a pharmaceutically acceptable excipient.

[0036] Section 26 Structure: [ka] Compounds having or pharmaceutically acceptable salts thereof; or [ka] The composition according to paragraph 25, comprising a compound having or a pharmaceutically acceptable salt thereof.

[0037] Paragraph 27 A method for treating renal impairment in a patient, comprising administering to the patient a compound described in any one of paragraphs 1 to 24 in an amount effective for treating renal impairment.

[0038] Paragraph 28: The method according to paragraph 27, wherein the renal injury is acute renal injury.

[0039] Paragraph 29: The method of paragraph 27, wherein the renal impairment is related to the patient's trauma.

[0040] Paragraph 30: The aforementioned kidney impairment is due to chronic kidney disease; reduced blood flow to the kidneys (e.g., due to blood or drug-induced kidney injury); loss of blood or fluids; use of blood pressure medications; heart attack; heart disease; infection; liver failure; sepsis; use of NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, or naproxen sodium; severe allergic reactions (e.g., anaphylaxis); burns; dehydration; thrombosis in the veins and arteries in and around the kidneys; and cholesterol that blocks blood flow to the kidneys. The methods described in paragraph 27 relating to: thrombus deposition; glomerulonephritis; glomeruloinflammation; hemolytic uremic syndrome; lupus; use of drugs such as chemotherapy drugs, antibiotics, or dyes used in imaging tests; scleroderma; thrombotic thrombocytopenic purpura; toxins, including, for example, alcohol, heavy metals, or cocaine; rhabdomyolysis; tumor lysis syndrome; bladder cancer; urinary tract thrombosis; cervical cancer; colon cancer; benign prostatic hyperplasia (e.g., benign prostatic hyperplasia); kidney stones; nerve damage, including nerves supplying the bladder; or prostate cancer.

[0041] Paragraph 31 A method for treating fibrosis in a patient, comprising administering to the patient a compound described in any one of paragraphs 1 to 24 in an amount and dosage regimen effective for treating fibrosis.

[0042] Paragraph 32: The method according to paragraph 31, wherein the fibrosis is a pulmonary fibrosis such as idiopathic pulmonary fibrosis.

[0043] Section 33 The method described in Section 31, relating to scleroderma; rheumatoid arthritis; Crohn's disease; ulcerative colitis; myelofibrosis; systemic lupus erythematosus; cirrhosis; non-alcoholic steatohepatitis; interstitial lung disease; acne; rosacea; renal fibrosis, pancreatic fibrosis, or cardiac fibrosis. [Brief explanation of the drawing]

[0044] [Figure 1] Figure 1 shows various compounds prepared as described in Figure 2. [Figure 2] Figure 2 provides an exemplary synthesis scheme of the compounds described herein. [Figure 3A]Figure 3A shows the structure and hazard ratio of the compounds described herein. [Figure 3B] Figure 3B shows the structure and hazard ratio of the compounds described herein. [Figure 4A] Figure 4A shows the structure of an exemplary derivative of UPHH207. [Figure 4B] Figure 4B shows the structure of an exemplary derivative of UPHH231. [Figure 5] Figure 5 shows the synthesis scheme and structure of further compounds. [Figure 6] Figure 6 shows the Kaplan-Meier curve for compound 207, illustrating the survival of zebrafish treated with 4 μM compound 207. [Figure 7] Figure 7 – qPCR results for inflammation and fibrosis markers (HAVCR1, HMOX1, IL6, CCL2, CCXCL1, COL1A1) in human kidney organoids treated with 25 μM hemin + / - and 0.2, 1, and 5 μM '207 + / -'. [Figure 8] Figure 8. Collagen 1A1 antibody staining of human kidney organoids treated with 25 μM hemin + / - and 0.04, 0.2, 1, and 5 μM '207 + / -' (left panel). Quantification of collagen 1A1 antibody staining using a one-way Anova test. ** = 0.01 (right panel). [Figure 9A] Figure 9A shows a graph illustrating the plasma concentration of compound 207. [Figure 9B] Figure 9B shows a graph illustrating the plasma concentrations of compounds 0020 and 186. [Figure 10] Figure 10 is a graph showing the blood urea nitrogen (BUN) levels over time in mice (n=4) treated with compound 207. [Figure 11] Figure 11 is a graph showing transcutaneous GFR (tGFR) 27 days after injury. [Figure 12] Figure 12 is a graph showing Sirius Red staining of collagen in kidney sections 28 days after injury, as an indicator of fibrosis. [Modes for carrying out the invention]

[0045] The use of numerical values ​​within the various ranges defined herein is described as approximations, as if preceded by the word “approximately” both the minimum and maximum values ​​within the stated ranges, unless otherwise explicitly indicated. Thus, slight variations above and below the stated ranges can be used to achieve substantially the same results as values ​​within that range. Furthermore, unless otherwise indicated, these disclosures are intended as continuous ranges encompassing all values ​​between the minimum and maximum values. With respect to the definitions provided herein, those definitions refer to the forms, synonyms, and grammatical variations of those words or phrases. As used herein, “one (a)” and “one (an)” refer to one or more.

[0046] As used herein, “comprising” is open-ended and may be synonymous with “including,” “containing,” or “characterized by.” As used herein, embodiments “comprising” one or more of the described elements or processes also include, but are not limited to, embodiments “essentially consisting of” and embodiments “spanning” those described elements or processes.

[0047] A "part" is a component of a chemical compound, including groups such as functional groups.

[0048] As used herein, “alkyl” refers to linear, branched, and / or cyclic hydrocarbon groups, including, for example, 1 to about 20 carbon atoms, such as, but not limited to, C1-C3, C1-C6, and C1-C10 groups, such as, but not limited to, linear and branched alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Alkyl groups can be, for example, substituted or unsubstituted C1, C2, C3, C4, C5, C6, C7, C8, C9, or C10 groups. “Lower alkyl” refers to C1-C6 alkyl groups. Not limited examples of linear alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Branched alkyl groups consist of any linear alkyl group substituted with any number of alkyl groups. Examples of branched alkyl groups, though not limited to them, include isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. “Unsaturated alkyl” consists of one or more carbon-carbon double bonds, e.g., 1, 2, 3, 4, or 5, and may be called an alkene or alkenyl, as described below. “Substitutive alkyl” may include alkyls substituted at one or more locations (e.g., 1, 2, 3, 4, 5, 6, or more), where these substituents are bonded to any available atoms to produce a stable compound having the substitutions described herein. “Optionally substituted alkyl” refers to an alkyl or a substituted alkyl. “Halogen,” “halide,” and “halo” refer to -F, -CI, -Br, and / or -I. "Alkylene" and "substituted alkylene" may include, but are not limited to, divalent alkyl and divalent substituted alkyl, respectively, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, or decamethylene. "Optionally substituted alkylene" may include alkylene or substituted alkylene.

[0049] Examples of cyclic alkyl groups, though not limited to these, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cyclic alkyl groups also include condensed bicyclic, cross-linked bicyclic, and spiro-bicyclic groups, as well as higher-order condensed, cross-linked, and spiro-systems. Cyclic alkyl groups can be substituted with any number of linear, branched, or cyclic alkyl groups. Cycloalkyl groups may be bonded via any atom. Cycloalkyl groups also envision condensed rings in which the cycloalkyl group is fused to an aryl or heteroaryl ring. Cycloalkyl groups may be unsubstituted or optionally substituted with one or more substituents as described later herein. "Cycloalkylene" refers to a divalent cycloalkyl group. The term "optionally substituted cycloalkylene" refers to a cycloalkylene substituted with at least one, two, or three substituents bonded at any available atom to produce a stable compound, the substituents as described herein. Cycloalkylenes may be formed by the combination of two "R groups," such as "R2 and R3 together," as referenced below.

[0050] An "alkene or alkenyl" can include a linear, branched, or cyclic hydrocarbyl group containing, for example, 2 to about 20 carbon atoms, having one or more carbon-carbon double bonds, e.g., 1, 2, 3, 4, or 5 carbon-carbon double bonds, and may be called an "unsaturated alkyl." One or more olefins of an alkenyl group may be, for example, E, Z, cis, trans, terminal, or exomethylene. An alkenyl or alkenylene group may be, for example, a substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, or C20 group. A halo-alkenyl group may be any alkenyl group substituted with any number of halogen atoms. "Substitutive alkenes" may include alkenes substituted in one or more positions, for example, 1, 2, 3, 4, or 5 positions, where these substituents are attached to any available atoms to form a stable compound, and substitutions are as described herein. "Optionally substituted alkenes" may include alkenes or substituted alkenes. Similarly, "alkenylenes" may refer to divalent alkenes. Examples of alkenylenes, but not limited to, include ethenylene (-CH=CH-) and all of its stereoisomers and conformational isomers. "Substitutive alkenylenes" may refer to divalent substituted alkenes. "Optionally substituted alkenylenes" may refer to alkenylenes or substituted alkenylenes.

[0051] An alkyne or "alkynyl" refers to a linear, branched, or cyclic unsaturated hydrocarbon having a specified number of carbon atoms and at least one triple bond. The triple bond of the alkyne or alkynyl group may be internal or terminal. Examples of (C2-C8)alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentine, 2-pentine, 1-hexine, 2-hexine, 3-hexine, 1-heptine, 2-heptine, 3-heptine, 1-octin, 2-octin, 3-octin, and 4-octin. The alkynyl group may be unsubstituted or optionally substituted with one or more substituents as described later herein. Alkynes or alkynyl groups can be, for example, substituted or unsubstituted C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, or C20 groups. Halo-alkynyl groups can be any alkynyl group substituted with any number of halogen atoms. The term "alkynylene" refers to divalent alkynes. Examples of alkynylenes, though not limited to, include ethynylene and propynylene. "Substitutive alkynylene" refers to divalent substituted alkynes.

[0052] "Carboxyl" or "carboxyl" refers to a group having a specified number of carbon atoms and a -C(O)OH group at its terminus, thus having the structure -RC(O)OH (where R is an unsubstituted or substituted divalent organic group that may include a linear, branched, or cyclic hydrocarbon). Examples of these, though not limited to them, include C1-C8 carboxyl groups, e.g., ethaneic acid, propanoic acid, 2-methylpropanoic acid, butanoic acid, 2,2-dimethylpropanoic acid, pentanoic acid, etc. "Amine" or "amino" refers to a group having a specified number of carbon atoms and a -NH2 group at its terminus, thus having the structure -R-NH2 (where R is an unsubstituted or substituted divalent organic group that may include, for example, a linear, branched, or cyclic hydrocarbon), possibly containing one or more heteroatoms. The term "alkylamino" refers to a group of the formula -NHR xor -NR x R x This refers to the radical, where each R x These are independently alkyl radicals as defined above. "Alkoxyl" or "alkoxy" refers to -O-alkyl groups such as methoxyl, ethoxyl, and propyloxyl.

[0053] "Aryl" refers to an aromatic ring system, such as phenyl or naphthyl, either alone or in combination. "Aryl" may also include aromatic ring systems fused with a cycloalkyl ring. "Substitutive aryl" is an aryl group independently substituted with one or more substituents bonded to any available atom to form a stable compound, the substituents as described herein. Substituents may be, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. "Optionally substituted aryl" refers to an aryl or substituted aryl group. An aryloxy group may be an oxygen atom substituted with any aryl group, such as phenoxy. An arylalkoxy group may be an oxygen atom substituted with any aralkyl group, such as benzyloxy. "Arirene" refers to a divalent aryl group, and "substituted arirene" refers to a divalent substituted aryl group. "Optionally substituted arirene" refers to an arirene or substituted arirene. Related terms such as "polycyclic aryl group" and "polycyclic aromatic group" refer to a group consisting of at least two fused aromatic rings. A "heteroaryl" or "heterosubstituted aryl" refers to an aryl group substituted with one or more heteroatoms such as N, O, P, and / or S. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl, thiopyranil, benzothiophenyl, benzothiopyranil, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

[0054] Examples of substituted benzothiophenyl and benzothiopyranyl groups (for example, as "A" in structure (II) below, or as methylene or dimethylene in structure (I) below) include: [ka] Examples include, where X1 can independently be H or a substituent, such as (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl (-O-(C3-C7)aryl), or a halo group.

[0055] The term combining the above is arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkynyl This refers to any appropriate combination of the above, including alkenyl heteroaryl alkenyl, alkenyl heteroaryl alkynyl, alkynyl heteroaryl alkyl, alkynyl heteroaryl alkenyl, alkynyl heteroaryl alkynyl, alkyl heterocyclyl alkyl, alkyl heterocyclyl alkenyl, alkyl heterocyclyl alkynyl, alkenyl heterocyclyl alkyl, alkenyl heterocyclyl alkenyl, alkenyl heterocyclyl alkynyl, alkynyl heterocyclyl alkyl, alkynyl heterocyclyl alkenyl, alkynyl heterocyclyl alkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkyl heteroaryl, alkenyl heteroaryl, and alkynyl heteroaryl. For example, "arylalkylene" refers to a divalent alkylene in which one or more hydrogen atoms of the alkylene group are substituted with an aryl group such as a (C3-C8) aryl group. Examples of (C3-C8)aryl-(C1-C6)alkylene groups include, but are not limited to, 1-phenylbutylene, phenyl-2-butylene, l-phenyl-2-methylpropylene, phenylmethylene, phenylpropylene, and naphthylethylene. The term "(C3-C8)cycloalkyl-(C1-C6)alkylene" refers to a divalent alkylene in which one or more hydrogen atoms of a C1-C6 alkylene group are substituted with a (C3-C8)cycloalkyl group.Examples of (C3-C8)cycloalkyl-(C1-C6)alkylene groups include, but are not limited to, 1-cyclopropylbutylene, cyclopropyl-2-butylene, cyclopentyl-1-phenyl-2-methylpropylene, cyclobutylmethylene, and cyclohexylpropylene.

[0056] Terms not mentioned above may have meanings that are understood by those skilled in the art in the fields of chemistry and medicine.

[0057] A bioisostere with respect to a group or part refers to a structural motif that exhibits similar biological properties without the fundamental requirement that it exhibits similar shape or size, or close physicochemical attributes, as would be expected from the shared functionality of the equivalent relationship. Phenyl bioisosteres are common equivalent substitutions in medicinal chemistry. Exemplary potential bioisosteres of monosubstituted (terminal) and disubstituted (para, meta, ortho) benzene rings, as understood in the field of medicinal chemistry, are described in detail in (Subbaiah MAM, Meanwell NA. Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design. J Med Chem. 2021 Oct 14;64(19):14046-14128, see, for example, Figure 38). Similar to phenyl bioisosteres, suitable bioisoter substitutions of other groups are widely known to those skilled in the field of medicinal chemistry.

[0058] As used herein, “patient” or “subject” refers to any animal, including but not limited to humans, and “mammal” refers to all mammals, including but not limited to humans.

[0059] As used herein, “treatment” of a patient means administration to the patient by any appropriate dosing plan, procedure, and / or route of administration of a composition, device, or structure for the purpose of achieving a beneficial or desirable clinical / medical endpoint, including, but not limited to, preventing, reducing, and / or eliminating the symptoms of acute kidney injury or fibrosis. Any amount of any effective agent for treating a patient, administered by any appropriate route, is an amount that can prevent, reduce, and / or eliminate any symptoms of acute kidney injury or fibrosis. To determine the effectiveness of treatment, any appropriate clinical marker may be used, but not limited to, improved survival, improved renal function, or reduction of fibrosis, or any of the biological markers described above. Clinical test results can be said to have “normalized” when such clinical markers approach or enter the normal or healthy range for the patient.

[0060] The compositions described herein can be administered by any effective route, such as parenteral administration, intravenous, intramuscular, subcutaneous, intradermal, perfusion of organs or tissues, or application to organs or tissues, and these formulations are described below and in the reference publications below and are also widely known to those skilled in the art.

[0061] Suitable dosage forms may include single-dose or multi-dose vials, or other containers such as medical syringes, containing a composition comprising the active ingredient, such as the compounds described herein.

[0062] An activator (e.g., a drug), such as a pharmaceutical or medical composition comprising a compound described herein, can be prepared by any method known in the pharmaceutical field, for example, by associating the active ingredient with a carrier or excipient. As used herein, “pharmaceutically acceptable excipient,” “carrier,” or “pharmaceutically acceptable carrier” includes any physiologically compatible solvent, dispersion medium, coating, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. Examples of pharmaceutically acceptable excipients include one or more of water, physiological saline, phosphate-buffered saline, glucose, glycerol, ethanol, and combinations thereof. Often, it is preferable to include an isotonic agent, such as sugar, polyhydric alcohol (mannitol, sorbitol, etc.), or sodium chloride in the composition. A pharmaceutically acceptable carrier may further contain small amounts of auxiliary substances that enhance the shelf life or efficacy of the activator, such as wetting agents, emulsifiers, preservatives, or buffers. The activator can be prepared with a carrier that protects the compound from rapid release, such as in controlled-release formulations including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used in the delivery system. In addition to the above, non-limiting examples of useful excipients available in the pharmaceutical / formulation technology field include antifouling agents, binders, rheological modifiers, coatings, disintegrants, emulsifiers, oils, buffers, salts, acids, bases, fillers, diluents, solvents, fragrances, colorants, flow enhancers, lubricants, preservatives, antioxidants, adsorbents, vitamins, and sweeteners. Methods for preparing such formulations are widely known to those skilled in the art.

[0063] Furthermore, the activator-containing composition may be in various forms. The preferred form depends on the intended mode of administration and therapeutic application, which in turn determines the type of carrier / excipient. Suitable forms, but are not limited to, include liquid, semi-solid, and solid dosage forms.

[0064] Pharmaceutical formulations suitable for oral administration may include, but are not limited to, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foaming agents or whipping agents; or individual units such as oil-in-water or water-in-oil liquid emulsions. In certain embodiments, the activator may be included in a formulation suitable for oral administration, for example, by combining the activator with an inert diluent or assimilated edible carrier. The activator (and optionally other components) may be encapsulated in hard-shell or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, the compound may be formulated with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. To administer the compounds of the present invention by means other than parenteral administration, it may be necessary to coat the compounds with a substance to prevent inactivation or to co-administer the compounds with such substances.

[0065] Pharmaceutical formulations suitable for topical administration can be formulated as, for example, ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils, but are not limited to these. Formulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohol, or solutions of nucleic acids in liquid or solid oily bases. Solutions may also contain buffers, diluents, and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for parenteral administration that do not react adversely with nucleic acids may be used.

[0066] Pharmaceutical formulations suitable for nasal administration, where the carrier is solid, include, for example, coarse powders with particle sizes ranging from 20 to 500 microns, which are administered by rapid inhalation through the nasal cavity from a container of powder held near the nose, similar to how olfactory agents are taken orally. Formulations suitable for administration as nasal sprays or nasal drops, where the carrier is liquid, include aqueous or oily solutions of the active ingredient.

[0067] Pharmaceutical formulations suitable for inhalation administration include, but are not limited to, particulate dust or mist that can be generated by various types of metered-dose pressurized aerosols, nebulizers, or inhalers. In the context of inhalation delivery of active ingredients as described herein, inhalation medications such as metered-dose inhalers, which are widely known in the pharmaceutical field, are used. Metered-dose inhalers are configured to deliver a single dose of active ingredient in a single action, although multiple actions may be required to effectively treat a given patient.

[0068] Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain, but are not limited to, antioxidants, buffers, bacteriostatic agents, lipids, liposomes, emulsifiers, and anti-precipitation and rheological modifiers. The formulations may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Ready-to-prepare injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0069] Therapeutic compositions other than live cell therapies can be sterile and stable under manufacturing and storage conditions. For example, sterile injections can be prepared by compounding the required amount of activator with one or a combination of the components listed above, as needed, in a suitable solvent, followed by filtration sterilization. Generally, dispersions are prepared by compounding the active compound in a sterile vehicle containing a basic dispersion medium and other necessary components from the components listed above. In the case of sterile powders for sterile injection preparation, typical preparation methods are vacuum drying and freeze-drying to obtain the active ingredient powder and desired additional components from a pre-filtered sterilized solution. Appropriate fluidity of the solution can be maintained, for example, by using a coating such as lecithin, and in the case of dispersions, by using a surfactant to maintain the required particle size. Extension of the absorption of injection compositions can be achieved by including absorption-delaying agents, such as monostearate and gelatin, in the composition.

[0070] The compounds described herein may form complexes with cyclodextrins. Cyclodextrins are compounds substantially recognized in the pharmaceutical field, for example, as excipients (e.g., carriers, vehicles, etc.) in oral and intravenous dosage forms. Cyclodextrins can form non-covalent inclusion complexes and / or aggregates in solution with poorly soluble drugs, such as BCS class II and IV drugs (which have high and low intestinal permeability, respectively, but are in either case poorly soluble). Cyclodextrins are cyclic oligosaccharides having a hydrophilic outer surface and a lipophilic central cavity. They consist of α-1,4 linked α-D-glucopyranose units. Naturally occurring cyclodextrins include α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, which have 6, 7, and 8 glucopyranose units, respectively. Natural cyclodextrins can be used orally or topically, but natural β-cyclodextrins and γ-cyclodextrins cannot be used parenterally. Many cyclodextrin derivatives have been formulated with various uses through different routes of administration. Common, non-limited, examples of cyclodextrin derivatives include hydroxypropyl-β-cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin), hydroxypropyl-γ-cyclodextrin (e.g., 2-hydroxypropyl-γ-cyclodextrin), hydroxyethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, permethylated β-cyclodextrin, sulfobutyl ether β-cyclodextrin (e.g., sodium salt), sulfobutyl-γ-cyclodextrin, branched cyclodextrin (e.g., glucosyl-β-cyclodextrin or maltosyl-β-cyclodextrin, e.g., 6-O-maltosyl-β-cyclodextrin or glucosyl-β-cyclodextrin) and randomly acetylated amorphous-β-cyclodextrin.Cyclodextrins can form inclusion complexes (complexes) with drugs in a 1:1 molar ratio solution, but the relative amounts of drug or cyclodextrin can be increased or decreased during formulation to facilitate the reaction. Excess cyclodextrin may be utilized if the drug aggregates instead of being contained within the cyclodextrin. It should be recognized that the inclusion or aggregation process can be optimized, including manipulating the relative cyclodextrin-active ingredient ratio, to obtain optimal solubility and bioavailability or other desirable characteristics of the final product. For a description of cyclodextrins and their use in the pharmaceutical field, see, for example, Loftsson et al. “Self-Association of Cyclodextrins and Cyclodextrin Complexes” J. Pharm. Sci. 93(5):1091-1099 (2004); Loftsson et al. “Cyclodextrins in Drug Delivery” Expert. Opin. Drug Deliv. 2:335-351 (2005); Brewster et al. “Cyclodextrins as Pharmaceutical Solubilizers” Advanced Drug Delivery Reviews 59:645-666 (2007); and Rasheed et al., “Cyclodextrins as Drug Carrier Molecule: A review” Sci. Pharm. 76:567-598 (2008). As used herein, "cyclodextrin" refers not only to naturally occurring α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, but also to cyclodextrin derivatives, including, but not limited to, those described above.Similarly, "α-cyclodextrin," "β-cyclodextrin," and "γ-cyclodextrin" refer to both naturally occurring cyclodextrins and cyclodextrin derivatives (for example, "β-cyclodextrin" includes both β-cyclodextrin and, but is not limited to, β-cyclodextrin derivatives such as hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, randomly methylated β-cyclodextrin, methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, permethylated β-cyclodextrin, sulfobutyl ether β-cyclodextrin, and branched β-cyclodextrin).

[0071] The formulation may be a liposome, lipid nanoparticles, drug-loaded extracellular vesicles, or a multiphase (liquid comprising multiple phases such as oil in water, water in oil, liposomes, or multilamellar structures) composition. Multiphase systems containing liposomes are widely used in the pharmaceutical field. In the case of liposomes, the pharmaceutical may comprise a composition comprising phospholipids, nonionic detergents, and cationic lipids, such as phosphatidylcholine, nonionic surfactants, and quaternary ammonium salts of lipid-substituted D or L glutamic acid or aspartic acid, and an aqueous solvent. Liposomes or multiphase liquids and their components are pharmaceutically acceptable. They are typically formulated using water, saline, or an aqueous solvent such as PBS.

[0072] Phospholipids include any natural or synthetic diacylglyceryl phospholipids (such as phosphatidylcholine, phosphotidylethanolamine, phosphotidylserine, phosphatidylinositol, and phosphatidylinositol phosphate) and phosphosphingolipids that can form self-assembling liposomes. For example, the phospholipid is phosphatidylcholine, a compound comprising a choline head group, glycerophosphate, and a fatty acid. Phosphatidylcholine can be obtained from eggs, soybeans, or any suitable source, and can also be synthesized.

[0073] Nonionic surfactants are surfactants that do not contain charged groups. Nonionic surfactants comprise a hydrophilic head group and a lipophilic tail group, such as single or double lipophilic chain surfactants. Examples of lipophilic tail groups include lipophilic saturated or unsaturated alkyl groups (fatty acid groups), steroid groups, such as cholesteryl, and vitamin E (e.g., tocopheryl) groups, such as polysorbate (polyoxyethylene sorbitan), such as Tween 20, 40, 60, or 80. More broadly, nonionic surfactants include glyceryl esters, including monoglycerides, diglycerides, and triglycerides; fatty alcohols; and fatty acid esters of fatty alcohols or other alcohols, such as propylene glycol, polyethylene glycol, sorbitan, sucrose, and cholesterol.

[0074] Cationic lipids are compounds that have a cationic head and a lipophilic tail. Examples include lipid-substituted D and quaternary ammonium salts such as glutamic acid dialkylamides including L-glutamic acid-1,5,-dioleilamide, and quaternary ammonium salts such as quaternary ammonium salts of L-glutamic acid or aspartic acid. Other commercially available cationic lipids (e.g., from Avanti Polar Lipids) include DC-cholesterol (3β-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride), DOTAP (e.g., 1,2-dioleoyl-3-trimethylammonium-propane (chloride salt)), DODAP (e.g., 1,2-dioleoyl-3-dimethylammonium-propane), DDAB (e.g., dimethyldioctadecylammonium (bromide salt)), ethyl-PC (e.g., 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine (chloride salt)), and DOTMA (e.g., 1,2-di-O-octadecenyl-3-trimethylammoniumpropane (chloride salt)).

[0075] The ratio of components (phospholipids:nonionic surfactants:cationic lipids) can be broadly modified as long as a useful multi-lamellar structure capable of delivering the activators described herein is obtained. Furthermore, different combinations of components may have different optimal ratios. As described herein and as is generally known in pharmaceutical technology, the ability of any formulation to deliver activators is easily tested, so excessive experimentation is not required to determine the optimal ratio. Liposomes and multi-lamellar structures are common delivery vehicles for activators, and their manufacture, physical testing, and biological assays for determining efficacy are well known. Useful phospholipid:nonionic surfactant:cationic lipid ratios include, for example, 0.1-10:0.1-10:0.1-10 (w / w), and in specific examples, the nonionic surfactant:cationic lipid (w / w) ratio is approximately equal, and / or the phospholipid component is 2-10 times (w / w) the nonionic surfactant and cationic lipids.

[0076] Antibody-drug conjugates, in which targeted antibodies are reversibly bound to a drug or incorporated into a complex with the drug such as a vesicular (e.g., lipid-mediated) drug delivery vehicle or lipid nanoparticles, can be used to target drugs to specific tissues or organs in a patient (see, for example, Fu, Z, et al. Antibody drug conjugate: the "biological missile" for targeted cancer therapy. Signal Transduct Target Ther. 2022 Mar 22;7(1):93; Marques AC, et al. Lipid Nanoparticles Functionalized with Antibodies for Anticancer Drug Therapy. Pharmaceutics. 2023 Jan 8;15(1):216; and Topping LM, et al. Targeting Extracellular Vesicles to the Arthritic Joint Using a Damaged Cartilage-Specific Antibody. Front Immunol. 2020 Feb 14;11:10).

[0077] A "therapeutically effective dose" refers to the amount of a drug or activator that is effective in the dose and duration required to achieve the desired therapeutic outcome. For the treatment of a particular condition, an "effective dose" is the amount of an activator or dosage form, such as a single or multiple injections, tablets, capsules, or a metered dose from a metered-dose inhaler, that is effective in achieving a determinable endpoint. The "effective dose" is preferably safe—at least to the extent that the therapeutic benefits outweigh the disadvantages, and / or that the disadvantages are acceptable to those skilled in the art and / or to the appropriate regulatory body, such as the U.S. Food and Drug Administration. A therapeutically effective dose of an activator can be modified depending on factors such as the individual's condition, age, sex, and weight, as well as the activator's ability to elicit the desired response in the individual. A therapeutically effective dose is also the amount in which the toxicity or adverse effects of the activator outweigh the therapeutically beneficial effects. A "preventively effective dose" refers to the amount that is effective in the dose and duration required to achieve the desired preventive outcome. Generally, since preventive doses are used for targets in the pre- or early stages of a disease, a preventively effective dose may be less than a therapeutically effective dose.

[0078] The administration plan can be adjusted to provide the optimal desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, or several divided doses may be administered over time, or the composition may be administered in a continuous or pulsed manner, with doses or partial doses administered at regular intervals, such as every 10, 15, 20, 30, 45, 60, 90, or 120 minutes, every 2 to 12 hours daily, or every other day. The dose may be proportionally reduced or increased, as shown, depending on the urgency of the treatment situation. In some cases, it may be particularly advantageous to formulate parenteral or inhalation compositions in unit dosage forms for ease of administration and dose uniformity. The specifications of the unit dosage forms of the present invention may depend directly on (a) the unique properties of the active compound and the specific therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the technique of formulating such active compounds for the treatment of hypersensitivity in an individual.

[0079] The compound may be administered locally or topically to the site of a wound, graft, or fibrotic lesion to prevent or treat inflammation, fibrosis, or scarring. Topical administration includes intraocular delivery or dosage forms. In patients with pulmonary fibrosis or other inflammatory conditions of the lungs and / or airways, the compound may be administered topically, for example by spray, atomization, aerosolization, inhalation, or bronchoalveolar lavage, or systemically, for example, intravenously.

[0080] The compounds can be systemically administered to a patient for the treatment of renal impairment, acute kidney injury, improvement of renal function, inhibition of histone deacetylase in cells, proliferation of renal progenitor cells, and / or stimulation of renal repair in in vitro, ex vivo, or in vivo (patient) cells, and / or suppression of fibrosis, for example, fibrotic activity. Compositions are also provided for delivering the compounds to a patient. Methods are also provided for the treatment of renal impairment, acute kidney injury, improvement of renal function, inhibition of histone deacetylase in cells, proliferation of renal progenitor cells, and / or stimulation of renal repair in in vitro, ex vivo, or in vivo (patient) cells, comprising contacting cells with or administering to a patient one or more compounds in an amount effective for improving the patient's renal function, inhibition of histone deacetylase in cells, proliferation of renal progenitor cells, and / or stimulation of renal repair in cells. Thus, in vitro (including ex vivo) or in vivo (in-patient) methods are provided. The efficacy of the compounds is described below. The compounds described herein can be administered in any manner effective for the treatment of renal injury, acute kidney injury, improvement of renal function, inhibition of histone deacetylase in cells, expansion and proliferation of renal progenitor cells, and / or stimulation of renal repair in the patient's cells. The compounds described herein can also be administered in any manner effective for the treatment of fibrosis or for reducing or suppressing fibrotic activity. Examples of delivery routes include, but are not limited to, topical, e.g., percutaneous, inhalation, enema, ocular, ocular, ocular, and nasal delivery; enteral, e.g., oral, by gastric feeding tube or swallowing, and rectal; and parenteral, e.g., intravenous, intra-arterial, intramuscular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, percutaneous, iontophoresis, transmucosal, epidural, and intravitreous administration. Oral or intravenous approaches may be used for the treatment of renal impairment, acute kidney injury, promotion of renal repair in cells, improvement of renal function, inhibition of histone deacetylases in cells, and / or the expansion and proliferation of renal progenitor cells.

[0081] As described above, fibrosis can lead to permanent scarring, organ failure, and death, as in end-stage liver disease, cirrhosis, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure. Collagen deposition plays a crucial and reversible role in wound healing in normal tissue repair. However, if tissue damage is severe or repeated, or if the wound healing response is dysregulated, an irreversible fibrotic reaction may occur. Many chronic autoimmune diseases, including but not limited to scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus, result in fibrosis. Fibrosis can also affect tumor invasion and metastasis, chronic graft rejection, and the pathogenesis of many progressive myopathy. For the treatment of fibrosis, the compounds described herein can be administered via any appropriate route and administration plan. For example, in the case of wound healing and scar prevention, the compound can be formulated as a topical preparation such as a cream, ointment, tincture, spray, or drop (e.g., for topical use in the eyes or ears). For example, in the case of gastrointestinal wound healing, for example, for the prevention of scarring or stricture in surgical patients or patients with ulcers or inflammatory bowel disease such as Crohn's disease or ulcerative colitis, the composition can be administered orally, via suppositories, or parenterally, systemically, for example, by subcutaneous, intramuscular, intravenous, or intraperitoneal delivery routes. Other suitable delivery routes can be used for specific diseases, such as intrathecal administration for the treatment or prevention of epidural fibrosis.

[0082] In several embodiments, pharmaceutically acceptable salts or hydrates of any of the compounds described herein are provided for use in the methods described herein. The pharmaceutically acceptable salt forms or hydrates of the compounds described herein can be prepared by conventional methods known in the pharmaceutical art for use in human or veterinary medicinal products. For example, if a compound comprises a carboxylic acid group, a suitable salt thereof may be formed by reacting the compound with a suitable base to provide a corresponding base addition salt. Examples, but not limited to, include alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethanolate and sodium propanolate; and various organic bases such as piperidine, diethanolamine, and N-methylglutamine.

[0083] Acid addition salts and base addition salts can be prepared by methods known in the art by contacting a free base form with a sufficient amount of the desired acid or base to produce a salt. The free base can be regenerated by contacting the salt form with the base or acid (depending on the properties of the salt) and isolating the free base. The free base form differs somewhat from the respective salt form in certain physical properties, such as solubility in polar solvents, but otherwise, the salt is equivalent to the respective free base form for the purposes described herein.

[0084] Compounds containing a basic nitrogen-containing group include methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides, etc. 1-4 Alkyl halides; such as dimethyl, diethyl, and diamyl sulfates. 1-4 Alkyl sulfates; such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides. 10-18 Alkyl halides; as well as aryl-C halides such as benzyl chloride and phenethyl bromide. 1-4Quaternization can be performed using agents such as alkyl halides. Such salts allow for the preparation of both water-soluble and oil-soluble compounds.

[0085] Examples of pharmaceutically acceptable base salts, not limited to these, include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, and zinc salts. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and salts of basic ion exchange resins such as arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris-(hydroxymethyl)-methylamine (tromethamine).

[0086] Acid addition salts can be prepared by treating compounds with pharmaceutically acceptable organic and inorganic acids, and include, but are not limited to, hydrohalides such as hydrochlorides, hydrobroms, and hydroiodides; other inorganic acids and their corresponding salts such as sulfates, nitrates, and phosphates; alkyl- and mono-aryl sulfons such as ethanesulfons, toluenesulfons, and benzenesulfons; and other organic acids and their corresponding salts such as acetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, and ascorbicates.

[0087] Examples of pharmaceutically acceptable salts, not limited to these, include acetate, adipine, alginate, alginate, aspartate, benzoate, besilate (benzenesulfonate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor sulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galacterate, galacturonate, glucoheptanate, gluconate, glutamate, glycerophosphate, hemico Examples include saccharates, hemisulfates, heptanoates, hexanoates, hippurates, hydrochlorides, hydrobroms, hydroiodides, 2-hydroxyethanesulfonates, iodides, isethionates, isobutyrates, lactates, lactobionates, malates, maleates, malons, mandelates, metaphosphates, methanesulfonates, methylbenzoates, monohydrogen phosphates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, oleates, pamoates, pectinates, persulfates, phenylacetates, 3-phenylpropionates, phosphates, phosphonates, and phthalates.

[0088] Multiple salt forms are also considered pharmaceutically acceptable salts. Common, unspecified examples of multiple salt forms include bicarbonate tartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium, and trihydrochloride. Hydrates and esters of the described compounds can also be prepared by known methods.

[0089] When used herein, for example in structure, unless otherwise specified, all compounds and / or structures described herein comprise all possible individual stereoisomers or mixtures thereof. These compounds and / or structures may be enantiomerically pure preparations essentially consisting of (-) or (+) enantiomers of the compound, or they may be mixtures of enantiomers in equal (racemic) or unequal proportions.

[0090] Therapeutic / pharmaceutical compositions are prepared according to acceptable pharmaceutical procedures. Any of the compounds described herein may be incorporated into a composition suitable for use in a pharmaceutical dosage form or other pharmaceutical product in which the compound is the active ingredient, or may be manufactured by other means. For example, pharmaceutical products described herein include oral tablets, capsules, caplets, liquid-filled capsules, or gel-filled capsules. Compositions may comprise pharmaceutically acceptable carriers or excipients. Excipients are inert substances used as carriers for the active ingredients of a pharmaceutical product. Although “inert” excipients, they can promote and assist in increasing the delivery, stability, or bioavailability of the active ingredient in a pharmaceutical product. Not limited examples of useful excipients available in the pharmaceutical / compounding technology field include antifouling agents, binders, rheological modifiers, coatings, disintegrants, emulsifiers, oils, buffers, salts, acids, bases, fillers, diluents, solvents, fragrances, colorants, flow enhancers, lubricants, preservatives, antioxidants, adsorbents, vitamins, and sweeteners.

[0091] Structure(I): [ka] (In the formula, A is a (C5-C7)(hetero)aryl ring and / or phenyl bioequivalent; X is a (C1-C7) divalent (hetero)alkyl; Y is either a methylene (-CH2-) or dimethylene (-CH2-CH2-) molecule forming a five-membered or six-membered ring with 0, 1, or 2 double bonds, or is absent; R1 is (C1-C7)(hetero)alkyl, (C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)aryl, (C1-C6)(hetero)alkoxyl, (C3-C7)(hetero)aryl-oxyl, or (hetero)aryl. Here, A, X, or Y are independently optionally substituted with one or more (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo groups. A compound or a pharmaceutically acceptable salt thereof is provided.

[0092] The compound has structure (II): [ka] (In the formula, B is [ka] (wherein R2 is a C5-C7 (hetero)aryl ring, or a bicyclic heteroaryl group comprising a thiophene ring or thiopyran ring and a (C5-C7)aryl ring, for example, a benzothiophenyl moiety or a benzothiopyranyl moiety); X is a (C1-C7) divalent (hetero)alkyl; R1 is a (C1-C7)(hetero)alkyl, (C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)aryl, (C1-C6)(hetero)alkoxyl, (C3-C7)(hetero)aryl-oxyl, halo, or any of the above bioequivalents; B or X is independently, optionally, substituted with one or more (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)(hetero)aryl-oxyl, (C3-C7)(hetero)aryl-amino, (C3-C7)(hetero)aryl-cyano, (C3-C7)(hetero)aryl-nitro, or (C3-C7)(hetero)aryl-halo groups (excluding X, halo, or any of the aforementioned bioequivalents). It has or is a pharmaceutically acceptable salt thereof.

[0093] The compound has the following structure: [ka] (In the formula, R3 is one or more of the following: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, or halo group.) It has or is a pharmaceutically acceptable salt thereof.

[0094] The compound has the following structure: [ka] It has or is a pharmaceutically acceptable salt thereof.

[0095] In the examples, in structures (I) and (II), X may be substituted with one or two methyl groups. In either of the above, R1 may be methyl. In one example, in structure (II), R1 may be methyl and R2 may be o-methylphenyl.

[0096] The compound has the following structure: [ka] It has or is a pharmaceutically acceptable salt thereof.

[0097] The compound has the following structure: [ka] (wherein R1 is ethyl, cyclopropyl, n-propyl, isopropyl, or t-butyl) It has or is a pharmaceutically acceptable salt thereof.

[0098] The compound has the following structure: [ka] It has or is a pharmaceutically acceptable salt thereof.

[0099] The compound has the following structure: [ka] (In the formula, R4 is one or more of H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo group, and R5 is (C1-C7)(hetero)alkyl or (C1-C7)(hetero) )Alkyl(hetero)aryl groups, possibly their bioequivalents, or substituted with one or more of the following: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo groups. It has or is a pharmaceutically acceptable salt thereof. The compound has the structure: [ka] Having a mixture thereof, and / or a pharmaceutically acceptable salt thereof, or structure: [ka] or a mixture thereof, and / or a pharmaceutically acceptable salt thereof.

[0100] A composition is provided comprising any of the aforementioned compounds and a pharmaceutically acceptable excipient. The composition has the following structure: [ka] It may contain a compound or a pharmaceutically acceptable salt thereof having the property.

[0101] This specification provides a method for treating renal impairment in a patient, where the renal impairment is caused by any disease or disorder, for example, a method of administering to the patient an effective amount of one of the compounds described herein, which is administered in an effective amount to treat the patient's renal impairment. This impairment may be acute kidney injury, and may or may not be related to trauma, but may also be chronic kidney disease; reduced blood flow to the kidneys (e.g., due to blood or drug-induced kidney injury); loss of blood or fluids; use of blood pressure medications; heart attack; heart disease; infection; liver failure; sepsis; use of NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, or naproxen sodium; severe allergic reactions (e.g., anaphylaxis); burns; dehydration; thrombosis in the veins and arteries in and around the kidneys; kidney Cholesterol deposits blocking blood flow to the organs; glomerulonephritis; inflammation of the glomeruli; hemolytic uremic syndrome; lupus; use of drugs such as chemotherapy drugs, antibiotics, or dyes used in imaging tests; scleroderma; thrombotic thrombocytopenic purpura; toxins, including, for example, alcohol, heavy metals, or cocaine; rhabdomyolysis; tumor lysis syndrome; bladder cancer; urinary tract thrombosis; cervical cancer; colon cancer; benign prostatic hyperplasia (e.g., benign prostatic hyperplasia); kidney stones; nerve damage, including nerves supplying the bladder; or may be associated with any form of kidney disease or injury, such as prostate cancer.

[0102] Furthermore, this specification provides a method for treating fibrosis in a patient, for example, a method for administering to a patient an effective amount of the compound described herein, which is administered in an amount effective for treating the patient's fibrosis. Fibrosis may result from trauma, such as wound healing, or it may result as part of a disease or condition. Fibrosis may be pulmonary fibrosis, such as idiopathic pulmonary fibrosis. Fibrosis may be associated with, for example, but not limited to, scleroderma; rheumatoid arthritis; Crohn's disease; ulcerative colitis; myelofibrosis; systemic lupus erythematosus; cirrhosis; non-alcoholic steatohepatitis; interstitial lung disease; renal fibrosis, pancreatic fibrosis, and cardiac fibrosis; acne; and / or rosacea. [Examples]

[0103] Example 1 - Compound Synthesis and Zebrafish Assay Using the synthesis scheme shown in Figure 2, a library of compounds was prepared as shown in Figure 1.

[0104] Potential efficacy was tested essentially using a zebrafish assay as follows: Zebrafish were maintained as described (see, e.g., Cianciolo Cosentino, C., et al. (2013) Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol, 24 (6), 943-53 and Skrypnyk, NI, et al. (2016) Delayed treatment with PTBA analogs reduces postinjury renal fibrosis after kidney injury. Am J Physiol Renal Physiol, 310 (8), F705-F716), and Pitt AB wild-type embryos were used. Zebrafish larvae were given a single injection of 7 ng of gentamicin on postfertilization day 3 as described above. Prior to gentamicin injection, 3-day-old postfertilized zebrafish larvae were anesthetized with 0.2% tricaine / E3 medium (5 mM NaCl, 0.33 mM CaCl2, 0.33 mM MgSO4, and 0.17 mM KCl). A microneedle was prepared by pulling a glass capillary and aspirated with 10 ml of 7 ng / nL gentamicin solution diluted in filtered saline (Aspen Veterinary Resources, catalog no. 17861615). 1 nL of gentamicin solution was delivered to the larvae via the common cardinal vein. After injection, the larvae were incubated in 50 μg / mL penicillin / streptomycin diluted with E3 medium. The test compound was diluted with E3 medium containing 0.5% DMSO. From day 2 post-injection, the larvae were treated with either DMSO or the test compound (4 mM).

[0105] The data was analyzed for compounds that prolonged survival time, as measured by Kaplan-Meier estimates. UPHD 25 (a compound previously shown to be protective in renal impairment) was used as a positive control and was statistically significant in all survival assays.

[0106] Table A shows the preliminary hazard ratios (n=1) for the test compounds (see also Figures 3A and 3B). A hazard ratio less than 1 indicates a higher probability of zebrafish survival with the compound. A hazard ratio greater than 1 indicates a higher probability of zebrafish death with the compound. Thus, compounds 207 and 231 were the most promising under the test conditions. Due to the small sample size (n=1), compounds with high hazard ratios cannot be excluded as promising candidates. For example, the effective therapeutic range may differ depending on the specific compound.

[0107] [Table 1]

[0108] Based on the results shown in Table A, additional compounds based on compounds UPHH-207 and UPHH-231 can be formulated essentially as shown in Figure 2. These compounds are shown in Figures 4A and 4B.

[0109] Additional derivatives having a pendant methyl group (a branched alkylene group for X in formula (I)) and / or a benzothiophene group can be synthesized as shown in Figures 2 and 5.

[0110] Prtt AB wild-type zebrafish embryos were used. A single injection of 7 ng of gentamicin was administered to zebrafish larvae on day 3 postfertilization. Prior to gentamicin injection, day 3 postfertilization zebrafish larvae were anesthetized with 0.2% tricaine / E3 medium (5 mM NaCl, 0.33 mM CaCl2, 0.33 mM MgSO4, and 0.17 mM KCl). A microneedle was prepared by pulling a glass capillary and aspirated with 10 μL of 7 ng / nL gentamicin solution diluted in filtered saline (Aspen Veterinary Resources, catalog no. 17861615). 1 nL of gentamicin solution was delivered to the larva via the common main vein. After injection, the larvae were incubated in 50 μg / mL penicillin / streptomycin diluted with E3 medium. The test compound was diluted with E3 medium containing 0.5% DMSO. From the second day after injection, the larvae were treated with DMSO, UPHD25, or UPHH207 (4 μM).

[0111] When assayed 5–11 days post-fertilization, both the control (UPHD25) and the test compound (UPHH207) showed increased larval survival rates compared to injured, untreated controls.

[0112] In addition to the hazard ratios described above, Kaplan-Meier curves were constructed for zebrafish treated with 4 μM of compound UPHH-207, essentially as shown above. Figure 6 shows that the efficacy of UPHH 207 is essentially equivalent to that of UPHD 25.

[0113] The effect of compound 207 on hemin injections for kidney organoids.: Injury, inflammation, and fibrosis. Organoid assay. iPSCs were maintained in 10 cm cell culture dishes coated with Geltrex (Thermo Fisher) and mTeSR1 (Stemcell Technologies) medium. All experiments were performed using the MANZ-2-2 iPSC strain prepared in the Davidson lab. The kidney organoid assay was performed as previously described33. Briefly, after dispase treatment, iPSC clusters were suspended in a medium consisting of TeSR-E5 (Stemcell Technologies), 0.1% ITS-X, 1% CD Lipid concentrate (Gibco), 0.25% polyvinyl alcohol, 1% penicillin / streptomycin (Gibco), and 2.5 ug / mL plasmosin. On day 3 of the assay, embryoid bodies were transferred to Stage II medium consisting of DMEM-Low Glucose, 10% KOSR (Thermo Fisher), 1% non-essential amino acids, 1% penicillin / streptomycin, 1% HEPES, 1% GlutaMAX, 0.25% polyvinyl alcohol, and 2.5 mg / mL plasmosin. Hemin was prepared with 0.1 M NaOH. On day 14, organoids were washed three times with DMEM-Low Glucose and then seeded in a protein-free medium containing hemin (1:1 ratio DMEM-Low Glucose and Hams F-12 Nutrient mixture, 1% HEPES, 1% penicillin / streptomycin (Gibco), and 2.5 ug / mL plasmosin) in a 6-well ultra-low adhesion plate. The hemin concentration was 12.5 μM. The control well contained the same volume of 0.1 M NaOH as a vehicle control. All treatments were maintained for 48 hours.

[0114] Hemin processing.Hemin (Millipore-Sigma) stock solution at a concentration of 10 mM was resuspended in 0.1 M NaOH, filtered and sterilized, and a fresh solution was prepared for each experiment. After washing the organoids three times with DMEM-Low Glucose on day 14, the hemin-containing protein-free medium (1:1 ratio DMEM-Low Glucose and Hams F-12 Nutrient mixture, 1 × HEPES (to stabilize pH), 1% penicillin / streptomycin (Gibco), and 2.5 ug / mL plasmosin) was transferred to a 6-well ultra-low adhesion (ULA) plate. The assay was then placed on a magnetic stirring plate (2mag-USA) at 120 rpm, 25% power. Unless otherwise stated, the hemin concentration was 25 μ3 M. The control wells contained the same volume of 0.1 M NaOH as a vehicle control. All treatments were maintained for 48 hours, after which the cells were washed three times with Stage II medium (DMEM - low glucose, 10% knockout serum replacement, 1% penicillin / streptomycin (Gibco), 1% Glutamax (Gibco), 1% HEPES (Gibco), 1% MEM non-essential amino acids, 0.5% polyvinyl alcohol, 2.5 ug / mL plasmosin) before compound treatment. To rule out the possibility of damage due to pH changes, the pH of the control and hemin-containing media was checked after 48 hours of incubation. The measured pH was 7.7 for the control and 7.55 for the hemin-containing medium, both within the normal range, indicating no impact on cell apoptosis.

[0115] Compound treatment. Kidney organoids (after hemin treatment) on day 16 were treated daily with the UPHD25 compound. Stage II medium (Stage II-DMSO) was prepared by adding 0.3% DMSO. First, a 2x stock solution of the compound was prepared in Stage II-DMSO, and the amount calculated as a total of 3 mL per well of a 6-well ULA plate was added to each well to create a 1x calibration solution. The plate was maintained on a magnetic stirrer at 25% power and 120 rpm until fixation on day 26.

[0116] Histochemistry and AnalysisThe kidney organoids were fixed with 4% paraformaldehyde and embedded in paraffin. Briefly, 6-μm thick sections were deparaffinized and heat-induced antigen retrieval was performed with sodium citrate pH 6.0 buffer. The primary antibodies used were as follows; HAVCR1 / KIM-1 (R&D Systems, AF1750), phosphorylated histone H2A.X (ThermoFisher, 50-194-123), HMOX-1 (Santa Cruz, sc-136960), nitrotyrosine (Novus, NB110-96877), collagen 1a1 (Abcam, ab138492). Fluorescently stained sections were imaged with a Zeiss LSM700 confocal microscope. Imaging of COL1A1 was performed with the same settings established with a hemin-free control. Analysis was performed using ImageJ by combining single-channel images into one stack, subtracting the background (rolling ball radius 50.0 pixels, sliding paraboloid), and applying a threshold. The threshold was determined based on the control for each assay and then applied to the stack. Next, the area of the threshold was measured and calculated by dividing by the DAPI threshold area value. For analysis, more than 10 individual organoid sections per condition were used and at least 3 assays were examined.

[0117] Figure 7 shows the qPCR quantification of damage markers (HAVCR1, HMOX1) and inflammatory markers (IL6, CCL2, Col1A1) in organoids damaged with 25 uM hemin and treated with different doses of UPHH207 as shown in the figure. All markers show at least one data point with a significant decrease in gene expression at either 0.05 ( * ) or 0.1 ( ** ).

[0118] Figure 8 shows antibody staining of collagen 1A1, a fibrosis marker, using Col1A1 Ab. The left panel shows an organoid image with collagen deposition. The right panel shows the quantification of the image, with each dot representing one organoid. Overall, 0.2 uM of UPHH207 significantly reduces the amount of collagen (fibrosis) compared to damage with hemin alone.

[0119] 207 exposure (ip) in mice Figures 9A and 9B show the plasma concentration-time profiles (mean ± SD) of UPHH-207 in male CD-1 mice after a single intraperitoneal administration (dose: 50 mg / kg), compared with those of the prodrugs UPHH-186 and UPHH-20.

[0120] The objective of this study was to investigate the plasma pharmacokinetics of UPHH-207 after a single intraperitoneal administration of 50 mg / kg to male CD-1 mice. A total of nine mice (n=9) were used in this study, with a plan of 3 mice per time point. The animals were administered UPHH-207 solution intraperitoneally. The formulation vehicles were 5% v / v NMP, 5% v / v Solutol HS-15, 30% v / v PEG-400, and 60% v / v saline.

[0121] Blood samples (approximately 60 μL) were collected from a set of three mice under mild isoflurane anesthesia (Surgivet®) from the posterior orbital plexus at pre-administration, 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Immediately after blood collection, plasma was collected by centrifugation at 4000 rpm, 4°C for 10 minutes, and the samples were stored at 70±10°C until bioanalysis. All samples were processed by protein precipitation for analysis and analyzed by appropriate LC-MS / MS method (plasma LLOQ = 2.00 ng / mL). Plasma pharmacokinetic parameters were estimated using the non-compartmental analysis tool of Phoenix® WinNonlin software (Ver 8.0), and the parameters are summarized as follows: Route - IP; Dose (mg / kg) - 50; T max (time)-0.08;C max (ng / mL)-73198.40; AUC last (time * ng / mL)-23360.27; and T 1 / 2 (time)-0.56.

[0122] After a single intraperitoneal administration of UPHH-207 at a dose of 50 mg / kg to male CD-1 mice, peak plasma concentrations were observed at 0.08 hours, suggesting rapid absorption. The terminal elimination plasma half-life was 0.56 hours.

[0123] In an in vivo AKI model, unilateral injury was induced, and the compound was administered once daily for 7 days. After 8 days, the uninjured contralateral kidney was removed, and renal function was evaluated at various time points using post-nephrectomy blood urea nitrogen (BUN) Figure 10 and transcutaneous glomerular filtration rate (tGFR) Figure 11. BUN showed the expected increase at 9 and 14 days post-injury, but there was no significant difference between the groups at 28 days. At 27 days post-injury, tGFR showed the expected decrease in GFR in the vehicle group compared to the nephrectomized control (Nx), while GFR increased in the 1 mg and 5 mg groups, with a significant increase at 5 mg. We also evaluated fibrosis by quantifying Sirius Red staining of collagen in kidney sections at 28 days post-injury. As expected, fibrosis was significantly increased in the vehicle group and significantly decreased in mice treated with 5 mg / kg UPHH 207.

[0124] Although the present invention has been described in terms of the above embodiments and detailed description, those skilled in the art will understand that modifications can be made within the spirit of the invention. Therefore, the above should not be considered limiting, and the scope of the invention is defined by the appended claims.

Claims

1. Structure (I): 【Chemistry 1】 (In the formula, A is a (C5-C7) (hetero)aryl ring and / or phenyl biological equivalent; X is a (C1-C7) divalent (hetero)alkyl; Y forms a five-membered or six-membered ring having 0, 1, or 2 double bonds, methylene (-CH ２ -) or dimethylene (-CH ２ -CH ２ -) or not present; R １ These are (C1-C7)(hetero)alkyl, (C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)aryl, (C1-C6)(hetero)alkoxyl, (C3-C7)(hetero)aryl-oxyl, or (hetero)aryl. Here, A, X, or Y are independently, optionally, substituted with one or more (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C3) alkyl-(C3-C7) cycloalkyl, (C1-C3) alkyl-(C3-C7) aryl, (C1-C6) alkoxyl, (C3-C7) (hetero)aryl-oxyl, (C3-C7) (hetero)aryl-amino, (C3-C7) (hetero)aryl-cyano, (C3-C7) (hetero)aryl-nitro, or (C3-C7) (hetero)aryl-halo groups. A compound or a pharmaceutically acceptable salt thereof having [a certain characteristic].

2. Structure (II): 【Chemistry 2】 (In the formula, B is, 【Transformation 3】 (In the formula, R ２ (This refers to a C5-C7 (hetero)aryl ring, or a bicyclic heteroaryl group comprising a thiophene ring or thiopyran ring and a (C5-C7)aryl ring, for example, a benzothiophenyl moiety or a benzothiopyranyl moiety; X is a (C1-C7) divalent (hetero)alkyl; R １ is a (C1-C7)(hetero)alkyl, (C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)(hetero)cycloalkyl, (C1-C3)(hetero)alkyl-(C3-C7)aryl, (C1-C6)(hetero)alkoxyl, (C3-C7)(hetero)aryl-oxyl, halo, or any biological equivalent thereof; B or X is independently, optionally, substituted with one or more (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C3) alkyl-(C3-C7) cycloalkyl, (C1-C3) alkyl-(C3-C7) aryl, (C1-C6) alkoxyl, (C3-C7) (hetero)aryl-oxyl, (C3-C7) (hetero)aryl-amino, (C3-C7) (hetero)aryl-cyano, (C3-C7) (hetero)aryl-nitro, or (C3-C7) (hetero)aryl-halo groups (excluding X, halo, or any of the aforementioned bioequivalents). A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

3. The compound according to claim 2, wherein the bicyclic heteroaryl group comprises a thiophene ring or a thiopyran ring and a (C5-C7)aryl ring.

4. The compound according to claim 3, wherein the bicyclic heteroaryl group is a benzothiophenyl moiety or a benzothiopyranyl moiety.

5. B 【Chemistry 4】 The compound according to claim 4.

6. B 【Transformation 5】 The compound according to claim 2.

7. R ２ The compound according to claim 6, wherein the compound is phenyl and optionally substituted with one or more of the following groups: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo, or is a biological equivalent of any of the above.

8. The compound according to any one of claims 2 to 7, wherein X is alkyl.

9. The compound according to claim 1, wherein Y is absent.

10. structure: 【Transformation 6】 (In the formula, R ３ (This is one or more of the following: (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C3) alkyl-(C3-C7) cycloalkyl, (C1-C3) alkyl-(C3-C7) aryl, (C1-C6) alkoxyl, (C3-C7) aryl-oxyl, (C3-C7) aryl-amino, (C3-C7) aryl-cyano, (C3-C7) aryl-nitro, or (C3-C7) aryl-halo group) A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

11. structure: 【Transformation 7】 A compound of claim 1 or a pharmaceutically acceptable salt thereof having the above.

12. R １ The compound according to any one of claims 1 to 11, wherein R is methyl.

13. structure: 【Transformation 8】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

14. structure: 【Chemistry 9】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

15. structure: 【Chemistry 10】 (In the formula, R １ (These are ethyl, cyclopropyl, n-propyl, isopropyl, or t-butyl.) A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

16. structure: 【Chemistry 11】 (In the formula, R １ (These are ethyl, cyclopropyl, n-propyl, isopropyl, or t-butyl.) The compound according to claim 1, having the following characteristics.

17. The compound according to claim 1 or 2, wherein X is substituted with one or two methyl groups.

18. R １ is methyl, R ２ The compound according to claim 17, wherein is o-methylphenyl.

19. structure: 【Chemistry 12】 (In the formula, R ４ is one or more of H, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo group, and R ５ (These are) (C1-C7) (hetero)alkyl or (C1-C7) (hetero)alkyl (hetero)aryl, possibly their bioequivalents, or substituted with one or more of the following: (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)cycloalkyl, (C1-C3)alkyl-(C3-C7)aryl, (C1-C6)alkoxyl, (C3-C7)aryl-oxyl, (C3-C7)aryl-amino, (C3-C7)aryl-cyano, (C3-C7)aryl-nitro, or (C3-C7)aryl-halo groups. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

20. R ５ The compound according to claim 19, wherein is methylphenyl.

21. R ４ The compound according to claim 19 or 20, wherein one or more of are H or methyl.

22. structure: 【Chemistry 13】 A compound according to claim 19 and / or a pharmaceutically acceptable salt thereof, comprising a mixture thereof.

23. R ４ The compound according to claim 22, wherein is H.

24. structure: 【Chemistry 14】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the above.

25. A composition comprising a compound according to any one of claims 1 to 24 and a pharmaceutically acceptable excipient.

26. structure: 【Chemistry 15】 Compounds having or pharmaceutically acceptable salts thereof; or 【Chemistry 16】 Compounds containing or pharmaceutically acceptable salts thereof The composition according to claim 25, comprising the following:

27. A method for treating renal impairment in a patient, comprising administering to the patient an amount effective for treating renal impairment of a compound described in any one of claims 1 to 24.

28. The method according to claim 27, wherein the kidney injury is acute kidney injury.

29. The method according to claim 27, wherein the renal impairment is related to the patient's trauma.

30. The aforementioned kidney damage may be due to: chronic kidney disease; reduced blood flow to the kidneys (e.g., due to blood or drug-induced kidney injury); loss of blood or body fluids; use of blood pressure medications; heart attack; heart disease; infection; liver failure; sepsis; use of NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, or naproxen sodium; severe allergic reactions (e.g., anaphylaxis); burns; dehydration; thrombosis in the veins and arteries within and around the kidneys; or cholesterol blocking blood flow to the kidneys. The method according to claim 27, relating to: uric acid deposition; glomerulonephritis; glomerular inflammation; hemolytic uremic syndrome; lupus; use of drugs such as chemotherapy drugs, antibiotics, or dyes used in imaging tests; scleroderma; thrombotic thrombocytopenic purpura; toxins, such as alcohol, heavy metals, or cocaine; rhabdomyolysis; tumor lysis syndrome; bladder cancer; urinary tract thrombosis; cervical cancer; colon cancer; benign prostatic hyperplasia (e.g., benign prostatic hyperplasia); kidney stones; nerve damage, including nerves supplying the bladder; or prostate cancer.

31. A method for treating fibrosis in a patient, comprising administering to the patient a compound according to any one of claims 1 to 24 in an amount and dosage regimen effective for treating fibrosis.

32. The method according to claim 31, wherein the fibrosis is a pulmonary fibrosis such as idiopathic pulmonary fibrosis.

33. The aforementioned fibrosis includes scleroderma; rheumatoid arthritis; Crohn's disease; The method according to claim 31, relating to ulcerative colitis; myelofibrosis; systemic lupus erythematosus; cirrhosis; non-alcoholic steatohepatitis; interstitial lung disease; acne; rosacea; renal fibrosis, pancreatic fibrosis, or cardiac fibrosis.

Images