Aldose reductase inhibitors and methods of use thereof

Abstract

To provide novel compounds and pharmaceutical compositions thereof for promoting healthy aging of skin, the treatment of skin disorders, the treatment of cardiovascular disorders, the treatment of renal disorders, the treatment of angiogenesis disorders, such as cancer, the treatment of tissue damage, such as non-cardiac tissue damage, the treatment of evolving myocardial infarction, the treatment of ischemic injury, and the treatment of various other disorders, such as complications arising from diabetes, with the compounds and compositions of the invention.SOLUTION: For example, the compound in the figure is demonstrated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 352,784, filed June 21, 2016, the entire contents of which are incorporated herein by reference in their entirety.

[0002] All patents, patent applications, and publications cited herein are incorporated by reference in their entirety, and the disclosures of these publications in their entireties are incorporated by reference into this application in order to more fully describe the state of the art known to those skilled in the art as of the date of the invention described and claimed herein.

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure, as it appears in the U.S. Patent and Trademark Office patent files or records, but otherwise reserves all copyright rights whatsoever.

[0004] FIELD OF THE INVENTION The present invention relates to novel compounds and pharmaceutical compositions thereof, and methods for promoting healthy aging of the skin, treating skin disorders, treating cardiovascular disorders, treating renal disorders, treating angiogenic disorders such as cancer, treating tissue damage such as non-cardiac tissue damage, treating progressive myocardial infarction, treating ischemic injury, and treating various other disorders such as complications resulting from diabetes, which may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, skin infections, peripheral vascular disease, stroke, asthma, and the like, with the compounds and compositions of the present invention. [Background technology]

[0005] Background of the Invention Diabetes is one of the most common chronic disorders, resulting from high blood glucose levels and a lack of insulin production and / or insulin sensitivity. Individuals with hyperglycemia metabolize more glucose through the glucose-sorbitol-fructose pathway in insulin-insensitive cells, such as the lens, peripheral nerves, and glomeruli. This results in excess sorbitol in the cells, which does not readily diffuse through the cell membrane. The increased sorbitol concentration causes water influx into the cells, causing swelling and potential damage.

[0006] Aldose reductase (AR) is a monomeric NADPH-dependent oxidoreductase enzyme in the aldo-keto reductase family. It is present in many parts of the body. It catalyzes the reduction of saturated and unsaturated aldehydes, including aldo sugars and monosaccharides, as well as a wide range of other substrates. Primarily, aldose reductase catalyzes the reduction of glucose to sorbitol, a step in the sorbitol pathway responsible for the formation of fructose from glucose. Aldose reductase activity increases as glucose concentrations rise in diabetic tissues lacking insulin sensitivity. These tissues include the lens, peripheral nerves, and glomeruli of the kidney. Sorbitol cannot readily diffuse through cell membranes and therefore accumulates, causing osmotic damage, which in turn leads to retinopathy, neuropathy, nephropathy, and cardiomyopathy. The mechanism of injury also results from increased oxidative stress and damage, as well as increased levels of advanced glycation end products. Therefore, inhibition of aldose reductase prevents the accumulation of sorbitol in insulin-insensitive cells in diabetes and represents a novel approach to prevent macrovascular and microvascular complications in diabetic patients. Additionally, aldose reductase inhibitors such as zopolrestat can help treat or ameliorate such effects and have shown efficacy in corneal epithelial wound healing in diabetic animal models. Finally, AR has recently been implicated in a wide range of therapeutic areas, including cancer, myocardial infarction and ischemic injury, asthma, and transplantation.

[0007] Previous clinical trials have shown that aldose reductase inhibitors are well tolerated by patients, but are minimally effective in combating disease. These shortcomings are due to the insufficient activity and short half-life of current aldose reductase inhibitors, which reduces their effectiveness. In addition, some aldose reductase inhibitors are toxic. Therefore, there is a need for new aldose reductase inhibitor compounds. Summary of the Invention

[0008] overview Unless otherwise indicated in the context, it will be understood that any of the embodiments described below can be combined in any desired manner, and that any embodiment or combination of embodiments can be applied to each of the aspects described below.

[0009] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025124733000001.tif28128 formula, R 1 is CO2R 2 or CO2 - X + and; R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, or (C1-C6)-aminoalkyl; X 1 is H or a halogen; X 2 is H or a halogen; Y is a bond, C═O, C═S, C═NH, or C═N(C1-C4)-alkyl; Z is TIFF2025124733000002.tif27128; A 1 is NR 7 , O, S or CH2; A 2 is N or CH; A3 is NR 7 , O, or S; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; and X + is the counterion.

[0010] In some embodiments, R 2 is hydrogen or (C1-C6)-alkyl; Y is C=O; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; and R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; or a pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, R 2 is hydrogen or tert-butyl; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, Z is TIFF2025124733000003.tif24128.

[0013] In some embodiments, R 2 is hydrogen or (C1-C6)-alkyl; Y is C=O; A 1 is NR 7 , O, or S; A 2 is N; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0014] In some embodiments, R 2 is hydrogen or tert-butyl; Y is C=O; A 1 is NR 7 , O or S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0015] In some embodiments, R 2 is hydrogen or tert-butyl; Y is C=O; A 1 is NR 7 , O or S; A 2 is N; R 3 ~R 6 are independently hydrogen, halogen, or CF3; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; A 1 is S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0017] In some embodiments, R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; A 1 is S; A 2 is N; R 3 , R 5 , and R6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, the compound of formula (I) has the formula TIFF2025124733000004.tif27128; or a pharmaceutically acceptable salt or solvate thereof.

[0019] In some embodiments, R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 1 is S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 1 is S; A 2 is N; R 3 , R 5 , and R 6 is hydrogen; R4 is hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0021] In some embodiments, the compound of formula (I) has the formula TIFF2025124733000005.tif27128; or a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, Z is TIFF2025124733000006.tif24128.

[0023] In some embodiments, R 2 is hydrogen or (C1-C6)-alkyl; Y is C=O; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, R 2 is hydrogen or tert-butyl; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0025] In some embodiments, R 2 is hydrogen or tert-butyl; Y is C=O; R 3 ~R 6 are independently hydrogen or halogen; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0026] In some embodiments, R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0027] In some embodiments, R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen or halogen; and R 7is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0028] In some embodiments, the compound of formula (I) has the formula TIFF2025124733000007.tif35146; or a pharmaceutically acceptable salt or solvate thereof.

[0029] In some embodiments, R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0030] In some embodiments, R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 3 is NR 7 , O or S; and R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen or halogen; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0031] In some embodiments, the compound of formula (I) is TIFF2025124733000008.tif127158.

[0032] In some embodiments, the counterion is selected from the group consisting of sodium, lithium, potassium, calcium, magnesium, zinc, ammonium, and tetrafluoroborate.

[0033] In some embodiments, the counterion is TIFF2025124733000009.tif46161.

[0034] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0035] In another aspect, the present invention provides a method of inhibiting aldose reductase activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0036] In some embodiments, the subject has diabetes.

[0037] In some embodiments, the subject is a human.

[0038] In another aspect, the present invention provides a method of treating a disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

[0039] In some embodiments, the disorder is atherosclerosis.

[0040] In some embodiments, the disorder is diabetic nephropathy.

[0041] In some embodiments, the disorder is diabetic neuropathy.

[0042] In some embodiments, the disorder is diabetic retinopathy.

[0043] In some embodiments, the disorder is cardiovascular disease.

[0044] In some embodiments, the disorder is peripheral vascular disease.

[0045] In some embodiments, the disorder is an angiogenic disorder.

[0046] In some embodiments, the disorder is tissue damage.

[0047] In some embodiments, the disorder is diabetic cardiomyopathy.

[0048] In another aspect, the present invention provides a method for treating skin disorders or promoting healthy aging of the skin, comprising applying to a dermal substrate to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0049] In some embodiments, the skin substrate is human skin.

[0050] In another aspect, the present invention provides a method of treating a subject having progressing myocardial infarction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

[0051] The present invention is based, in part, on certain discoveries that are more fully described in the Examples section of this application, for example, the present invention is based, in part, on the discovery of compounds of formula (I) and the aldose reductase inhibition exhibited by such compounds.

[0052] [The present invention 1001] A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: TIFF2025124733000010.tif28128In formula, R 1 CO2R 2 or CO2 - X + and; R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, or (C1-C6)-aminoalkyl; X 1 is H or a halogen; X 2 is H or a halogen; Y is a bond, C═O, C═S, C═NH, or C═N(C1-C4)-alkyl; Z, TIFF2025124733000011.tif27128; A 1 NR 7 , O, S or CH2; A 2 is N or CH; A 3 NR 7 , O, or S; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; and X + is the counter ion. [The present invention 1002] R 2 is hydrogen or (C1-C6)-alkyl; Y is C=O; A 1 NR 7 , O, or S; A 2 is N; A 3 is O or S; and R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl, The compound of the present invention 1001 or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1003] R 2 is hydrogen or tert-butyl; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; The compound of the present invention 1002 or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1004] Z, Any of compounds 1001 to 1003 of the present invention, which is TIFF2025124733000012.tif24128. [The present invention 1005] R 2 is hydrogen or (C1-C6)-alkyl; Y is C=O; A 1 NR 7 , O, or S; A 2 is N; R 3 ~R 6are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; The compound of any one of the present invention 1001 to 1004 or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1006] R 2 is hydrogen or tert-butyl; Y is C=O; A 1 NR 7 , O or S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any of the compounds 1001 to 1005 of the present invention or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1007] R 2 is hydrogen or tert-butyl; Y is C=O; A 1 NR 7 , O or S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or CF3; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; The compound of any one of the present inventions 1001 to 1006, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1008] R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; A 1 is S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; The compound of any one of the present inventions 1001 to 1006, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1009] R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; A 1 is S; A 2 is N; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any one of the compounds 1001 to 1008 of the present invention or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1010] formula The compound of the present invention 1001, represented by TIFF2025124733000013.tif27128, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1011] R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 1 is S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; The compound of any one of the present inventions 1001 to 1006, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1012] R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 1 is S; A 2 is N; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; The present invention relates to any one of compounds 1001 to 1007 and 1011, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1013] formula The compound of the present invention 1001 represented by TIFF2025124733000014.tif27128 or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1014] Z, Any of compounds 1001 to 1003 of the present invention, which is TIFF2025124733000015.tif24128. [The present invention 1015] R 2 is hydrogen or (C1-C6)-alkyl; Y is C=O; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; The present invention relates to any one of compounds 1001 to 1003 and 1014, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1016] R 2 is hydrogen or tert-butyl; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any one of compounds 1001 to 1003 and 1014 to 1015 of the present invention, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1017] R 2 is hydrogen or tert-butyl; Y is C=O; R 3 ~R 6 are independently hydrogen or halogen; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any one of the compounds 1001 to 1003 and 1014 to 1016 of the present invention, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1018] R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any one of the compounds 1001 to 1003 and 1014 to 1016 of the present invention, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1019] R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen or halogen; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any one of the compounds 1001 to 1003 and 1014 to 1018 of the present invention, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1020] formula The compound of the present invention 1001, represented by TIFF2025124733000016.tif37147, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1021] R 2 is hydrogen; X1 is Cl; X 2 is Cl; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; Any one of the compounds 1001 to 1003 and 1014 to 1016 of the present invention, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1022] R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 3 NR 7 , O or S; and R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen or halogen; and R 7 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; The present invention relates to any one of compounds 1001 to 1003, 1014 to 1017, and 1021, or a pharmaceutically acceptable salt or solvate thereof. [The present invention 1023] 1001. A compound of the present invention selected from the group consisting of TIFF2025124733000017.tif128159. [The present invention 1024] The compound of any one of claims 1001 to 1023, wherein the counter ion is selected from the group consisting of sodium, lithium, potassium, calcium, magnesium, zinc, ammonium, and tetrafluoroborate. [The present invention 1025] The counter ion is Any of compounds 1001 to 1023 of the present invention selected from the group consisting of TIFF2025124733000018.tif47161. [The present invention 1026] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1025 and a pharmaceutically acceptable carrier. [The present invention 1027] A method for inhibiting aldose reductase activity in a subject, comprising the step of administering to a subject in need thereof a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1025. [The present invention 1028] The method of claim 1027, wherein the subject has diabetes. [The present invention 1029] The method of any one of claims 1027 to 1028, wherein the subject is a human. [The present invention 1030] A method for treating a disorder in a subject, comprising the step of administering to a subject in need thereof a therapeutically effective amount of any of the compounds of the present invention 1001-1025. [The present invention 1031] The method of claim 1030, wherein the disorder is atherosclerosis. [The present invention 1032] The method of claim 1030, wherein the disorder is diabetic nephropathy. [The present invention 1033] The method of claim 1030, wherein the disorder is diabetic neuropathy. [The present invention 1034] The method of claim 1030, wherein the disorder is diabetic retinopathy. [This invention 1035] The method of claim 1030, wherein the disorder is a cardiovascular disease. [The present invention 1036] The method of claim 1030, wherein the disorder is peripheral vascular disease. [This invention 1037] The method of claim 1030, wherein the disorder is an angiogenic disorder. [The present invention 1038] The method of claim 1030, wherein the injury is tissue damage. [This invention 1039] The method of claim 1030, wherein the disorder is diabetic cardiomyopathy. [The present invention 1040] A method for treating skin disorders or promoting healthy aging of the skin, comprising the step of applying a therapeutically effective amount of any of the compounds of inventions 1001 to 1025 or the composition of invention 1026 to a dermal substrate of a subject in need thereof. [The present invention 1041] The method of claim 1040, wherein the skin substrate is human skin. [The present invention 1042] A method for treating a subject having a progressing myocardial infarction, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds of the present inventions 1001 to 1025 or the composition of the present invention 1026. These and other aspects of the present invention are further described in the following sections of this application, including the detailed description, examples, and appended claims. Still other objects and advantages of the present invention will be apparent to those skilled in the art from the disclosures herein, which are merely illustrative and not limiting. Accordingly, other embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0053] Detailed Description Aldose reductase inhibitors are described, for example, in U.S. Pat. Nos. 8,916,563; 5,677,342; 5,304,557; 5,155,259; 4,954,629; 4,939,140; U.S. Patent Application Publication No. US 2006 / 0293265; Roy et al., Diabetes Research and Clinical Practice 1990, 10(1), 91-97; CN101143868A; and Chatzopoulou et al., Expert Opin. Ther. Pat. 2012, 22, 1303; and references cited therein; each of which is incorporated herein by reference in its entirety. Aldose reductase inhibitors include, for example, zopolrestat, epalrestat, ranirestat, berberine and sorbinil.A new family of aldose reductase inhibitors has been discovered and is described herein.Surprisingly, this new family comprises compounds that show dramatically improved properties, such as binding affinity, solubility and polarity, compared with other aldose reductase inhibitors, such as zopolrestat.Compounds such as zopolrestat are described in, for example, U.S. Patent No. 4,939,140; U.S. Patent No. 6,159,976; and U.S. Patent No. 6,570,013; each of which is incorporated herein by reference in its entirety.

[0054] The compounds and / or compositions of the present invention may be effective in treating, reducing, and / or inhibiting complications associated with aldose reductase activity, such as atherosclerosis, neuropathy, retinopathy, nephropathy, cardiomyopathy, and many other complications in diabetic patients. The compounds and / or compositions of the present invention may also be effective in treating, reducing, and / or inhibiting cardiovascular and nephropathy in non-diabetic patients, as well as promoting healthy aging of the skin or wound healing. Treatments using aldose reductase inhibitors are described, for example, in CN102512407A; WO2008002678A2; CN101143868A; Srivastava et al., Chem Biol Interact. 2011, 30, 330; Hu et al., PLoS One 2014, 9(2), e87096; Satoh et al., J Diabetes Res. 2016, 2016, 5383797; Chatzopoulou et al., Expert Opin. Ther. Pat. 2012, 22, 1303; each of which is incorporated herein by reference in its entirety.

[0055] Abbreviations and Definitions The term " aldose reductase inhibitor " refers to compounds and their salts or solvates that function by inhibiting the enzyme activity of aldose reductase, which is mainly responsible for the regulation of metabolic reduction of aldose.Exemplary aldoses include, but are not limited to, glucose or galactose, and their corresponding polyols, such as sorbitol and galactitol.Exemplary aldose reductase inhibitors can be found in U.S. Patent No. 8,916,563; U.S. Patent No. 5,677,342; U.S. Patent No. 5,304,557; U.S. Patent No. 5,155,259; U.S. Patent No. 4,954,629; U.S. Patent No. 4,939,140; U.S. Patent Application Publication No. US 2006 / 0293265; and Roy et al., Diabetes Research and Clinical Practice 1990, 10(1), 91-97; each of which is incorporated herein by reference in its entirety.

[0056] The term "compounds of the invention," as used herein, means compounds of Formula (I). This term is also intended to encompass salts, hydrates, prodrugs, and solvates thereof.

[0057] The term "composition of the present invention" as used herein means a composition comprising a compound of the present invention, and its salts, hydrates, prodrugs, or solvates. The composition of the present invention may further comprise other agents, such as excipients, stabilizers, lubricants, solvents, etc.

[0058] The term "alkyl," as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon radical having straight-chain, branched-chain, monocyclic, or polycyclic moieties, or combinations thereof, which radical is optionally substituted on one or more carbons of the straight-chain, branched-chain, monocyclic, or polycyclic moiety, or combinations thereof, and has one or more substituents on each carbon, the one or more substituents being independently C1 to C6. 10 Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0059] The term "solvate" as used herein means a compound or a pharmaceutically acceptable salt thereof, in which molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is physiologically acceptable at the administered dosage. Examples of suitable solvents include ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate."

[0060] The term "pharmaceutically acceptable salts" is intended to include salts derived from inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, phosphoric acid, formic acid, acetic acid, lactic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, glycolic acid, salicylic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, benzoic acid, malonic acid, trifluoroacetic acid, trichloroacetic acid, naphthalene-2 ​​sulfonic acid, and other acids; and salts derived from inorganic or organic bases, such as sodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine, histidine, polyhydroxylated amines, or tetrafluoroborate. Exemplary pharmaceutically acceptable salts are found, for example, in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and U.S. Pat. Nos. 6,570,013 and 4,939,140; each incorporated herein by reference in its entirety. Pharmaceutically acceptable salts are also intended to encompass hemisalts, where the ratio of compound to acid is 2:1, respectively. Exemplary hemisalts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. Other exemplary hemisalts are those derived from dibasic mineral acids, such as sulfuric acid. Exemplary preferred hemisalts include, but are not limited to, hemimaleates, hemifumarates, and hemisuccinates.

[0061] The term "acid" refers to any pharmaceutically acceptable inorganic or organic acid. Inorganic acids include mineral acids such as hydrohalic acids, e.g., hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic, and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids, and fatty acids. Preferred acids are linear or branched, saturated or unsaturated C1-C20 aliphatic carboxylic acids or C6-C12 aromatic carboxylic acids, optionally substituted with a halogen or hydroxyl group. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids, e.g., glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid, and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid, and lactobionic acid.

[0062] As used herein, the term "about" is used herein to mean approximately, in the region of, in the vicinity of, or near. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (high or low).

[0063] An "effective amount," "sufficient amount," or "therapeutically effective amount," as used herein, is an amount of a compound that is sufficient to produce a beneficial or desired result, including a clinical result. Thus, an effective amount may be sufficient, for example, to reduce or ameliorate the severity and / or duration of an aldose reductase-associated affliction, or one or more symptoms thereof, to prevent the progression of a condition or symptom associated with an aldose reductase-associated affliction, or to enhance or otherwise improve the prophylactic or therapeutic efficacy of another therapy. An effective amount also includes an amount of a compound that avoids or substantially attenuates undesirable side effects.

[0064] As used herein and as is well understood in the art, "treatment" refers to an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, the alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, a decrease in the severity of a disease or condition, a stabilized (i.e., non-worsening) state of a disease or condition, prevention of the spread of a disease or condition, a delay or slowing of the progression of a disease or condition, an improvement or alleviation of a disease or condition, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival compared to the survival expected in the absence of treatment.

[0065] The phrase "in need thereof" refers to a need for symptomatic or asymptomatic relief from a condition associated with aldose reductase activity or that may otherwise be alleviated by the compounds and / or compositions of the present invention.

[0066] In one aspect, the aldose reductase inhibitors described herein include compounds of formula (I): TIFF2025124733000019.tif28128In formula, R 1 is CO2R 2 or CO2 - X+ and; R 2 is H, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, or (C1-C6)-aminoalkyl; X 1 is H or a halogen; X 2 is H or a halogen; Y is a bond, C═O, C═S, C═NH, or C═N(C1-C4)-alkyl; Z is TIFF2025124733000020.tif27128; A 1 is NR 7 , O, S or CH2; A 2 is N or CH; A 3 is NR 7 , O, or S; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl; and X + is the counterion.

[0067] By those skilled in the art, Z is TIFF2025124733000021.tif24128 or Z is The specification that it is TIFF2025124733000022.tif24128 means that Z is TIFF2025124733000023.tif24128, then the compound of formula (I) TIFF2025124733000024.tif28128; and Z is TIFF2025124733000025.tif24128, then the compound of formula (I) It will be appreciated that the term "TIFF2025124733000026.tif34143" indicates that the term "TIFF2025124733000026.tif34143" is understood to encompass the term "TIFF2025124733000026.tif34143."

[0068] In some embodiments, R 1 is CO2R 2 or CO2 - X + In some embodiments, R 1 is CO2R 2 In some embodiments, R 1 is CO2 - X + is.

[0069] In some embodiments, R 2 is hydrogen or (C1-C6)-alkyl. In some embodiments, R 2 is hydrogen or (C1-C4)-alkyl. In some embodiments, R 2 is hydrogen or (C1-C3)-alkyl. In some embodiments, R 2 is hydrogen, methyl, or ethyl. 2 is hydrogen or methyl. In some embodiments, R 2 is methyl or ethyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is (C1-C6)-alkyl. In some embodiments, R 2 is (C1-C6)-n-alkyl. In some embodiments, R 2 is (C1-C2)-alkyl. In some embodiments, R 2 is (C1-C3)-alkyl. In some embodiments, R 2 is (C1-C4)-alkyl. In some embodiments, R 2 is tert-butyl.

[0070] In some embodiments, R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl.

[0071] In some embodiments, R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl. 3 ~R 6 are independently hydrogen, halogen, or trihaloalkyl.

[0072] In some embodiments, R 3 and R 6 is hydrogen. In some embodiments, R 3 , R 5 , and R 6 is hydrogen.

[0073] In some embodiments, R 4 is hydrogen, halogen, or haloalkyl. 4 is hydrogen. In some embodiments, R 4 is halogen. In some embodiments, R 4 is haloalkyl. In some embodiments, R 4 is CF3.

[0074] In some embodiments, R 3 ~R 6 is hydrogen. In some embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen or haloalkyl. In some embodiments, R 3 , R 5 , R 6 is hydrogen and R 4is haloalkyl. In some embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is CF3. In some embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is halogen. In some embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is F. In some embodiments, R 3 , R 5 , R 6 is hydrogen and R 4 is Cl.

[0075] In some embodiments, Y is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In some embodiments, Y is C=O or C=S. In some embodiments, Y is C=O. In some embodiments, Y is C=S. In some embodiments, Y is C=NH, or C=N(C1-C4)-alkyl.

[0076] In one embodiment, A 1 is NR 7 , O, S or CH2. In some embodiments, A 1 is NR 7 , O or S. In some embodiments, A 1 is NR 7 , S or CH2. In some embodiments, A 1 is NR 7 or O. In some embodiments, A 1 is NR 7 or S. In some embodiments, A 1 is NR 7 In one embodiment, A 1 is O. In some embodiments, A 1 is S.

[0077] In one embodiment, A 2is N or CH. In some embodiments, A 2 is N. In some embodiments, A 2 is CH.

[0078] In one embodiment, A 3 is NR 7 , O, or S. In some embodiments, A 3 is O. In some embodiments, A 3 is S. In some embodiments, A 3 is NR 7 is.

[0079] In one embodiment, X 1 and X 2 is hydrogen.

[0080] In one embodiment, X 1 and X 2 is a halogen. 1 and X 2 is Cl.

[0081] In one embodiment, X 1 and X 2 is independently hydrogen or halogen. 1 is hydrogen and X 2 is Cl. In some embodiments, X 1 is Cl and X 2 is hydrogen.

[0082] In some embodiments, Z is TIFF2025124733000027.tif24128.

[0083] In some embodiments, Z is TIFF2025124733000028.tif24128.

[0084] In some embodiments, R 7 is hydrogen, C1-C4 alkyl, or C(O)O—(C1-C4)-alkyl. In some embodiments, R7 is hydrogen. In some embodiments, R 7 is C1-C4 alkyl. In some embodiments, R 7 is C1-C3 alkyl. In some embodiments, R 7 is C1-C2 alkyl. In some embodiments, R 7 is C1-C4n-alkyl. In some embodiments, R 7 is C1-C3n-alkyl. In some embodiments, R 7 is C(O)O—(C1-C4)-alkyl. In some embodiments, R 7 is C(O)O—(C1-C3)-alkyl. In some embodiments, R 7 is C(O)O—(C1-C2)-alkyl. In some embodiments, R 7 is C(O)O—(C1-C4)-n-alkyl. In some embodiments, R 7 is C(O)O—(C1-C3)-n-alkyl.

[0085] In some embodiments, R 1 is CO2R 2 and; R 2 is H or (C1-C6)-alkyl; X 1 is H; X 2 is H; Y is C=O; Z is TIFF2025124733000029.tif26128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 3 ~R 6are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0086] In some embodiments, R 1 is CO2R 2 and; R 2 is H or tert-butyl; X 1 is H; X 2 is H; Y is C=O; Z is TIFF2025124733000030.tif27128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 6 ~R 6 are independently hydrogen, halogen, haloalkyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0087] In some embodiments, R 1 is CO2R 2 and; R 2 is H or tert-butyl; X 1 is H; X 2 is H; Y is C=O; Z is TIFF2025124733000031.tif26128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0088] In some embodiments, R 1 is CO2R 2 and; R 2 is H or (C1-C6)-alkyl; X 1 is a halogen; X 2 is a halogen; Y is C=O; Z is TIFF2025124733000032.tif26128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylsulfinyl, or (C1-C4)-alkylsulfonyl; and R 7is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0089] In some embodiments, R 1 is CO2R 2 and; R 2 is H or tert-butyl; X 1 is a halogen; X 2 is a halogen; Y is C=O; Z is TIFF2025124733000033.tif27128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 3 ~R 6 are independently hydrogen, halogen, haloalkyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0090] In some embodiments, R 1 is CO2R 2 and; R 2 is H or tert-butyl; X 1 is Cl; X 2 is Cl; Y is C=O; Z is TIFF2025124733000034.tif27128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 3 ~R 6 are independently hydrogen, halogen, haloalkyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0091] In some embodiments, R 1 is CO2R 2 and; R 2 is H or tert-butyl; X 1 is Cl; X 2 is Cl; Y is C=O; Z is TIFF2025124733000035.tif27128; A 1 is NR 7 , O, or S; A 2 is N; A 3 is O or S; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl.

[0092] In some embodiments, the compound of formula (I) is TIFF2025124733000036.tif129158.

[0093] In some embodiments, the compound of formula (I) is TIFF2025124733000037.tif27128 or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound of formula (I) is TIFF2025124733000038.tif27128 or a pharmaceutically acceptable salt thereof.

[0095] In one embodiment, X + is a counterion. In some embodiments, the counterion is sodium, lithium, potassium, calcium, ammonium, or tetrafluoroborate. In some embodiments, the counterion is sodium, lithium, potassium, calcium, ammonium, or a protonated amino acid. In some embodiments, the counterion is sodium, lithium, potassium, ammonium, or a protonated amino acid. In some embodiments, the counterion is sodium or ammonium. In some embodiments, the counterion is lithium or potassium. In some embodiments, the counterion is sodium, ammonium, or an amino acid. In some embodiments, the counterion is potassium, ammonium, or an amino acid. In some embodiments, the counterion is sodium or calcium. In some embodiments, the counterion is lithium, potassium, or calcium. In some embodiments, the counterion is sodium. In some embodiments, the counterion is lithium. In some embodiments, the counterion is potassium. In some embodiments, the counterion is calcium. In some embodiments, the counterion is ammonium. In some embodiments, the counterion is tetrafluoroborate. In some embodiments, X + When is the counterion, the compound of formula (I) is highly water-soluble. It is well known in the art that highly water-soluble pharmaceutical preparations, when orally administered, result in efficient absorption of such preparations from the gastrointestinal tract into the systemic circulation. Another characteristic of such preparations is the rapid rate at which they are absorbed into the systemic circulation, which results in high concentrations of the active drug in the blood. Furthermore, water-soluble preparations are particularly suitable for parenteral administration, for example, intravenous administration.

[0096] In some embodiments, the counterion is a protonated amino acid or a protonated aminoglycoside. In some embodiments, the aminoglycoside is glucosamine, galactosamine, mannosamine, or muramic acid. In some embodiments, the aminoglycoside is glucosamine, galactosamine, or mannosamine. In some embodiments, the aminoglycoside is glucosamine or galactosamine. In some embodiments, the aminoglycoside is glucosamine. In some embodiments, the amino acid is galactosamine. In some embodiments, the amino acid is lysine, arginine, or histidine. In some embodiments, the amino acid is lysine or arginine. In some embodiments, the amino acid is lysine. In some embodiments, the amino acid is arginine.

[0097] In some embodiments, the counterion is TIFF2025124733000039.tif64140. In some embodiments, the counterion is TIFF2025124733000040.tif19128. In some embodiments, the counterion is TIFF2025124733000041.tif14128. In some embodiments, the counterion is TIFF2025124733000042.tif12128. In some embodiments, the counterion is TIFF2025124733000043.tif11128. In some embodiments, the counterion is TIFF2025124733000044.tif20128. In some embodiments, the counterion is TIFF2025124733000045.tif16128. In some embodiments, the counterion is The file is TIFF2025124733000046.tif17128.

[0098] synthesis The compounds described herein can be prepared according to known processes. Schemes 1-4 show general synthetic schemes for preparing compounds of formula (I). These schemes are illustrative and are not intended to limit the possible techniques that one skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Various modifications to these methods can be envisioned by those skilled in the art to achieve results similar to those provided by the inventors below. For example, any protecting groups can be prepared according to the methods described, for example, in Greene et al., Protective Groups in Organic Synthesis (4 th ed. 2006).

[0099] Compounds of formula (I-1) can generally be prepared, for example, according to Scheme 1: TIFF2025124733000047.tif46153, X 1 , X 2 , R 1 , A 1 , A 2 , R 2 , R 3 ~R 7 is defined as above, and Q is a halogen, such as Cl, Br, I, etc., or any other leaving group, such as OSO2Me, OMs, OTs, OTf, etc.

[0100] Compounds of formula (I-2) can generally be prepared, for example, according to Scheme 2: TIFF2025124733000048.tif48152, X 1 , X 2 , R 1 , A 1 , A 2 , R 2 , R 3 ~R 7 is defined as above, and Q is a halogen, such as Cl, Br, I, etc., or any other leaving group, such as OSO2Me, OMs, OTs, OTf, etc.

[0101] Compounds of formula (I-3) can generally be prepared, for example, according to Scheme 3: TIFF2025124733000049.tif46154, X 1 , X 2 , R 1 , A 1 , A 2 , R 2 , R 3 ~R 7 is defined as above, and Q is a halogen, such as Cl, Br, I, etc., or any other leaving group, such as OSO2Me, OMs, OTs, OTf, etc.

[0102] In certain embodiments, the reaction can be carried out in the presence of a base, such as potassium tert-butoxide, sodium hydride, sodium methoxide, sodium ethoxide, and the like.

[0103] In some embodiments, the reaction can be carried out using an aprotic solvent, such as DMF, THF, NMP, etc. In some embodiments, the reaction can be carried out using an alcohol solvent, such as methanol, ethanol, etc.

[0104] In one embodiment, the reaction can be carried out at a temperature of about 5°C to about 80°C, for example, 20°C to 30°C.

[0105] In certain embodiments, the reaction may be followed by further separation and purification steps, such as chromatography (eg, flash, HPLC, MPLC, etc.), crystallization, and the like.

[0106] Compounds of formula (I-1) can also be generally prepared according to exemplary Scheme 4. Cyclic anhydride 5 is converted to compound 6 under acidic methanolysis conditions. Activation of compound 6, followed by nucleophilic addition and decarboxylation, provides ketoester 7. Treatment of compound 7 with hydrazine affords cyclized compound 8. Compound 8 is then coupled to compound 2 under basic conditions to provide a compound of formula 9. Deprotection or hydrolysis of compound 9 provides a compound of formula 10. TIFF2025124733000050.tif132154

[0107] The compound of formula (I-2) can also be TIFF2025124733000051.tif26128 TIFF2025124733000052.tif26128. Similarly, compounds of formula (I-3) can also be prepared according to Scheme 4 by substituting TIFF2025124733000053.tif26128 It can generally be prepared according to Scheme 4 by substituting TIFF2025124733000054.tif26128.

[0108] Other suitable reactions, such as hydrolysis of compounds of formula (I), are possible to obtain different forms of compounds of formula (I-1), (I-2), or (I-3). For example, R 2 Compounds having groups such as tert-butoxy, methoxy, ethoxy, etc. as R are hydrolyzed by reaction with a suitable reagent such as trifluoroacetic acid (TFA), HCl, KOH, etc. to give R 2 Compounds of formula (I) having hydrogen as the radical can be obtained.

[0109] For example, the following exemplary synthesis can be carried out according to Scheme 5. TIFF2025124733000055.tif48138

[0110] In some other embodiments where Y is C=O, a subsequent reaction can be performed to replace the C=O with C=S or C=N, or the like.

[0111] Compound of formula (2) There are different possibilities for obtaining the compound of formula (2). The compound of formula (2) can be synthesized by a variety of different reactions, for example, a condensation reaction as shown diagrammatically in Scheme 6 below. The reaction can be carried out using a variety of solvents, for example, ethanol, methanol, DMF, AcOH, etc. The reaction can be carried out at a temperature of about 5°C to about 80°C, for example, 55°C to 65°C. TIFF2025124733000056.tif46159

[0112] Additional exemplary descriptions of the synthesis of certain compounds of formula (2) are provided in J. Med. Chem. (1991), Vol. 34, pp. 108-122; J. Med. Chem. (1992), Vol. 35, No. 3, pp. 457-465; and U.S. Pat. No. 8,916,563; each of which is incorporated herein by reference in its entirety.

[0113] Compound of formula (1) There are different possibilities for obtaining a compound of formula (1). For example, a compound of formula (1) can be synthesized as shown in Scheme 7. For example, to obtain a compound of formula (1) in which Y is C=O, a compound of formula (13) can be reacted with a reagent that causes an addition-cyclization reaction, such as hydrazine, as shown in Scheme 7. The reaction can be carried out using various solvents, such as ethanol, methanol, THF, etc. The reaction can be carried out at a temperature of about 20°C to about 100°C, for example, 60°C to 80°C. TIFF2025124733000057.tif45128

[0114] The compound of formula (13) can be obtained, for example, by reacting an anhydride with a reagent that induces a Wittig reaction, such as (tert-butoxycarbonylmethylene)-triphenylphosphorane, as shown in Scheme 8. The reaction can be carried out using an aprotic solvent, such as CHCl, THF, 1,4-dioxane, or toluene. The reaction can be carried out at a temperature of about 20°C to about 110°C, for example, 55°C to 70°C. TIFF2025124733000058.tif42128

[0115] In certain embodiments, as exemplified below (Scheme 9), the reaction of an anhydride, such as compound 15, with a reagent that effects a Wittig reaction can result in a mixture of specific compounds represented by 16 and 17. In such cases, the mixture can be separated and purified, if necessary, to obtain the specific compound of interest (e.g., compound 16 or 17). TIFF2025124733000059.tif41128

[0116] In certain embodiments, compounds of formula (13) can be obtained via the Perkins Reaction, as shown in Scheme 10. The Perkin Reaction uses KOAc / AcO, as shown in Scheme 10. However, other temperatures and other bases, such as KCO, can be utilized. Additional details of the Perkin Reaction can be found in WO 03 / 061660, the contents of which are incorporated herein by reference in their entirety. TIFF2025124733000060.tif46128

[0117] The compound of formula (14) can be obtained by reacting a dicarboxylic acid derivative of formula (18) with a suitable anhydride-forming reagent, such as dicyclohexylcarbodiimide (DCC) or acetic anhydride, to obtain the compound of formula (14), as shown diagrammatically below (Scheme 11). The reaction can be carried out using acetic anhydride and a non-nucleophilic solvent such as THF. The reaction can be carried out at a temperature of about 20°C to about 100°C, for example, 60°C to 80°C. TIFF2025124733000061.tif41128

[0118] Compounds of formula (14) can also be obtained as described in Ayres et al. Tetrahedron, 1975, 31, 1755-1760 (incorporated herein by reference in its entirety). Compounds of formula (14) can be converted to compounds of formula (I) by known methods, for example, as previously described in U.S. Pat. No. 8,916,563 (incorporated herein by reference in its entirety).

[0119] Compounds of formula (18) are generally available through commercial sources such as Sigma-Aldrich. Alternatively, compounds of formula (18) can be obtained by reacting a suitable precursor of formula (19) or formula (20) with a suitable dicarboxylic acid derivatizing reagent, such as NaMnO4 and / or NaOH, to obtain compounds of formula (18), as shown diagrammatically below (Schemes 12 and 13). The reaction can be carried out using an aqueous solvent, such as water. The reaction can be carried out at a temperature of about 50°C to about 100°C, e.g., 85°C to 95°C. TIFF2025124733000062.tif89159

[0120] X 1 and X 2Compounds of formula (18), in which is Cl, can be obtained as described in Ayres et al. Tetrahedron, 1975, 31, 1755-1760 (incorporated herein by reference in its entirety), as shown in Scheme 14. Bis-iodination of compound 34, followed by transmetallation and carboxylation, provides compound 36. Other halogenated derivatives can also be used as starting materials to provide compounds of formula (18). Subsequent conversion of the dicarboxylic acid functionality of compounds of formula (18) to form cyclic anhydrides, as described above, provides compounds of formula (14). Compounds of formula (14) can be converted to compounds of formula (I) by known methods. Exemplary methods are described in U.S. Pat. No. 8,916,563 (incorporated herein by reference in its entirety). TIFF2025124733000063.tif45129

[0121] Additional Synthetic Schemes for Compounds of Formula (I) The synthetic schemes described above for preparing compounds of formula (I) are illustrative and are not intended to limit the possible techniques that a person skilled in the art can use to prepare the compounds disclosed herein. Different methods will be apparent to those skilled in the art. Additional reactions can be carried out to synthesize additional embodiments of the compounds represented by formula (I).

[0122] To obtain compounds of formula (I) where Y is C=S, the following synthesis can be carried out (Scheme 15): Treatment of compound 21 with Lawesson's reagent provides the corresponding thiocarbonyl derivative 22. Subsequent deprotection or hydrolysis provides compound 23. TIFF2025124733000064.tif112155

[0123] Y is C=NR * In order to obtain compounds of formula (I), where R* represents hydrogen or an alkyl substituent, for example, the following synthesis can be carried out (Scheme 16): TIFF2025124733000065.tif118158

[0124] Compounds of formula (I) where Y is a covalent bond can be prepared as previously described in US Pat. No. 8,916,563.

[0125] Other substitutions and modifications are also possible, as will be apparent to those skilled in the art. For example, in Scheme 17, KOH can be used in place of NaOH. In Scheme 18 below, KOH can be used in place of NaH. t Bu can be used. In addition, NMP or THF can be used instead of DMF. TIFF2025124733000066.tif155151

[0126] In some embodiments, the following alternative synthesis can be performed (Scheme 19). TIFF2025124733000067.tif115147

[0127] The compound or composition of the present invention can be useful in the application that benefits from the enzyme inhibition of aldose reductase.The exemplary usefulness of aldose reductase inhibition can be found, for example, in U.S. Patent No. 8,916,563; U.S. Patent No. 5,677,342; U.S. Patent No. 5,155,259; U.S. Patent No. 4,939,140; U.S. Patent Application Publication No. US 2006 / 0293265; and Roy et al., Diabetes Research and Clinical Practice 1990, 10(1), 91-97; and the references cited therein; each of which is incorporated herein by reference in its entirety. Inhibition of aldose reductase has also been found to block colon cancer metastasis and colon cancer cell mitosis (see, e.g., Tammali, R. et al., Inhibition of Aldose Reductase Prevents Colon Cancer Metastasis, Carcinogenesis 2011, doi: 10.1093 / carcin / bgr102; published online: June 3, 2011; Angiogenesis 2011 May;14(2):209-21; and Mol. Cancer Ther. 2010, Apr;9(4):813-824; each of which is incorporated herein by reference in its entirety).

[0128] In certain embodiments, the compounds and / or compositions of the present invention may be useful in promoting healthy aging of the skin, treating skin disorders, treating angiogenic disorders such as cancer, including colon cancer, treating non-cardiac tissue damage, treating cardiovascular disorders, treating renal disorders, treating progressive myocardial infarction, treating ischemic injury, and treating various other disorders, such as complications resulting from diabetes. Such disorders may include, but are not limited to, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infections, peripheral vascular disease, stroke, asthma, etc.

[0129] In some embodiments, the compounds and / or compositions of the present invention can be useful for cardiovascular applications.For example, the compounds and / or compositions of the present invention can be used to treat patients who have undergone cardiac bypass surgery, and improve postoperative recovery.In another example, the compounds and / or compositions of the present invention can be used to inhibit or reduce the accumulation or rapid development of atherosclerotic plaque.

[0130] In some other embodiments, the compounds and / or compositions of the present invention may be useful for topical application. For example, the compounds and / or compositions of the present invention may be used to slow or reduce skin aging.

[0131] In some embodiments, a compound of Formula (I) can be administered to a subject in need of treatment at a dosage ranging from about 0.5 to about 25 mg / kg body weight of the subject being treated, e.g., about 1.0 to 10 mg / kg, per day, although additional variations are within the scope of the invention.

[0132] The compound of formula (I) can be administered alone or in combination with a pharmaceutically acceptable carrier, such as a diluent, a filler, an aqueous solution, and even an organic solvent. The compound and / or composition of the present invention can be administered as a tablet, a powder, a lozenge, a syrup, an injection, etc. Additional ingredients, such as flavoring agents, binders, excipients, etc., are also within the scope of the present invention.

[0133] In some embodiments, the pharmaceutically acceptable composition may contain a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 2 wt%, e.g., 0.01 to about 1 wt% or about 0.05 to about 0.5 wt%. The composition may be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition may be prepared as an aqueous solution and may contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-modifying components, and the like.

[0134] Other equivalent modes of administration can be found in US Pat. No. 4,939,140, ​​which is incorporated herein by reference in its entirety.

[0135] In one aspect, the present invention provides the use of a pharmaceutical composition and / or medicament comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in a method for treating a disease state and / or condition caused by or associated with aldose reductase.

[0136] In another embodiment, the method of treatment comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; and (iii) administering said compound of formula (I) in a therapeutically effective amount to treat, inhibit, and / or prevent a disease state or condition in the subject in need of such treatment.

[0137] In another embodiment, the method of treatment comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof; and (iii) administering the composition in a therapeutically effective amount to treat, inhibit, and / or prevent the disease state or condition in the subject in need of such treatment.

[0138] In one embodiment, the subject in need is an animal. In another embodiment, the patient in need is an animal. Animals include all members of the animal kingdom, but are not limited to humans, mice, rats, cats, monkeys, dogs, horses, and pigs. In some embodiments, the subject in need is a human. In some embodiments, the subject in need is a mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the patient in need is a human. In some embodiments, the patient in need is a mouse, rat, cat, monkey, dog, horse, or pig.

[0139] In one embodiment, the compound or composition is administered orally. In another embodiment, the compound or composition is administered intravenously.

[0140] In one embodiment, the method comprises administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0141] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants, and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient. Often, pharmaceutically acceptable carriers are chemically inert to the active compound and non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers may include, for example, water or saline, polymers such as polyethylene glycol, carbohydrates and their derivatives, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. In addition, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. Other examples of suitable pharmaceutical carriers are found in, for example, Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 thEd. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7 th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)), each of which is incorporated herein by reference in its entirety.

[0142] In one embodiment, pharmaceutical composition is the mixture of one or more of the compounds described herein or their pharmaceutically acceptable salts, solvates, prodrugs or hydrates with other chemical components, such as physiologically acceptable carriers and excipients.The purpose of pharmaceutical composition is to facilitate the administration of compound to organism or subject.

[0143] In another embodiment, a method for treating, preventing, and / or suppressing a condition associated with aldose reductase comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier; and (iii) administering the compound or composition in a therapeutically effective amount to treat, prevent, and / or suppress the disease state or condition associated with aldose reductase in the subject in need of such treatment.

[0144] A "prodrug" or "prodrug" refers to an agent that is converted into an active drug in vivo. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug is less bioavailable or not bioavailable at all. In some embodiments, a prodrug has improved solubility in pharmaceutical compositions over the parent drug. For example, the compound possesses a protecting group that is removed in vivo, thus releasing the active compound. The term "prodrug" can be applied to a functional group, such as the acidic functional group of a compound of Formula (I). A prodrug can be constructed in which the acidic group is masked, for example, as an ester or amide. Further examples of prodrugs are discussed herein and in, for example, Alexander et al., J. Med. Chem. 1988, 31, 318 (incorporated herein by reference in its entirety).

[0145] In one embodiment, the present invention also encompasses methods involving prodrugs of compounds of Formula (I) and / or pharmaceutical compositions thereof. Prodrugs include derivatives of compounds that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide active compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds of the present invention that contain biohydrolyzable moieties, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogs. Prodrugs may be constructed from structures in which acidic groups are masked, for example, as esters or amides. Further examples of prodrugs are discussed, for example, in Alexander et al., J. Med. Chem. 1988, 31, 318; and The Practice of Medicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press; incorporated herein by reference in their entireties). Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the parent drug has poor or no bioavailability. In some embodiments, the prodrug has improved solubility in pharmaceutical compositions over the parent drug. For example, the compound possesses protecting groups that can be removed in vivo, thus releasing the active compound.

[0146] In certain embodiments, prodrugs of compounds with a carboxyl functional group are (C1-C4) alkyl esters of the carboxylic acid. The carboxylic acid esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs are typically prepared as described in Burger's Medicinal Chemistry and Drug Discovery 6 thThey can be prepared using well-known methods, such as those described by Prodrug Design and Application (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh; each of which is incorporated herein by reference in its entirety). The biohydrolyzable portion of the compound of formula (I) (i) does not interfere with the biological activity of the compound but can confer advantageous properties to the compound in vivo, such as uptake, duration of action, or onset of action; or (ii) may be biologically inactive but is converted to a biologically active compound in vivo. Examples of biohydrolyzable esters include, but are not limited to, (C1-C4) alkyl esters, alkoxyacyloxy esters, alkylacylaminoalkyl esters, and choline esters. Examples of biohydrolyzable amides include, but are not limited to, (C1-C4) alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, but are not limited to, (C1-C4) alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyetheramines. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkyl ester, alkoxyacyloxyester, alkylacylaminoalkyl ester, or choline ester. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkyl ester, alkoxyacyloxyester, or alkylacylaminoalkyl ester. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkyl ester or alkoxyacyloxyester. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkyl ester. In some embodiments, the biohydrolyzable moiety is a (C1-C3) alkyl ester. In some embodiments, the biohydrolyzable moiety is a methyl ester or ethyl ester.In some embodiments, the biohydrolyzable moiety is a t-butyl ester. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamide, α-amino acid amide, alkoxyacyl amide, or alkylaminoalkylcarbonyl amide. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamide, α-amino acid amide, or alkoxyacyl amide. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamide or α-amino acid amide. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamide.

[0147] In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamine, substituted ethylenediamine, amino acid, hydroxyalkylamine, heterocyclic amine, heteroaromatic amine, or polyetheramine. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamine, amino acid, hydroxyalkylamine, heterocyclic amine, heteroaromatic amine, or polyetheramine. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamine, amino acid, hydroxyalkylamine, or polyetheramine. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamine, amino acid, or hydroxyalkylamine. In some embodiments, the biohydrolyzable moiety is a (C1-C4) alkylamine.

[0148] In one embodiment, the compound of the present invention is formulated into a pharmaceutical composition for administration to a subject in a biologically compatible form suitable for in vivo administration. According to another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) mixed with a pharmaceutically acceptable diluent and / or carrier. A pharmaceutically acceptable carrier is "acceptable" in the sense that it is compatible with the other components of the composition and not harmful to the recipient. As used herein, a pharmaceutically acceptable carrier can be selected from a variety of organic or inorganic materials used as pharmaceutical formulation materials and incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, bulking agents, glidants, solubilizers, stabilizers, suspending agents, isotonicity agents, vehicles, and thickeners. Pharmaceutical additives, such as antioxidants, fragrances, colorants, flavor enhancers, preservatives, and sweeteners, can also be added. Examples of acceptable pharmaceutical carriers include, among others, carboxymethylcellulose, microcrystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc, and water. In one embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the United States Federal or State government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0149] Surfactants, such as detergents, are also suitable for use in the formulation.Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, or polyoxyethylenated sorbitan esters; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives, such as methacrylates; anionic surfactants, such as alkaline stearates, especially sodium, potassium, or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, especially fatty acids derived from coconut oil; cationic surfactants, such as those of the formula N + R'R''R'''R''''Y - wherein the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals, and Y - is an anion of a strong acid, such as a halide, sulfate, and sulfonate anion; cetyltrimethylammonium bromide is one type of cationic surfactant that can be used; + Amine salts of R'R''R''', where the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one type of cationic surfactant that can be used; nonionic surfactants, such as optionally polyoxyethylated sorbitan esters, especially polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearates, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids, or copolymers of ethylene oxide and propylene oxide; amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0150] When administered to subject, the compound of formula (I) and pharmaceutically acceptable carrier can be sterilized.Suitable pharmaceutical carrier can also contain excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20 etc.The present composition can contain a small amount of wetting agent or emulsifying agent, or pH buffering agent if necessary.

[0151] The pharmaceutical preparations of the present invention are prepared by methods well known in the pharmaceutical field. Optionally, one or more auxiliary ingredients (e.g., buffers, flavoring agents, surfactants, etc.) are also added. The choice of carrier is determined by the solubility and chemical properties of the compound, the selected route of administration, and standard pharmaceutical practice.

[0152] Additionally, the compounds and / or compositions of the present invention are administered to a human or animal subject by known procedures, including oral, sublingual, or buccal administration. In one embodiment, the compounds and / or compositions are administered orally.

[0153] For oral administration, the compound of the present invention can be prepared in dosage forms such as capsules, tablets, powders, granules, or as suspensions or liquids.Capsule preparations can be gelatin, soft gel, or solid.Tablet and capsule preparations can further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which is known in the art.Examples of these include carbohydrates such as lactose or sucrose, anhydrous dibasic calcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffers, disintegrants, and coloring agents. Orally administered compositions may contain one or more optional agents to provide a pharmaceutically palatable preparation, such as sweetening agents, e.g., fructose, aspartame, or saccharin; flavoring agents, e.g., peppermint, oil of wintergreen, or cherry; coloring agents; and preservatives.

[0154] In some embodiments, the composition is in unit dosage form, e.g., a tablet, capsule, or single-dose vial. The appropriate unit dosage, i.e., the therapeutically effective amount, may be determined during appropriately designed clinical trials for each of the conditions for which administration of the selected compound is indicated, and will, of course, vary depending on the desired clinical endpoint.

[0155] In accordance with the methods of the invention, the compounds of the invention are administered to a subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms associated with aldose reductase activity in the subject, which amount is readily determined by one of ordinary skill in the art based on known procedures, including analysis of titration curves established in vivo and the methods and assays disclosed herein.

[0156] In one embodiment, the method comprises administering a therapeutically effective dosage of a compound of the invention. In some embodiments, a therapeutically effective dosage is at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight, at least about 25 mg / kg body weight, at least about 30 mg / kg body weight, at least about 40 mg / kg body weight, at least about 50 mg / kg body weight, at least about 75 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 250 mg / kg body weight, mg / kg body weight, at least about 300 mg / kg body weight, at least about 350 mg / kg body weight, at least about 400 mg / kg body weight, at least about 450 mg / kg body weight, at least about 500 mg / kg body weight, at least about 550 mg / kg body weight, at least about 600 mg / kg body weight, at least about 650 mg / kg body weight, at least about 700 mg / kg body weight, at least about 750 mg / kg body weight, at least about 800 mg / kg body weight, at least about 900 mg / kg body weight, or at least about 1000 mg / kg body weight. It will be recognized that any of the dosage amounts recited herein may constitute an upper or lower dosage range, or may be combined with any other dosage amount to form a dosage range inclusive of the upper and lower limits.

[0157] In some embodiments, the methods involve a single dosage or administration (e.g., as a single injection or deposition). Alternatively, the methods involve administering to a subject in need thereof once daily, twice daily, three times daily, or four times daily for about 2 to about 28 days, or about 7 to about 10 days, or about 7 to about 15 days or more. In some embodiments, the methods involve chronic administration. In still other embodiments, the methods involve administering over weeks, months, years, or decades. In still other embodiments, the methods involve administering over weeks. In still other embodiments, the methods involve administering over months. In still other embodiments, the methods involve administering over years. In still other embodiments, the methods involve administering over decades.

[0158] The administered dosage may vary depending on known factors, such as the pharmacodynamic properties of the active ingredient and its mode and route of administration; the time of administration of the active ingredient; the age, sex, health, and weight of the recipient; the nature and extent of symptoms; the type of concomitant treatment, frequency of treatment, and desired effect; and excretion rate, all of which can be readily determined and used by those skilled in the art to adjust or set the dosage and / or dosing regimen.

[0159] The precise dose to be employed in the compositions will also depend on the route of administration and should be determined according to the judgment of the practitioner and each patient's circumstances. In specific embodiments of the present invention, suitable dose ranges for oral administration of the compounds of the present invention are generally from about 1 mg / day to about 1000 mg / day. In one embodiment, the oral dose is from about 1 mg / day to about 800 mg / day. In one embodiment, the oral dose is from about 1 mg / day to about 500 mg / day. In another embodiment, the oral dose is from about 1 mg / day to about 250 mg / day. In another embodiment, the oral dose is from about 1 mg / day to about 100 mg / day. In another embodiment, the oral dose is from about 5 mg / day to about 50 mg / day. In another embodiment, the oral dose is about 5 mg / day. In another embodiment, the oral dose is about 10 mg / day. In another embodiment, the oral dose is about 20 mg / day. In another embodiment, the oral dose is about 30 mg / day. In another embodiment, the oral dose is about 40 mg / day. In another embodiment, the oral dose is about 50 mg / day. In another embodiment, the oral dose is about 60 mg / day. In another embodiment, the oral dose is about 70 mg / day. In another embodiment, the oral dose is about 100 mg / day. It will be recognized that any of the dosage amounts recited herein may constitute an upper or lower dosage range, and may be combined with any other dosage amount to form a dosage range inclusive of the upper and lower limits.

[0160] Any of the compounds and / or compositions of the present invention may be provided in a kit comprising the compound and / or composition. Thus, in one embodiment, the compounds and / or compositions of the present invention are provided in a kit.

[0161] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein, and such equivalents are intended to be within the scope of this invention.

[0162] The present invention is further illustrated by the following non-limiting examples. [Example]

[0163] To facilitate a more complete understanding of the present invention, examples are provided below. The following examples serve to illustrate exemplary modes of making and practicing the present invention. However, the scope of the present invention should not be construed as being limited to the specific embodiments disclosed in these examples, which are merely illustrative.

[0164] Example 1: Preparation of Compound VII Compound VII was prepared as shown diagrammatically below. TIFF2025124733000068.tif100158

[0165] 2-(Chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound IS): Compound IS was prepared using the same method as previously described in US Pat. No. 8,916,563.

[0166] 4,6-Dichloro-1H,3H-thieno[3,4-c]furan-1,3-dione (Compound II): Compound II was prepared using the same method as previously described in Ayres, BE, Longworth, SW, McOmie, JFW Tetrahedron, 1975, 31, 1755-1760.

[0167] 2,5-Dichloro-4-(methoxycarbonyl)thiophene-3-carboxylic acid (Compound III): A solution of 0.495 g (2.22 mmol) of 4,6-dichloro-1H,3H-thieno[3,4-c]furan-1,3-dione (Compound II) in 4.0 mL of MeOH was treated with TFA (1 drop) and heated to 65 °C overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. To the resulting residue was added ether, followed by saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was extracted with ether (1x). The aqueous layer was then acidified to pH = 2 by the addition of concentrated HCl. The aqueous layer was extracted with EtOAc (3x), and the combined organics from the second extraction were washed with brine (1x). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give 0.537 g (95% crude yield) of 2,5-dichloro-4-(methoxycarbonyl)thiophene-3-carboxylic acid (compound III) as a white solid, which was used without further purification: TIFF2025124733000069.tif20158

[0168] Methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)-2,5-dichlorothiophene-3-carboxylate (Compound IV): In a first flask, a solution of 0.537 g (2.11 mmol) of Compound III in 8.0 mL of DMF was slowly treated with 0.393 g (2.42 mmol) of CDI. The reaction mixture was stirred at ambient temperature for 2 hours. In a separate second flask, 0.261 g (2.74 mmol) of MgCl was added to a solution of 0.439 g (2.74 mmol) of mono-tert-butyl malonate in 8.0 mL of DMF cooled to 0 °C. After stirring at 0 °C for 5 minutes, 1.2 mL (8.42 mmol) of triethylamine was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. After 2 hours, the contents of flask #1 were added to flask #2, and the combined reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then cooled to 0° C., treated with aqueous 1.0 M HCl, and stirred for 20 minutes. The mixture was extracted with ether (3×) and washed successively with water (2×) and brine (1×). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford 0.170 g (23% crude yield) of crude methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)-2,5-dichlorothiophene-3-carboxylate (Compound IV), which was used without further purification.

[0169] 2-(5,7-Dichloro-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)tert-butyl acetate (Compound V): To 0.170 g (0.482 mmol) of Compound IV in 4.0 mL of MeOH was added 17 μL (0.530 mmol) of hydrazine. The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions afforded 0.091 g (57% yield) of 2-(5,7-dichloro-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)tert-butyl acetate (Compound V) as a white solid: TIFF2025124733000070.tif5129

[0170] 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)tert-butyl acetate (Compound VI): To a solution of 0.091 g (0.271 mmol) of Compound V in 3.0 mL of DMF, add 0.037 g (0.326 mmol) of KO. tBu was added. The resulting dark mixture was stirred at ambient temperature for 10 minutes, after which 0.082 g (0.326 mmol) of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (Compound IS) was added. After stirring the reaction mixture at ambient temperature for 2 hours, the reaction mixture was partitioned between water and ether, the layers were separated, and the aqueous layer was extracted with ether (2x). The combined ether layers were washed successively with saturated aqueous NaHCO3 (1x), water (1x), 1.0 M aqueous HCl (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) eluting with 4:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.072 g (48% yield) of tert-butyl 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound VI): TIFF2025124733000071.tif20157

[0171] 2-(5,7-Dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (Compound VII): To a solution of 0.072 g (0.131 mmol) of Compound VI in 1.0 mL of THF was added 5.0 mL of formic acid (88% in water) and 0.5 mL of water. The reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ether and saturated aqueous NaHCO3. The layers were separated, and the aqueous layer was acidified to pH 2 by the addition of concentrated HCl. The precipitated solid was collected by filtration to give 8 mg (12% yield) of 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (Compound VII) as a white solid: mp = 205-207 °C (no recrystallization); TIFF2025124733000072.tif22159

[0172] Example 2: Preparation of Compound XII Compound XII was prepared as shown diagrammatically below. TIFF2025124733000073.tif73158

[0173] 4-(Methoxycarbonyl)thiophene-3-carboxylic acid (Compound VIII): Compound VIII was prepared using the same method as previously described in Hawker, DD, Silverman, RB Bioorg. Med. Chem., 2012, 20, 5763-5773.

[0174] Methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)thiophene-3-carboxylate (Compound IX): In a first flask, a solution of 5.27 g (28.31 mmol) of Compound VIII in 35 mL of NMP was slowly treated with 5.28 g (32.55 mmol) of CDI. The reaction mixture was stirred at ambient temperature for 2 hours. In a separate second flask, 3.37 g (35.39 mmol) of MgCl was added to a solution of 5.67 g (35.39 mmol) of mono-tert-butyl malonate in 50 mL of NMP cooled to 0 °C. After stirring at 0 °C for 5 minutes, 14.8 mL (84.93 mmol) of N,N-diisopropylethylamine was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. After 2 hours, the contents of flask #1 were added to flask #2, and the combined reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then cooled to 0°C, treated with aqueous 1.0 M HCl, and stirred for 20 minutes. The mixture was extracted with ether (3x) and washed successively with water (2x) and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in 10 mL of ethyl acetate, and 110 mL of hexane was added. After stirring for 10 minutes, the solid precipitate was filtered off. The filtrate was concentrated in vacuo, and the crude methyl 4-(3-(tert-butoxy)-3-oxopropanoyl)thiophene-3-carboxylate (Compound IX) was carried on without further purification.

[0175] tert-Butyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound X): To a solution of 8.04 g (28.31 mmol) of crude Compound IX in 70 mL of MeOH at 0 °C, 2.7 mL (42.46 mmol) of hydrazine hydrate (50-60% in HO) was added. The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water, and the precipitated solid was collected by filtration to give 2.99 g (40% yield over two steps) of tert-butyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound X) as a white solid: TIFF2025124733000074.tif20150

[0176] 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)tert-butyl acetate (Compound XI): To a solution of 0.100 g (0.376 mmol) of Compound X in 2.5 mL of DMF, add 0.044 g (0.391 mmol) of KO. t Bu was added. The resulting dark mixture was stirred at ambient temperature for 15 minutes, after which 0.104 g (0.414 mmol) of compound IS was added. After stirring the reaction mixture at ambient temperature for 2 hours, the reaction mixture was partitioned between water and ether, the layers were separated, and the aqueous layer was extracted with ether (2x). The combined ether layers were washed successively with 1.0 M NaOH (1x), water (1x), 1.0 M aqueous HCl (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.058 g (32% yield) of tert-butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound XI): TIFF2025124733000075.tif20155

[0177] 2-(4-Oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (Compound XII): A solution of 0.058 g (0.121 mmol) of Compound XI in 1.0 mL of trifluoroacetic acid and 1.0 mL of CHCl was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ether and saturated aqueous NaHCO. The layers were separated, and the ether layer was washed with saturated aqueous NaHCO (1x). The aqueous layer was acidified to pH = 2 by addition of concentrated HCl, and the precipitated solid was collected by filtration to give 20 mg (39% yield) of 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (Compound XII) as a white solid: mp = 174-176 °C (not recrystallized); TIFF2025124733000076.tif20156

[0178] Example 3: Preparation of Compound XIII TIFF2025124733000077.tif33128

[0179] Compound XIII, shown above, was prepared as follows: Using the same molar proportions as before, the preparation described for compound XI was repeated, except that 2-(bromomethyl)-5-fluorobenzo[d]thiazole was the reagent used instead of compound IS. In this case, the final product obtained was tert-butyl 2-(3-((5-fluorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound XIII), which was used crude after washing with 2:1 (v / v) hexane:ethyl acetate and filtering over a plug of silica.

[0180] Example 4: Preparation of Compound XIV TIFF2025124733000078.tif32128

[0181] Compound XIV, shown above, was prepared as follows: The preparation described for compound XII was repeated, except that compound XIII was used as the starting material instead of compound XI. In this case, the final product obtained was 2-(3-((5-fluorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XIV); yield 25%: mp = 172-173 °C (without recrystallization); TIFF2025124733000079.tif12162

[0182] Example 5: Preparation of Compound XV TIFF2025124733000080.tif33128

[0183] Compound XV, shown above, was prepared as follows: Using the same molar proportions as before, the preparation described for compound XI was repeated, except that 2-(bromomethyl)benzo[d]thiazole was the reagent used instead of compound IS. In this case, the final product obtained was tert-butyl 2-(3-(benzo[d]thiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound XV), which was used crude after washing with 3:1 (v / v) hexane:ethyl acetate and filtering over a plug of silica.

[0184] Example 6: Preparation of Compound XVI TIFF2025124733000081.tif32128

[0185] Compound XVI, shown above, was prepared as follows: The preparation described for compound XII was repeated, except that compound XV was used as the starting material instead of compound XI. In this case, the final product obtained was 2-(3-(benzo[d]thiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XVI); yield 7%: mp = 172-173 °C (without recrystallization); TIFF2025124733000082.tif23162

[0186] Example 7: Preparation of Compound XVII TIFF2025124733000083.tif40128

[0187] Compound XVII, shown above, was prepared as follows: Using the same molar proportions as before, the preparation described for Compound XI was repeated, except that 3-(bromomethyl)-5-chlorobenzo[b]thiophene was the reagent used instead of Compound IS. In this case, the final product obtained was 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)tert-butyl acetate (Compound XVII). The resulting product was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 3:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions afforded Compound XVII in 18% yield: TIFF2025124733000084.tif20153

[0188] Example 8: Preparation of Compound XVIII TIFF2025124733000085.tif38128

[0189] Compound XVIII shown above was prepared as follows: The preparation described for compound XII was repeated, except that compound XVII was the starting material used instead of compound XI. In this case, the final product obtained was 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XVIII); yield 25%: TIFF2025124733000086.tif30156

[0190] Example 9: Preparation of Compound XIX TIFF2025124733000087.tif34128

[0191] Compound XIX, shown above, was prepared as follows: The preparation described for compound XI was repeated using the same molar proportions as before, except that 5-chloro-2-(chloromethyl)benzo[d]thiazole was the reagent used instead of compound IS. In this case, the final product obtained was tert-butyl 2-(3-((5-chlorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound XIX). The resulting product was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 4:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions afforded compound XIX in 47% yield: TIFF2025124733000088.tif22163

[0192] Example 10: Preparation of Compound XX TIFF2025124733000089.tif33128

[0193] Compound XX shown above was prepared as follows: The preparation described for compound XII was repeated, except that compound XIX was used as the starting material instead of compound XI. In this case, the final product obtained was 2-(3-((5-chlorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XX); yield 61%: mp = 184-185 °C (without recrystallization); TIFF2025124733000090.tif23157

[0194] Example 11: Preparation of Compound XXI TIFF2025124733000091.tif32128

[0195] Compound XXI, shown above, was prepared as follows: The preparation described for Compound XI was repeated using the same molar ratios as before, except that 2-(chloromethyl)-6-fluorobenzo[d]oxazole was the reagent used instead of Compound IS. In this case, the final product obtained was 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)tert-butyl acetate (Compound XXI). The resulting product was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 4:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions afforded Compound XXI in 30% yield: TIFF2025124733000092.tif19165

[0196] Example 12: Preparation of Compound XXII TIFF2025124733000093.tif32128

[0197] Compound XXII shown above was prepared as follows: The preparation described for compound XII was repeated, except that compound XXI was the starting material used instead of compound XI. In this case, the final product obtained was 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XXII); yield 40%: TIFF2025124733000094.tif20159

[0198] Example 13: Preparation of Compound XXIII TIFF2025124733000095.tif35128

[0199] Compound XXIII, shown above, was prepared as follows: The preparation described for Compound XI was repeated using the same molar ratios as before, except that 5-chloro-2-(chloromethyl)benzofuran was the reagent used instead of Compound IS. In this case, the final product obtained was tert-butyl 2-(3-((5-chlorobenzofuran-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound XXIII). The resulting product was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions afforded Compound XXIII in 33% yield: mp = 117-118 °C (without recrystallization); TIFF2025124733000096.tif20152

[0200] Example 14: Preparation of Compound XXIV TIFF2025124733000097.tif32128

[0201] Compound XXIV shown above was prepared as follows: The preparation described for compound XII was repeated, except that compound XXIII was used as the starting material instead of compound XI. In this case, the final product obtained was 2-(3-((5-chlorobenzofuran-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XXIV); yield 54%: mp = 154-155 °C (without recrystallization); TIFF2025124733000098.tif29162

[0202] Example 15: Preparation of Compound XXV TIFF2025124733000099.tif36128

[0203] Compound XXV shown above was prepared as follows: The preparation described for compound XI was repeated using the same molar ratios as before, except that 2-(chloromethyl)benzofuran was the reagent used instead of compound IS. In this case, the final product obtained was tert-butyl 2-(3-(benzofuran-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound XXV). The resulting product was purified by flash column chromatography on silica gel (monitored by thin-layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions afforded compound XXV in 44% yield: TIFF2025124733000100.tif27157

[0204] Example 16: Preparation of Compound XXVI TIFF2025124733000101.tif34128

[0205] Compound XXVI, shown above, was prepared as follows: The preparation described for compound XII was repeated, except that compound XXV was used as the starting material instead of compound XI. In this case, the final product obtained was 2-(3-(benzofuran-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XXVI); yield 28%: mp = 158-159 °C (without recrystallization); TIFF2025124733000102.tif30162

[0206] Example 17: Physical, Chemical, and Biological Assay Methods and Results Characterization of aldose reductase inhibitor compounds The compounds were synthesized as summarized above and characterized biochemically by their physical properties (solubility and LogD) and by their ability to inhibit the enzymatic activity of aldose reductase in vitro. These assay methods and results are summarized below.

[0207] Equilibrium solubility in phosphate buffer solution at pH 7.4 The equilibrium solubility of test articles was measured in pH 7.4 aqueous buffer. pH 7.4 buffer was prepared by combining 50 mL of 0.2 M KH2PO4 with 150 mL of HO and then adjusting to pH 7.4 with 10 N NaOH. At least 1 mg of powder for each test article was combined with 1 mL of buffer to create a mixture of ≥ 1 mg / mL. These samples were shaken overnight at room temperature on a Thermomixer®. The samples were then centrifuged at 10,000 rpm for 10 minutes. The supernatant was sampled and diluted 10x, 100x, and 10,000x in duplicate into a 1:1 buffer:acetonitrile (ACN) mixture prior to analysis. All samples were assayed by LC-MS / MS using electrospray ionization against standards prepared in a 1:1 assay buffer:ACN mixture. Standard concentrations ranged from 1.0 μM to 1.0 nM.

[0208] Octanol / buffer partition coefficient (LogD) at pH 7.4The octanol / buffer partition coefficients of three test articles were measured at pH 7.4. pH 7.4 buffer was prepared by combining 50 mL of 0.2 M KH2PO4 solution with 150 mL of dH2O and then adjusting to pH 7.4 with 10 N NaOH. In a single incubation, 15 μL of a 10 mM DMSO solution of each test article (100 μM) was added to a test tube containing 0.75 mL of octanol and 0.75 mL of pH 7.4 phosphate buffer. Testosterone was also introduced into each tube as an internal standard at a dosing concentration of 100 μM. These samples were gently mixed on a benchtop rotator for 1 hour at room temperature. The tubes were then removed from the rotator, and the aqueous and organic phases were allowed to separate for 1 hour. An aliquot of the organic layer was removed and diluted 200-fold into a 1:1 buffer:acetonitrile (ACN) mixture. Aliquots of the aqueous layer were removed and diluted 2x, 10x, and 200x into a 1:1 buffer:ACN mixture. All samples were assayed by LC-MS / MS using electrospray ionization. Testosterone was used as a positive control (with a published / known LogD of 3.0-3.4).

[0209] Enzyme inhibition of aldose reductase All compounds and zopolrestat were individually tested in the microplate assay for AR inhibition using D-glyceraldehyde and NADPH as substrates, and the absorbance change at 340 nm was monitored.% inhibition was calculated for ARI at concentrations ranging from 0.1 nm to 10 uM. Enzyme inhibition assay was carried out as described in WO 2012 / 009553, which is incorporated herein by reference in its entirety.

[0210] (Table 1) Physical, chemical, and biological assay results: TIFF2025124733000103.tif220160

[0211] While the invention has been described and illustrated in the foregoing exemplary embodiments, it will be understood that the disclosure has been made by way of example only, and that numerous changes in the details of its implementation are possible without departing from the spirit and scope of the invention, which is limited only by the appended claims. Features of the disclosed embodiments can be combined and rearranged in various ways within the scope and spirit of the invention.

Claims

1. A compound of formula (I) below or a pharmaceutically acceptable salt or solvate thereof: During the ceremony, R 1 CO 2 R 2 or CO 2 - X + and R 2 However, H, (C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-hydroxyalkyl, or (C 1 ~C 6 )-aminoalkyl; X 1 is H or halogen; X 2 is H or halogen; Y is a bond, C=O, C=S, C=NH, or C=N(C 1 ~C 4 )-alkyl; Z, and A 1 NR 7 , O, S or CH 2 and A 2 is N or CH; A 3 NR 7 , O, or S; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )-alkoxy, (C 1 ~C 4 )-alkylthio, (C 1 ~C 4 )-alkylsulfinyl, or (C 1 ~C 4 )-alkylsulfonyl; R 7 But hydrogen, C 1 ~C 4 Alkyl, or C(O)O-(C 1 ~C 4 )-alkyl; and X + is the counter ion.

2. R 2 is hydrogen or (C 1 ~C 6 )-alkyl; Y is C=O; A 1 NR 7 , O, or S; A 2 is N; A 3 is O or S; and R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )-alkoxy, (C 1 ~C 4 )-alkylthio, (C 1 ~C 4 )-alkylsulfinyl, or (C 1 ~C 4 )-alkylsulfonyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. R 2 is hydrogen or tert-butyl; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 3. The compound of claim 2, or a pharmaceutically acceptable salt or solvate thereof.

4. Z, The compound of any one of claims 1 to 3, wherein

5. R 2 is hydrogen or (C 1 ~C 6 )-alkyl; Y is C=O; A 1 NR 7 , O, or S; A 2 is N; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )-alkoxy, (C 1 ~C 4 )-alkylthio, (C 1 ~C 4 )-alkylsulfinyl, or (C 1 ~C 4 )-alkylsulfonyl; and R 7 But hydrogen, C 1 ~C 4 Alkyl, or C(O)O-(C 1 ~C 4 )-alkyl; 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof.

6. R 2 is hydrogen or tert-butyl; Y is C=O; A 1 NR 7 , O or S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof.

7. R 2 is hydrogen or tert-butyl; Y is C=O; A 1 NR 7 , O or S; A 2 is N; R 3 ~R 6 are independently hydrogen, halogen, or CF 3 and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

8. R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; A 1 is S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

9. R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; A 1 is S; A 2 is N; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof.

10. formula 2. The compound of claim 1, wherein:

11. R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 1 is S; A 2 is N; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof.

12. R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 1 is S; A 2 is N; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 12. The compound of any one of claims 1 to 7 and 11, or a pharmaceutically acceptable salt or solvate thereof.

13. formula 2. The compound of claim 1, wherein:

14. Z, The compound of any one of claims 1 to 3, wherein

15. R 2 is hydrogen or (C 1 ~C 6 )-alkyl; Y is C=O; R 3 ~R 6 are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )-alkoxy, (C 1 ~C 4 )-alkylthio, (C 1 ~C 4 )-alkylsulfinyl, or (C 1 ~C 4 )-alkylsulfonyl; and R 7 But hydrogen, C 1 ~C 4 Alkyl, or C(O)O-(C 1 ~C 4 )-alkyl; 15. The compound of any one of claims 1 to 3 and 14, or a pharmaceutically acceptable salt or solvate thereof.

16. R 2 is hydrogen or tert-butyl; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 16. The compound according to any one of claims 1 to 3 and 14 to 15, or a pharmaceutically acceptable salt or solvate thereof.

17. R 2 is hydrogen or tert-butyl; Y is C=O; R 3 ~R 6 is independently hydrogen or halogen; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 17. The compound according to any one of claims 1 to 3 and 14 to 16, or a pharmaceutically acceptable salt or solvate thereof.

18. R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 17. The compound according to any one of claims 1 to 3 and 14 to 16, or a pharmaceutically acceptable salt or solvate thereof.

19. R 2 is hydrogen; X 1 is H; X 2 is H; Y is C=O; R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen or halogen; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 19. The compound according to any one of claims 1 to 3 and 14 to 18, or a pharmaceutically acceptable salt or solvate thereof.

20. formula 2. The compound of claim 1, wherein:

21. R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; R 3 ~R 6 is independently hydrogen, halogen, or haloalkyl; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 17. The compound according to any one of claims 1 to 3 and 14 to 16, or a pharmaceutically acceptable salt or solvate thereof.

22. R 2 is hydrogen; X 1 is Cl; X 2 is Cl; Y is C=O; A 3 NR 7 , O or S; and R 3 , R 5 , and R 6 is hydrogen; R 4 is hydrogen or halogen; and R 7 But hydrogen, (C 1 ~C 4 )-alkyl, or C(O)O-tert-butyl; 22. The compound of any one of claims 1 to 3, 14 to 17, and 21, or a pharmaceutically acceptable salt or solvate thereof.

23. The compound of claim 1 selected from the group consisting of:

24. 24. The compound of any one of claims 1-23, wherein the counterion is selected from the group consisting of sodium, lithium, potassium, calcium, magnesium, zinc, ammonium, and tetrafluoroborate.

25. The counter ion is 24. The compound of any one of claims 1 to 23, selected from the group consisting of:

26. 26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25 and a pharmaceutically acceptable carrier.

27. 30. A method of inhibiting aldose reductase activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-25.

28. 28. The method of claim 27, wherein the subject has diabetes.

29. 29. The method of claim 27 or 28, wherein the subject is a human.

30. 30. A method of treating a disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-25.

31. 31. The method of claim 30, wherein the disorder is atherosclerosis.

32. 31. The method of claim 30, wherein the disorder is diabetic nephropathy.

33. 31. The method of claim 30, wherein the disorder is diabetic neuropathy.

34. 31. The method of claim 30, wherein the disorder is diabetic retinopathy.

35. 31. The method of claim 30, wherein the disorder is a cardiovascular disease.

36. 31. The method of claim 30, wherein the disorder is peripheral vascular disease.

37. 31. The method of claim 30, wherein the disorder is an angiogenic disorder.

38. 31. The method of claim 30, wherein the disorder is tissue damage.

39. 31. The method of claim 30, wherein the disorder is diabetic cardiomyopathy.

40. 27. A method of treating skin disorders or promoting healthy aging of the skin, comprising applying to a dermal substrate a therapeutically effective amount of a compound of any one of claims 1-25 or a composition of claim 26 to a subject in need thereof.

41. 41. The method of claim 40, wherein the skin substrate is human skin.

42. 27. A method of treating a subject having a progressing myocardial infarction, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 25 or a composition of claim 26.

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