Aldose reductase inhibitors

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, as well as methods of promoting healthy aging of the skin using the compounds and compositions of the present invention, treatment of skin disorders, treatment of cardiovascular disorders, treatment of renal disorders, treatment of angiogenic disorders such as cancer, treatment of tissue damage such as non-cardiac tissue damage, treatment of progressive myocardial infarction, treatment of ischemic injury, and treatment of various other disorders such as complications resulting from diabetes, which may include, but are not limited to, atherosclerosis, cardiomyopathy, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, skin infections, peripheral vascular disease, stroke, galactosemia, asthma, PMM2-CDG, etc.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 827,362, filed April 1, 2019, and U.S. Provisional Patent Application No. 62 / 928,735, filed October 31, 2019, the entire teachings of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to novel compounds and pharmaceutical compositions thereof, as well as methods of promoting healthy aging of the skin using the compounds and compositions of the present invention, treatment of skin disorders, treatment of skin aging, treatment of cardiovascular disorders, treatment of renal disorders, treatment of angiogenic disorders such as cancer, treatment of tissue damage such as non-cardiac tissue damage, treatment of progressive myocardial infarction, treatment of ischemic injury, and treatment of various other disorders such as complications resulting from diabetes. Other disorders may include, but are not limited to, atherosclerosis, cardiomyopathy, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, skin infections, peripheral vascular disease, stroke, galactosemia, PMM2-CDG, asthma, etc. [Background technology]

[0003] 2. Background of the Invention An estimated 15 million people worldwide suffer from stroke each year. A stroke is a condition in which insufficient blood flow to the brain leads to cell death. There are two main types of stroke: ischemic, caused by restricted blood flow, and hemorrhagic, caused by bleeding. Ischemic stroke accounts for approximately 87% of cases. Both types of stroke can affect proper brain function either temporarily or permanently.

[0004] Despite the ubiquity of stroke, few interventions exist. The only FDA-approved drug for treating ischemic stroke is tissue plasminogen activator (tPA), a thrombolytic drug. tPA must be given within 3-4.5 hours of the first symptoms of stroke. (Xin et al., Neurochemistry International 2014, 68, 18-27, incorporated herein by reference in its entirety). Medications may also be used to treat brain swelling that sometimes occurs after a stroke.

[0005] In addition to limiting the duration of ischemia by treatment with thrombolytic drugs, an alternative strategy is to limit the severity of ischemic damage (i.e., neuroprotection). Neuroprotective strategies can potentially protect the penumbra tissue and extend the time window for revascularization techniques. However, at present, there are no neuroprotective treatments and no neuroprotective agents that have been shown to affect clinical outcomes in ischemic stroke.

[0006] Recent studies have shown that much of the neuronal damage caused by stroke is associated with high levels of endoplasmic reticulum stress and reactive oxygen species (ROS). Aldose reductase inhibitors (ARIs) have been shown to attenuate ROS production and reduce stroke damage in mice. For example, inhibition of the enzyme aldose reductase (AR) has beneficial effects during ischemic stroke. AR knockout (deficient) mice were subjected to cerebral infarction (2 h of ischemia followed by 22 h of reperfusion) and the results were compared with those of normal mice. The results showed a significant reduction (25-33%) in infarct volume in brain sections of AR knockout mice compared to the control group. Furthermore, using normal mice, it was shown that a single dose treatment (orally) of mice with an aldose reductase inhibitor (Fidarestat) either 30 min before ischemia or 1 h 45 min after ischemia also showed a significant reduction (16-25%) in infarct volume resulting from ischemic injury.

[0007] Aldose reductase (AR) is a monomeric NADPH-dependent oxidoreductase of the aldo-ketoreductase family of enzymes. It is an enzyme present in many parts of the body. Aldose reductase catalyzes the reduction of saturated and unsaturated aldehydes, including aldo- and monosaccharides, as well as a wide range of other substrates. Primarily, aldose reductase catalyzes the reduction of glucose to sorbitol, one of the steps in the sorbitol pathway responsible for the formation of fructose from glucose. AR has been implicated in a wide range of therapeutic areas in recent years, including cancer, myocardial infarction and ischemic injury, asthma, transplantation, and adverse inflammatory responses. (Chatzopoulou et al., Expert Opin Drug Discov, 2013, 8(11), 1365-80). Aldose reductase also exists in human brain in significant amounts.Aldose reductase inhibitors can act as adjunctive treatments to provide neuroprotection during revascularization of brain tissue.However, aldose reductase inhibitors may need to cross the blood-brain barrier to be effective.Therefore, there is a need for aldose reductase inhibitor compounds that can cross the blood-brain barrier. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] CXin et al., Neurochemistry International 2014, 68, 18-27 [Non-Patent Document 2] Chatzopoulou et al., Expert Opin Drug Discov, 2013, 8(11), 1365-80 Summary of the Invention [Means for solving the problem]

[0009] overview It is 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, unless the context dictates otherwise.

[0010] In one aspect, the present invention provides a compound of formula (I) [ka] (In the formula, X 1 is N or CR 1 and; X 2 N, CR 2 or S; X 3 N, CR 3 or a combination; X 4 is N or CR 4 where X 2 If S, then X 1 is CR 1 and X 4 is CR 4 and X 3 is a single bond; or X 1 , X 2 , X 3 or X 4 Two or three of these are N; Y is a bond, C=O, C=S, C=NH, or C=N(C1-C4)-alkyl; Z is [ka] and; A 1 is NR 9 , O, S or CH2; A 2 is N or CH; A 3 is NR 9 , O or S; R 1 ~R 8are 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; or R 1 ~R 4 or R 5 ~R 8 two of which taken together are (C1-C4)-alkylenedioxy; R 9 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; X 5 is QR 10 and; Q is O, NH, O-(C1-C6)-alkyl, O-(C1-C6)-hydroxyalkyl, O-(C1-C6)-aminoalkyl, O-aryl, O-heteroaryl, O-biaryl, O-benzyl, NH-(C1-C6)-alkyl, NH-(C1-C6)-hydroxyalkyl, NH(C1-C6)aminoalkyl, NH-aryl, NH-heteroaryl, NH-biaryl, NH-benzyl, or a bond; R 10 teeth [ka] [ka] , aryl, heteroaryl, biaryl, benzyl, heterocycle, C(O)OR 11 and OH; provided that when Q is NH, R 10 may be H; R 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13, (C1-C6)-alkyl optionally substituted with one or more substituents selected from the group consisting of aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2; Or R 11 and R 12 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring; R 13 is H or (C1-C6)-alkyl; (n is 0, 1, or 2) or a pharma- ceutically acceptable salt thereof.

[0011] In formula (I), R 10 can be bonded to any substitutable atom in Q. For example, when Q is O-(C1-C6)alkyl, R 10 can be attached to any carbon atom in the alkyl.

[0012] In some embodiments, X 1 and X 4 is N and X 2 and X 3 is CH; or X 1 CR 1 and X 4 CR 4 and X 2 is S and X 3 is a bond; or a pharma- ceutically acceptable salt or solvate thereof.

[0013] In some embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; A 3 is O or S; R 5 ~R 8are 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; or a pharma- ceutically acceptable salt or solvate thereof.

[0014] In some embodiments, R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; R 9 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0015] In some embodiments, Z is [ka] It is.

[0016] In some embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; R 5 ~R 8 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; R 9 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0017] In some embodiments, Y is C=O; A 1 NR9 , O or S; A 2 is N; R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; R 9 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0018] In some embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; R 5 ~R 8 are independently hydrogen, halogen, or CF3; R 9 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0019] In some embodiments, X 1 CR 1 and X 4 CR 4 and X 2 is S and X 3 is a bond; Y is C=O; A 1 is S; A 2 is N; R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0020] In some embodiments, X 1 and X 4 is N and X 2 and X 3 is CH; Y is C=O; A 1 is S; A 2 is N; R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0021] In some embodiments, Q is a bond. R 10 but [ka] It is.

[0022] In some embodiments, Q is O-(C1-C6)-alkyl, O-(C1-C6)-hydroxyalkyl, O-(C1-C6)-aminoalkyl; R 10 but [ka] It is.

[0023] In some embodiments, Q is O—(C1-C6)-aminoalkyl; R 10 but [ka] and; n is 0.

[0024] In some embodiments, Q is NH-(C1-C6)-alkyl, NH-(C1-C6)-hydroxyalkyl, NH-(C1-C6)-aminoalkyl; R 10 but [ka] It is.

[0025] In some embodiments, Q is NH-(C1-C6)-aminoalkyl; R 10 but [ka] and; n is 0.

[0026] In some embodiments, Q is O—(C1-C6)-alkyl, or NH—(C1-C6)-alkyl, or a bond; R 10 but [ka] , aryl, heteroaryl, biaryl, benzyl or a heterocycle.

[0027] The present disclosure relates to a compound of formula (I-4) [ka] (In the formula, R 5 , R 6 , R 7 , R 8 and X 5 is as defined in formula (I) and pharma- ceutically acceptable salts thereof. In an embodiment of the compound of formula (I-4), X 5 is selected from the group consisting of [ka] .

[0028] In certain preferred embodiments of the compounds of formula (I-4), R 5 , R 7 and R 8 are H and R 6 is a halogen of haloalkyl, preferably R 6 is trifluoromethyl, and X 5 is selected from the group consisting of

[0029] [ka] .

[0030] The present disclosure further provides a compound of formula (II) [ka] (In the formula, X 1 is N or CR 1 and; X 2 N, CR 2 or S; X 3 N, CR 3 or a combination; X 4 is N or CR 4 where X 2 If S, then X 1 is CR 1 and X 4 is CR 4 and X 3 is a single bond; or X 1 , X 2 , X 3 or X 4 Two or three of these are N; Y is a bond, C=O, C=S, C=NH, or C=N(C1-C4)-alkyl; Z is [ka] and; A 1 is NR 9 , O, S or CH2; A 2 is N or CH; A 3 is NR 9 , O or S; R 1 ~R 8are 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; or R 1 ~R 4 or R 5 ~R 8 two of which taken together are (C1-C4)-alkylenedioxy; R 9 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; X 6 is S(O)2-OR 13 , S(O)2-NHR 13 , heteroaryl or heterocycloalkyl; R 13 is H or (C1-C6)-alkyl) and pharma- ceutically acceptable salts thereof.

[0031] The present disclosure further comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0032] The present disclosure further comprises: [ka] and pharma- ceutically acceptable salts thereof.

[0033] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or other compounds disclosed herein and a pharma- ceutically acceptable carrier.

[0034] In another aspect, the invention provides a method for 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) or other compounds disclosed herein.

[0035] In some embodiments, the subject is a human.

[0036] 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) or other compound disclosed herein.

[0037] In some embodiments, the disorder is stroke.

[0038] In some embodiments, the disorder is ischemic stroke.

[0039] In some embodiments, the injury is tissue damage.

[0040] In some embodiments, the disorder is brain injury.

[0041] In some embodiments, the disorder is nerve damage.

[0042] In some embodiments, the disorder is an autoimmune disease.

[0043] In some embodiments, the disorder is galactosemia.

[0044] In some embodiments, the disorder is phosphomannomutase 2-congenital glycosylation disorder (PMM2-CDG).

[0045] The present disclosure also relates to a method of treating a diabetic complication, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or other compounds disclosed herein. The diabetic complication may be diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy or diabetic nephropathy.

[0046] The present disclosure also relates to a method of treating a cardiovascular disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or other compounds disclosed herein. The cardiovascular disorder can be a cardiomyopathy.

[0047] The present disclosure also relates to a method of treating skin aging, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or other compounds disclosed herein. The compound may be administered topically to the skin.

[0048] 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 the compounds of formula (I) or other compounds disclosed herein, and the aldose reductase inhibition exhibited by such compounds.

[0049] These and other embodiments of the present invention are further described in the following sections of this application, including the detailed description, examples, and 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. Thus, other embodiments will be recognized by those skilled in the art without departing from the spirit and scope of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] Detailed Description Aldose reductase inhibitors are described, for example, in WO 2017 / 223179; 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. 2006 / 0293265; Roy et al., Diabetes Research and Clinical Practice 1990, 10(1), 91-97; Chinese Patent Application Publication No. 101143868; and Chatzopoulou et al., Expert Opin. Ther. Pat. 2012, 22, 1303; and references cited therein, each of which is incorporated 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 includes compounds that show dramatically improved properties (for example, binding affinity, solubility and polarity, etc.) compared to, for example, other aldose reductase inhibitors (for example, zopolrestat, etc.).Compounds such as zopolrestat are described, for example, in 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.

[0051] The compounds and / or compositions of the invention may be effective in treating, reducing and / or inhibiting complications associated with aldose reductase activity, such as, for example, atherosclerosis, neuropathy, retinopathy, nephropathy, cardiomyopathy, and multiple complications in diabetic patients. The compounds and / or compositions of the 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 CN102512407; WO2008002678; CN101143868; 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 by reference in its entirety.

[0052] Reagent abbreviations CDCl3 Deuterated Chloroform CDI 1,1'-Carbonyldiimidazole CD3OD Deuterated Methanol DMAP 4-(Dimethylamino)pyridine DMF N,N-Dimethylformamide D2O heavy water EDC HCl N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EtOAc Ethyl acetate EtOH Ethanol HCl Hydrochloric acid HOBT 1-Hydroxybenzotriazole H3PO4 Phosphate H2SO4 Sulfuric acid LiOH Lithium hydroxide KOH Potassium hydroxide MeOH Methanol NaBr Sodium Bromide NaHCO3 Sodium Bicarbonate NaI Sodium iodide NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NMP 1-Methyl-2-pyrrolidinone NHS N-hydroxysuccinimide i Pr2NEt N,N-Diisopropylethylamine i PrOH Isopropanol TBAB Tetrabutylammonium bromide TBAC Tetrabutylammonium Chloride TBAI Tetrabutylammonium iodide TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran

[0053] Abbreviations and Definitions

[0054] The term "aldose reductase inhibitor" refers to compounds and their salts or solvates that function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the metabolic degradation of aldoses. Exemplary aldoses include, but are not limited to, glucose or galactose, and their corresponding polyols, such as sorbitol and galactitol.

[0055] As used herein, the term "compounds of the invention" means compounds of formula (I). This term is also intended to encompass salts, hydrates, prodrugs, and solvates thereof.

[0056] As used herein, the term "composition of the invention" refers to a composition comprising a compound of the invention, and its salts, hydrates, prodrugs, or solvates. The composition of the invention may further comprise other agents, such as, for example, excipients, stabilizers, lubricants, solvents, etc.

[0057] The term "alkyl," as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon group having straight-chain, branched-chain, monocyclic, or polycyclic moieties, or combinations thereof, which group is optionally substituted on one or more carbons of the straight-chain, branched-chain, monocyclic, or polycyclic moieties, or combinations thereof, with one or more substituents on each carbon, and the one or more substituents are independently selected from the group consisting of 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, norbomyl, and the like.

[0058] The term "solvate" as used herein means a compound or a pharma- ceutically acceptable salt thereof in which molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically acceptable at the dosage administered. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate."

[0059] The term "pharmaceutically acceptable salts" is intended to include salts derived from inorganic or organic acids, including, for example, 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; as well as salts derived from inorganic or organic bases, including, for example, sodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine, histidine, polyhydroxylated amines, alkylamines, dialkylamines, trialkylamines, or tetrafluoroborates. Exemplary pharma- ceutically 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 of which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts are also intended to encompass hemi-salts in which the ratio of compound:acid is 2:1, respectively. Exemplary hemi-salts are salts 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 hemi-salts are salts derived from diprotic mineral acids, such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleates, hemifumarates, and hemisuccinates.

[0060] The term "acid" contemplates all pharma- ceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric, phosphoric and nitric acids. Organic acids include all pharma-ceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are linear or branched, saturated or unsaturated C1-C carboxylic acids, optionally substituted with halogen or hydroxyl groups. 20 Aliphatic carboxylic acids, or C6-C 12Aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alpha-hydroxy acids such as 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, tataric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharma- ceutically 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.

[0061] As used herein, the term "about" is used herein to mean approximately, roughly, roughly, or within the region thereof. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values ​​set forth. In general, the term "about" is used herein to modify numerical values ​​above and below the set forth value with a variance of 20% above and below (higher or lower).

[0062] As used herein, an "effective amount", "sufficient amount" or "therapeutically effective amount" is an amount of a compound 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 an aldose reductase-associated affliction or symptom, or to enhance or improve the prophylactic or therapeutic effect of another treatment. An effective amount also includes an amount of a compound that avoids or substantially attenuates undesirable side effects.

[0063] As used herein and as well understood in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, whether detectable or undetectable, reduction in the severity of disease or suffering, stabilized (i.e., not worsening) state of disease or suffering, prevention of disease or suffering from spreading, delay or slowing of progression of disease or suffering, improvement or alleviation of disease or suffering state, and remission (whether partial or total). "Treatment" may also mean prolonging survival compared to expected survival if not receiving treatment.

[0064] The phrase "in need thereof" refers to a need for symptomatic or asymptomatic relief from a condition associated with aldose reductase activity or a condition that can be alleviated by the compounds and / or compositions of the invention.

[0065] Without wishing to be bound by any particular theory, it is believed that the compounds disclosed herein are prodrugs that can be converted to their corresponding free carboxylic acid forms in vivo after administration.The free carboxylic acid forms may have higher aldose reductase inhibitor activity than the compounds disclosed herein.It is also believed that the compounds disclosed herein more easily cross the blood-brain barrier to enter the central nervous system (e.g., via passive intracellular diffusion or active transport, such as via the activity of monocarboxylic acid transporter 1, large neutral amino acid transporter 1 (LAT1), glucose transporter 1 GLUT1, etc.).

[0066] In one embodiment, the aldose reductase inhibitor described herein is a compound of formula (I) [ka] (In the formula, X 1 is N or CR 1 and; X 2N, CR 2 or S; X 3 N, CR 3 or a combination; X 4 is N or CR 4 where X 2 If S, then X 1 is CR 1 and X 4 is CR 4 and X 3 is a single bond; or X 1 , X 2 , X 3 or X 4 Two or three of these are N; Y is a bond, C=O, C=S, C=NH, or C=N(C1-C4)-alkyl; Z is [ka] and; A 1 is NR 9 , O, S or CH2; A 2 is N or CH; A 3 is NR 9 , O or S; R 1 ~R 8 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; or R 1 ~R 4 or R 5 ~R 8 two of which taken together are (C1-C4)-alkylenedioxy; R 9 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; X 5is QR 10 and; Q is O, NH, O-(C1-C6)-alkyl, O-(C1-C6)-hydroxyalkyl, O-(C1-C6)-aminoalkyl, O-aryl, O-heteroaryl, O-biaryl, O-benzyl, NH-(C1-C6)-alkyl, NH-(C1-C6)-hydroxyalkyl, NH-(C1-C6)aminoalkyl, NH-aryl, NH-heteroaryl, NH-biaryl, NH-benzyl, or a bond; R 10 teeth [ka] Aryl, heteroaryl, biaryl, benzyl, heterocycle, C(O)OR 11 and OH; provided that when Q is NH, R 10 may be H; R 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13 , (C1-C6)-alkyl optionally substituted with one or more substituents selected from the group consisting of benzyl, aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2; Or R 11 and R 12 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring; R 13 is H or (C1-C6)-alkyl; (n is 0, 1, or 2) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof and a prodrug thereof.

[0067] In formula (I), R 10 can be bonded to any substitutable atom in Q. For example, when Q is O-(C1-C6)alkyl, R 10can be attached to any carbon atom in the alkyl.

[0068] Z [ka] The designation is Z [ka] or Z is [ka] It will be appreciated by those skilled in the art that this indicates that

[0069] Z [ka] or Z [ka] or Z [ka] The designation is Z [ka] When the compound of formula (I) is [ka] It is understood that Z includes [ka] When the compound of formula (I) is [ka] is understood to include Z [ka] When the compound of formula (I) is [ka] It will be appreciated by those skilled in the art that the term "common" refers to the term "common" as used herein.

[0070] In certain embodiments, X 1 and X 4 is N and X 2 and X 3 is CH. In certain embodiments, X 1 CR 1 and X 4 CR 4 and X 2 is S and X 3 is a bond. In certain embodiments, X 1 and X 4 are CH and X 2 is S and X 3 is a bond.

[0071] In certain embodiments, R 1 and R 4 is hydrogen. In certain embodiments, R 1 and R 4 is halogen. In certain embodiments, R 1 and R 4 is Cl.

[0072] In certain embodiments, R 1 and R 4 is independently hydrogen or halogen. In certain embodiments, R 1 is hydrogen and R 4 is Cl. In certain embodiments, R 1 is Cl, and R 4 is hydrogen.

[0073] In certain embodiments, Q is O or NH. In certain embodiments, Q is O. In certain embodiments, Q is NH. In certain embodiments, Q is a bond.

[0074] In certain embodiments, Q is O-(C1-C6)-alkyl, O-(C1-C6)-hydroxyalkyl, O-(C1-C6)-aminoalkyl. In certain embodiments, Q is O-(C1-C4)-alkyl, O-(C1-C4)-hydroxyalkyl, O-(C1-C4)-aminoalkyl. In certain embodiments, Q is O-(C1-C3)-alkyl, O-(C1-C3)-hydroxyalkyl, O-(C1-C3)-aminoalkyl. In certain embodiments, Q is O-(C1-C2)-alkyl, O-(C1-C2)-hydroxyalkyl, O-(C1-C2)-aminoalkyl. In certain embodiments, Q is O-(C1-C6)-alkyl. In certain embodiments, Q is O-(C1-C6)-hydroxyalkyl. In certain embodiments, Q is O-(C1-C6)-aminoalkyl.

[0075] In certain embodiments, Q is O-(C1-C6)-n-alkyl, O-(C1-C6)-hydroxy-n-alkyl, O-(C1-C6)-amino-n-alkyl. In certain embodiments, Q is O-(C1-C4)-n-alkyl, O-(C1-C4)-hydroxy-n-alkyl, O-(C1-C4)-amino-n-alkyl. In certain embodiments, Q is O-(C1-C3)-n-alkyl, O-(C1-C3)-hydroxy-n-alkyl, O-(C1-C3)-amino-n-alkyl. In certain embodiments, Q is O-(C1-C2)-n-alkyl, O-(C1-C2)-hydroxy-n-alkyl, O-(C1-C2)-amino-n-alkyl. In certain embodiments, Q is O-(C1-C6)-n-alkyl. In certain embodiments, Q is O-(C1-C6)-hydroxy-n-alkyl. In certain embodiments, Q is O-(C1-C6)-amino-n-alkyl.

[0076] In certain embodiments, Q is NH-(C1-C6)-alkyl, NH-(C1-C6)-hydroxyalkyl, NH-(C1-C6)-aminoalkyl. In certain embodiments, Q is NH-(C1-C4)-alkyl, NH-(C1-C4)-hydroxyalkyl, NH-(C1-C4)-aminoalkyl. In certain embodiments, Q is NH-(C1-C3)-alkyl, NH(C1-C3)-hydroxyalkyl, NH-(C1-C3)-aminoalkyl. In certain embodiments, Q is NH-(C1-C2)-alkyl, NH-(C1-C2)-hydroxyalkyl, NH-(C1-C2)-aminoalkyl. In certain embodiments, Q is NH(C1-C6)-alkyl. In certain embodiments, Q is NH-(C1-C6)-hydroxyalkyl. In certain embodiments, Q is NH-(C1-C6)-aminoalkyl.

[0077] In certain embodiments, Q is NH-(C1-C6)-n-alkyl, NH-(C1-C6)-hydroxy-n-alkyl, NH-(C1-C6)-amino-n-alkyl. In certain embodiments, Q is NH-(C1-C4)-n-alkyl, NH-(C1-C4)-hydroxy-n-alkyl, NH-(C1-C4)-amino-n-alkyl. In certain embodiments, Q is NH-(C1-C3)-n-alkyl, NH-(C1-C3)-hydroxy-n-alkyl, NH-(C1-C3)-amino-n-alkyl. In certain embodiments, Q is NH-(C1-C2)-n-alkyl, NH-(C1-C2)-hydroxy-n-alkyl, NH-(C1-C2)-amino-n-alkyl. In certain embodiments, Q is NH-(C1-C6)-n-alkyl. In certain embodiments, Q is NH-(C1-C6)-hydroxy n-alkyl. In certain embodiments, Q is NH-(C1-C6)-amino-n-alkyl.

[0078] In certain embodiments, Q is O-aryl, O-heteroaryl, O-biaryl or O-benzyl. In certain embodiments, Q is O-aryl, O-heteroaryl or O-benzyl. In certain embodiments, Q is O-aryl or O-benzyl. In certain embodiments, Q is O-aryl or O-heteroaryl. In certain embodiments, Q is O-aryl. In certain embodiments, Q is O-heteroaryl. In certain embodiments, Q is O-biaryl. In certain embodiments, Q is O-benzyl.

[0079] In certain embodiments, Q is NH-aryl, NH-heteroaryl, NH-biaryl or NH-benzyl. In certain embodiments, Q is NH-aryl, NH-heteroaryl or NH-benzyl. In certain embodiments, Q is NH-aryl or NH-benzyl. In certain embodiments, Q is NH-aryl or NH-heteroaryl. In certain embodiments, Q is NH-aryl. In certain embodiments, Q is NH-heteroaryl. In certain embodiments, Q is NH-biaryl. In certain embodiments, Q is NH-benzyl.

[0080] In certain embodiments, R 10 but [ka] It is aryl, heteroaryl, biaryl, benzyl or a heterocycle.

[0081] In certain embodiments, R 10 but [ka] It is.

[0082] In certain embodiments, R 10 but [ka] In certain embodiments, R10 but [ka] In certain embodiments, R 10 but [ka] It is.

[0083] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] It is.

[0084] In certain embodiments, R 10 but [ka] It is.

[0085] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] It is.

[0086] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] It is.

[0087] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] It is.

[0088] In certain embodiments, R 10 but [ka] and n is 0. In certain embodiments, R 10 but [ka] and n is 0. In certain embodiments, R 10 but [ka] and n is 0.

[0089] In certain embodiments, R 10 but [ka] , aryl, heteroaryl, biaryl, benzyl, or heterocycloalkyl. In certain embodiments, R 10 is aryl, heteroaryl, biaryl, benzyl, or heterocycloalkyl. In certain embodiments, R 10 is aryl, heteroaryl, benzyl, or heterocycloalkyl. In certain embodiments, R 10 is aryl or benzyl. In certain embodiments, R 10 is heteroaryl. In certain embodiments, R 10 is heterocycloalkyl.

[0090] In certain embodiments, R 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13 , (C1-C6)-alkyl optionally substituted with one or more substituents selected from the group consisting of benzyl, aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2. 11 and R 12 Together with the atoms to which they are attached, they form a 3- to 7-membered heterocyclic ring.

[0091] In certain embodiments, R 11 and R 12 is independently H or (C1-C6)-alkyl. In certain embodiments, R 11 and R 12 is independently H or (C1-C4)-alkyl. In certain embodiments, R 11 and R 12 is independently H or (C1-C3)-alkyl. In certain embodiments, R11 and R 12 is independently H or (C1-C2)-alkyl.

[0092] In certain embodiments, R 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13 , (C1-C6)-alkyl optionally substituted with one or more substituents selected from the group consisting of benzyl, aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2. 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13 , (C1-C4)-alkyl optionally substituted with one or more substituents selected from the group consisting of benzyl, aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2. 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13 , (C1-C3)-alkyl optionally substituted with one or more substituents selected from the group consisting of benzyl, aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2. 11 and R 12 are independently H or OR 13 , N.H.R. 13 , S.R. 13 , CO2R 13 ,CONHR 13, (C1-C2)-alkyl optionally substituted with one or more substituents selected from the group consisting of benzyl, aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH2.

[0093] In certain embodiments, R 11 and R 12 is H; n is 0; R 10 but [ka] It is.

[0094] In certain embodiments, R 11 is H;R 12 is CH3; n is 0; R 10 but [ka] It is.

[0095] In certain embodiments, R 11 is H;R 12 is (C1-C3)-alkyl; n is 0; R 10 but [ka] It is.

[0096] In certain embodiments, R 11 is H;R 12 is (C1-C4)-alkyl; n is 0; R 10 but [ka] In certain embodiments, R 10 but [ka] In certain embodiments, R 10 but [ka] It is.

[0097] In certain embodiments, R 11 is H;R 12 is CHOH; n is 0; R 10 but [ka] It is.

[0098] In certain embodiments, R 11 is H;R 12 is CH(CH3)(OH); n is 0; R 10 but [ka] It is.

[0099] In certain embodiments, R 11 is H;R 12 is CHSH; n is 0; R 10 but [ka] It is.

[0100] In certain embodiments, R 11 is H;R 12 is CH2CH2SCH3; n is 0; R 10 but [ka] It is.

[0101] In certain embodiments, R 11 is H;R 12 is benzyl; n is 0; R 10 but [ka] It is.

[0102] In certain embodiments, R 11 is H;R 12 is 4-hydroxybenzyl; n is 0; R 10 but [ka] It is.

[0103] In certain embodiments, R 11 is H;R 12 is 2-indolyl; n is 0; R 10 but [ka] It is.

[0104] In certain embodiments, R 11 is H;R 12 is CH2CO2H; n is 0; R 10 but [ka] It is.

[0105] In certain embodiments, R 11 is H;R 12 is CH2CH2CO2H; n is 0; R 10 but [ka] It is.

[0106] In certain embodiments, R 11 is H;R 12 is CH2CONH2; n is 0; R 10 but [ka] It is.

[0107] In certain embodiments, R11 is H;R 12 is CH2CH2CONH2; n is 0; R 10 but [ka] It is.

[0108] In certain embodiments, R 11 is H;R 12 is 5-imidazolyl; n is 0; R 10 but [ka] It is.

[0109] In certain embodiments, R 11 is H;R 12 is CH2(CH2)3NH2; n is 0; R 10 but [ka] It is.

[0110] In certain embodiments, R 11 is H;R 12 is CH2(CH2)2NH(CNH)NH2; n is 0; R 10 but [ka] It is.

[0111] In certain embodiments, R 11 is CH3 and R 12 is CH2CH3, R 11 and R 12 together with the atoms to which they are attached form a pyrrolidine ring; n is 0; R 10 but [ka] It is.

[0112] In certain embodiments, R 11 is CH2CH3, R 12 is CH3 and R 11 and R 12 together with the atoms to which they are attached form a pyrrolidine ring; n is 0; R 10 but [ka] It is.

[0113] In certain embodiments, R 11 and R 12 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring. 11 and R 12 together with the atoms to which they are attached form a three-membered heterocyclic ring. In certain embodiments, R 11 and R 12 together with the atoms to which they are attached form a 4-membered heterocyclic ring. In certain embodiments, R 11 and R 12 together with the atoms to which they are attached form a 5-membered heterocyclic ring. In certain embodiments, R 11 and R 12 together with the atoms to which they are attached form a 6-membered heterocyclic ring. In certain embodiments, R 11 and R 12 together with the atoms to which they are attached form a seven-membered heterocyclic ring.

[0114] In certain embodiments, R 13 is H or (C1-C6)-alkyl. In certain embodiments, R 13 is H. In certain embodiments, R 13 is (C1-C6)-alkyl. In certain embodiments, R 13 is (C1-C4)-alkyl. In certain embodiments, R 13 is (C1-C3)-alkyl. In certain embodiments, R 13is (C1-C2)-alkyl.

[0115] In certain embodiments, n is 0, 1 or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0116] In certain embodiments, Z is [ka] It is.

[0117] In certain embodiments, Z is [ka] In certain embodiments, Z is [ka] It is.

[0118] In certain embodiments, R 5 ~R 8 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.

[0119] In certain embodiments, R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl. In certain embodiments, R 5 ~R 8 are independently hydrogen, halogen or trihaloalkyl.

[0120] In certain embodiments, R 5 ~R 8 is hydrogen. In certain embodiments, R 5 , R 7 and R 8 is hydrogen.

[0121] In certain embodiments, R 6 is hydrogen, halogen, or haloalkyl. In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is halogen. In certain embodiments, R 6 is haloalkyl. In certain embodiments, R 6 is CF3.

[0122] In certain embodiments, R 5 ~R 8 is hydrogen. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is halogen or haloalkyl. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is haloalkyl. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is CF3. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is halogen. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is F. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is Cl.

[0123] In certain embodiments, Y is C=O, C=S, C=NH, or C=N(C1-C4)-alkyl. In certain embodiments, Y is C=O or C=S. In certain embodiments, Y is C=O. In certain embodiments, Y is C=S. In certain embodiments, Y is C=NH or C=N(C1-C4)-alkyl.

[0124] In certain embodiments, A 1 NR 9 , O, S or CH2. In certain embodiments, A 1 NR 9 , O or S. In certain embodiments, A 1 NR 9 , S or CH2. In certain embodiments, A 1 NR 9 or O. In certain embodiments, A 1 NR 9 or S. In certain embodiments, A 1 NR 9 In certain embodiments, A 1 is O. In certain embodiments, A 1 is S.

[0125] In certain embodiments, A 2 is N or CH. In certain embodiments, A 2 is N. In certain embodiments, A 2 is CH.

[0126] In certain embodiments, A 3 NR 9 , O or S. In certain embodiments, A 3 is O. In certain embodiments, A 3 is S. In certain embodiments, A 3 NR 9 It is.

[0127] In certain embodiments, R 9 is hydrogen, C1-C4 alkyl, or C(O)-(C1-C4)-alkyl. In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C1-C4 alkyl. In certain embodiments, R 9 is C1-C3 alkyl. In certain embodiments, R 9 is C1-C2 alkyl. In certain embodiments, R 9is C1-C4n-alkyl. In certain embodiments, R 9 is C1-C3n-alkyl. In certain embodiments, R 9 is C(O)O-(C1-C4)-alkyl. In certain embodiments, R 9 is C(O)O-(C1-C3)-alkyl. In certain embodiments, R 9 is C(O)O-(C1-C2)-alkyl. In certain embodiments, R 9 is C(O)O-(C1-C4)-n-alkyl. In certain embodiments, R 9 is C(O)O-(C1-C3)-n-alkyl.

[0128] In certain embodiments, X 1 and X 4 is N and X 2 and X 3 is CH; or X 1 CR 1 and X 4 CR 4 and X 2 is S and X 3 is a bond.

[0129] In certain embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; A 3 is O or S; R 5 ~R 8 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; or a pharma- ceutically acceptable salt or solvate thereof.

[0130] In certain embodiments, R 5 ~R8 is independently hydrogen, halogen, or haloalkyl; R 9 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0131] In certain embodiments, Z is [ka] and; Y is C=O; A 1 NR 9 , O or S; A 2 is N; R 5 ~R 8 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; R 9 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0132] In certain embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; R 5 ~R 8 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; R 9is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0133] In certain embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; R 9 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0134] In certain embodiments, Y is C=O; A 1 NR 9 , O or S; A 2 is N; R 5 ~R 8 are independently hydrogen, halogen, or CF3; R 9 is hydrogen, (C1-C4)-alkyl, or C(O)O-tert-butyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0135] In certain embodiments, X 1 CR 1 and X 4 CR 4 and X 2 is S and X 3 is a bond; Y is C=O; A 1 is S; A 2 is N; R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0136] In certain embodiments, X 1 and X 4 is N and X 2 and X 3 is CH; Y is C=O; A 1 is S; A 2 is N; R 5 ~R 8 is independently hydrogen, halogen, or haloalkyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0137] In certain embodiments, Q is a bond and R 10 but [ka] It is.

[0138] In certain embodiments, Q is O-(C1-C6)-alkyl, O-(C1-C6)-hydroxyalkyl, O-(C1-C6)-aminoalkyl, and R 10 but [ka] It is.

[0139] In certain embodiments, Q is O—(C1-C6)-aminoalkyl; R 10 but [ka] and; n is 0.

[0140] In certain embodiments, Q is NH-(C1-C6)-alkyl, NH-(C1-C6)-hydroxyalkyl, NH-(C1-C6)-aminoalkyl, and R 10 but [ka] It is.

[0141] In certain embodiments, Q is NH—(C1-C6)-aminoalkyl; R 10 but [ka] and; n is 0.

[0142] In certain embodiments, Q is O—(C1-C6)-alkyl, or NH—(C1-C6)-alkyl, or a bond; R 10 but [ka] , aryl, heteroaryl, biaryl, benzyl or a heterocycle.

[0143] In certain embodiments, the pharma- ceutically acceptable salt of the compound of formula (I) is an alkylamine salt.

[0144] In certain embodiments, the compound of formula (I) is [ka] [ka] is selected from the group consisting of:

[0145] In an embodiment of the compound of formula (I), X 1 CR 1 ;X 2 is S;X 3 is a single bond; X 4 CR 4 Y is C=O; Z is [ka] A 1 is S;A 2 is N, and the compound is represented by formula (I-4) [ka]

[0146] (In the formula, R 5 , R 6 , R 7 , R 8 and X 5 is as defined in formula (I) For example, in an embodiment, R 5 ~R 8 is hydrogen. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is halogen or haloalkyl. In embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is haloalkyl. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is CF3. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is halogen. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 is F. In certain embodiments, R 5 , R 7 , R 8 is hydrogen and R 6 In a preferred embodiment of formula (I-4), X 5 is less than or equal to [ka] .

[0147] In embodiments, the aldose reductase inhibitor described herein is a compound of formula (II) [ka] (In the formula, X 1 is N or CR 1 and; X 2 N, CR 2 or S; X 3 N, CR 3 or a combination; X 4 is N or CR 4 where X 2 If S, then X 1 is CR 1 and X 4 is CR 4 and X 3 is a single bond; or X 1 , X 2 , X 3 or X 4 Two or three of these are N; Y is a bond, C=O, C=S, C=NH, or C=N(C1-C4)-alkyl; Z is [ka] and; A 1 is NR 9 , O, S or CH2; A 2 is N or CH; A 3 is NR 9 , O or S; R 1 ~R 8 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; or R1 ~R 4 or R 5 ~R 8 two of which taken together are (C1-C4)-alkylenedioxy; R 9 is hydrogen, C1-C4 alkyl, or C(O)O-(C1-C4)-alkyl; X 6 is S(O)2-OR 13 , S(O)2-NHR 13 , heteroaryl or heterocycloalkyl; R 13 is H or (C1-C6)-alkyl) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable salt thereof and a prodrug thereof.

[0148] In embodiments, the aldose reductase inhibitors described herein include the following compounds and pharma- ceutically acceptable salts and prodrugs thereof: [ka]

[0149] In embodiments, the aldose reductase inhibitors described herein include the following compounds and pharma- ceutically acceptable salts and prodrugs thereof: [ka] Preferred salts of these compounds include the hydrochloride salts. synthesis

[0150] The compounds described herein can be prepared according to known methods. Schemes 1-10 represent 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. Various 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 our results provided below. For example, any protecting group can be used, for example, as described in Greene et al., Protective Groups in Organic Synthesis (4th Edition 2006).

[0151] Compounds of formula (I-1) can generally be prepared, for example, according to Scheme 1: [ka] (In the formula, X 1 , X 2 , X 3 , X 4 , A 1 , A 2 , R 5 ~R 9 is defined as above, and Q 1 is a halogen, e.g., Cl, Br, I, etc., or any other leaving group, e.g., OSO2Me, OMs, OTs, OTf, etc.).

[0152] Compounds of formula (I-2) can generally be prepared, for example, according to Scheme 2: [ka] (In the formula, X 1 , X 2 , X 3 , X 4 , A 3 , R 5 ~R 9 is defined as above, and Q 1is a halogen, e.g., Cl, Br, I, etc., or any other leaving group, e.g., OSO2Me, OMs, OTs, OTf, etc.).

[0153] Compounds of formula (I-3) can generally be prepared, for example, according to Scheme 3: [ka] (In the formula, X 1 , X 2 , X 3 , X 4 , A 3 , R 5 ~R 9 is defined as above, and Q 1 is a halogen, e.g., Cl, Br, I, etc., or any other leaving group, e.g., OSO2Me, OMs, OTs, OTf, etc.).

[0154] 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.

[0155] In certain embodiments, the reaction can be carried out using an aprotic solvent such as DMF, THF, NMP, etc. In certain embodiments, the reaction can be carried out using an alcoholic solvent such as methanol, ethanol, etc.

[0156] In certain embodiments, the reaction can be carried out at a temperature between about 5°C and about 80°C, for example, 20°C to 30°C.

[0157] In certain embodiments, the reaction can then be followed by further separation and purification steps, such as chromatography (eg, flash, HPLC, MPLC, etc.), crystallization, and the like.

[0158] To obtain different forms of the compounds of formula (I-1), (I-2) or (I-3), respectively [ka] Other suitable reactions are possible, such as the esterification of Q 2 A compound having a carboxylic acid group as a carboxylic acid group (e.g., 5) can be activated with a suitable reagent, such as thionyl chloride (SOCl2), oxalyl chloride (COCl)2, or phosphoryl chloride (POCl3), and subsequently esterified by reaction with a suitable reagent, such as (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (9), to give X. 5 A compound of formula (I-1) having 3-glucosyl as the alkyl group (i.e., 10) can be obtained.

[0159] For example, the following exemplary syntheses can be carried out according to Scheme 4. [ka]

[0160] In certain embodiments, the reaction with compound 9 according to Scheme 4 can be carried out in the presence of a base such as triethylamine, diisopropylethylamine, imidazole, pyridine, and the like.

[0161] In certain embodiments, the reaction with compound 9 according to Scheme 4 can be carried out in the presence of an additive such as DMAP. In certain embodiments, the reaction with compound 9 can be carried out in the absence of an additive.

[0162] In certain embodiments, the reaction with compound 9 according to Scheme 4 can be carried out using an aprotic solvent such as DMF, THF, and the like.

[0163] In certain embodiments, the acid in the reaction according to Scheme 4 can be trifluoroacetic acid (TFA), or the like.

[0164] Other suitable esterification reactions of compounds of formula (5), (6) or (7) are possible to obtain different forms of compounds of formula (I-1), (I-2) or (I-3), respectively. For example, Q 2 A compound having a carboxylic acid group as a carboxylic acid group (e.g., 5) is reacted with compound 9 in the presence of an additive such as N,N'-dicyclohexylcarbodiimide (DCC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), carbonyldiimidazole (CDI), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC) to give X. 5 A compound of formula (I-1) having 3-glucosyl as the alkyl group (i.e., 10) can be obtained.

[0165] For example, the following exemplary syntheses can be carried out according to Scheme 5. [ka]

[0166] In certain embodiments, the reaction with compound 9 according to Scheme 5 can be carried out in the presence of a base such as triethylamine, diisopropylethylamine, imidazole, pyridine, and the like.

[0167] In certain embodiments, the reaction with compound 9 according to Scheme 5 can be carried out with DMAP and DCC, BOP, CDI, EDAC, etc. In certain embodiments, the reaction with compound 9 according to Scheme 5 can be carried out in the absence of DCC, BOP, CDI, EDAC, etc.

[0168] In certain embodiments, the reaction with compound 9 according to Scheme 5 can be carried out using an aprotic solvent such as DMF, THF, and the like.

[0169] In certain embodiments, the acid in the reaction according to Scheme 5 can be trifluoroacetic acid (TFA), or the like.

[0170] Other suitable reactions are possible, such as esterification of compounds of formula (5), (6) or (7) to obtain different forms of compounds of formula (I-1), (I-2) or (I-3), respectively. For example, Q 2 A compound having a carboxylic acid group as X (e.g., 5) can be esterified by reacting it with a suitable reagent such as glucose (11) to give X. 5 A compound of formula (I-1) having 6-glucosyl as the alkyl group (i.e., (12)) can be obtained.

[0171] For example, the following exemplary syntheses can be carried out according to Scheme 6. [ka]

[0172] In certain embodiments, the reaction according to Scheme 6 can be carried out in the presence of an enzyme, such as a lipase, triacylglycerol lipase.

[0173] In certain embodiments, the reaction according to Scheme 6 can be carried out in a solvent such as tert-butanol, acetone, and the like.

[0174] In certain embodiments, the reaction can be carried out at a temperature between about 20°C and about 80°C, such as 20°C to 30°C, 30°C to 40°C, 40°C to 50°C, 50°C to 60°C, 60°C to 70°C, 70°C to 80°C, etc.

[0175] Other suitable reactions of compounds of formula (5), (6) or (7) are possible to obtain different forms of compounds of formula (I-1), (I-2) or (I-3), respectively. For example, Q 2 A compound having a carboxylic acid group as a carboxylic acid group (e.g., 5) is reacted with a suitable reagent such as thionyl chloride (SOCl2), oxalyl chloride (COCl)2, phosphoryl chloride (POCl3), etc., followed by the HO-QR reaction. 10 (13), H2N-QR 10 Reaction with an appropriate reagent, such as (14), can provide a compound of formula (I-1), such as compound 15 or compound 16.

[0176] For example, the following exemplary syntheses can be carried out according to Scheme 7. [ka]

[0177] In certain embodiments, the reaction according to Scheme 7 can be carried out by replacing thionyl chloride (SOCl 2 ) with oxalyl chloride (COCl 2 ), phosphoryl chloride (POCl 3 ), and the like.

[0178] In certain embodiments, the reaction with compound 13 or 14 according to Scheme 7 can be carried out in the presence of a base such as triethylarnine, diisopropylethylamine, imidazole, pyridine, and the like.

[0179] In certain embodiments, the reaction with compound 13 or 14 according to Scheme 7 can be carried out in the presence of an additive such as DMAP. In certain embodiments, the reaction with compound 9 can be carried out in the absence of an additive.

[0180] In certain embodiments, the reaction with compounds 13 or 14 according to Scheme 7 can be carried out using an aprotic solvent such as DMF, THF, and the like.

[0181] In certain embodiments, compounds such as 13 or 14 contain protecting groups, which can be removed, for example, as described in Greene et al., Protective Groups in Organic Synthesis (4th ed. 2006). 2A compound having a carboxylic acid group as the aryl group (e.g., (5)) can be reacted with an appropriate reagent such as thionyl chloride (SOCl2), oxalyl chloride (COCl)2, phosphoryl chloride (POCl3), and subsequently with an appropriate reagent such as benzyl (1-((2-aminoethyl)amino)-1-oxopropan-2-yl)carbamate (18) to give compound 19. Deprotection of compound 19 gives compound of formula 20.

[0182] For example, the following exemplary syntheses can be carried out according to Scheme 8. [ka]

[0183] Other suitable reactions of compounds of formula (5), (6) or (7) are possible to obtain different forms of compounds of formula (I-1), (I-2) or (I-3), respectively. For example, Q 2 A compound having a carboxylic acid group as a carboxylic acid group (e.g., 5) is reacted with HO-QR in the presence of an additive such as N,N'-dicyclohexylcarbodiimide (DCC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), carbonyldiimidazole (CDI), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC). 10 (13), H2N-QR 10 Reaction with an appropriate reagent, such as (14), can provide compounds of formula (I-1), such as compound 15 or 16.

[0184] For example, the following exemplary syntheses can be carried out according to Scheme 9. [ka]

[0185] In certain embodiments, the reaction according to Scheme 9 can be carried out in the presence of a base, such as triethylamine, diisopropylethylarnine, imidazole, pyridine, and the like.

[0186] In certain embodiments, the reaction according to Scheme 9 can be carried out with DMAP and DCC, BOP, CDI, EDAC, etc. In certain embodiments, the reaction according to Scheme 9 can be carried out in the absence of DCC, BOP, CDI, EDAC, etc.

[0187] In certain embodiments, the reaction according to Scheme 9 can be carried out using an aprotic solvent such as DMF, THF, and the like.

[0188] Other suitable reactions of compounds of formula (5), (6) or (7) are possible to obtain different forms of compounds of formula (I-1), (I-2) or (I-3), respectively. For example, Q 2 A compound having a carboxylic acid group as X (e.g., 5) is reacted with X in the presence of an additive such as tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium iodide (TBAI), or tetra-n-butylammonium chloride (TBAC). 6 -QR 10 (17) (where X 6 is a halogen) to provide a compound of formula (I-1), such as compound 15.

[0189] For example, the following exemplary syntheses can be carried out according to Scheme 10. [ka]

[0190] In certain embodiments, X 6 -QR 10 (17) is Cl-QR 10 In certain embodiments, X 6 -QR 10 (17) is Br-QR10 In certain embodiments, X 6 -QR 10 (17) is the IQR 10 It is.

[0191] In certain embodiments, the reaction according to Scheme 10 can be carried out in the presence of a base, such as triethylamine, diisopropylethylamine, imidazole, pyridine, and the like.

[0192] In certain embodiments, the reaction according to Scheme 10 can be carried out in the absence of TBAI, TBAB, or TBAC.

[0193] In certain embodiments, the reaction according to Scheme 10 can be carried out using an aprotic solvent such as DMF, THF, and the like.

[0194] The compound of formula (I-2) is generally [ka] of [ka] Similarly, compounds of formula (I-3) can generally be prepared according to schemes 4-9 by replacing [ka] of [ka] It can also be prepared according to Schemes 4 to 9 by replacing

[0195] Exemplary descriptions of the synthesis of certain compounds of Formula (I-1), Formula (I-2) and Formula (I-3) are described in U.S. Pat. No. 8,916,563 and WO 2017 / 038505, each of which is incorporated by reference in its entirety. Compounds of formula (5), (6) and (7)

[0196] Exemplary descriptions of the synthesis of certain compounds of Formula (5), Formula (6), and Formula (7) are provided in U.S. Pat. No. 8,916,563 and WO 2017 / 38505, each of which is incorporated by reference in its entirety. Compound of formula (1)

[0197] Exemplary descriptions of the synthesis of certain compounds of Formula (1) are provided in U.S. Pat. No. 8,916,563 and WO 2017 / 38505, each of which is incorporated by reference in its entirety. Compounds of formula (2), (3) and (4)

[0198] Exemplary descriptions of the synthesis of certain compounds of Formula (2), Formula (3), and Formula (4) are provided in U.S. Pat. No. 8,916,563 and WO 2017 / 038505, each of which is incorporated by reference in its entirety.

[0199] Further exemplary syntheses of certain compounds of formulas (2), (3) and (4) are described 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.

[0200] Exemplary prodrug esters can be prepared as described in Placzek et al., Bioorganic & Medicinal Chemistry 2016, 24, 5842-5854, which is incorporated herein by reference in its entirety.

[0201] The compounds or compositions of the present invention can be useful in applications that benefit from the inhibition of aldose reductase enzyme.Exemplary usefulness of aldose reductase inhibition is described, for example, in U.S. Patent Nos. 8,916,563; 9,650,383; 5,677,342; 5,155,259; 4,939,140; U.S. Patent Application Publication No. 2006 / 0293265; WO 2017 / 223179; DKP Publication No. 2326632; U.S. Patent Application Publication No. 2017 / 0224651; KR Patent Application Publication No. 2017 / 0224652; each of which is incorporated herein by reference in its entirety. 10 20090084439; U.S. Patent Application Publication No. 2017 / 0319584; Korean Patent Application Publication No. 1020120055370; Lo et al., Journal of Cerebral Blood Flow & Metabolism 2007, 27, 1496-1509; Ip et al., BMC Complement Altern Med 2016, 16, 437; Shen et al., Brain Res 2010, 118-129; Ramirez et al., Pharmacotherapy 2008, 28(5), 646-55; Tang et al., PLoS One 2013, 8(4); P. Pacher, NIH Grant 1Z01AA000375-03; and Roy et al., Diabetes Research and Clinical Practice 1990, 10(1), 91-97; and references cited therein. Inhibition of aldose reductase has also been found to prevent colon cancer metastasis and mitosis in colon cancer cells (see, e.g., Tammali, R. et al., Inhibition of Aldose Reductase Prevents Colon Cancer Metastasis, Carcinogenesis 2011, doi:10.1093 / carcin / bgrl02; published online June 3, 2011; Angiogenesis 2011 May;14(2):209-21; and Mol. Cancer Ther. 2010 April;9(4):813-824, each of which is incorporated by reference in its entirety).

[0202] In certain embodiments, the compounds and / or compositions of the present invention may be useful for 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.

[0203] In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating stroke, ischemic stroke, tissue injury, brain injury, neurological injury, autoimmune disease, and galactosemia in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating stroke in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating ischemic stroke in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating tissue injury in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating brain injury in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating neurological injury in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating autoimmune disease in a subject. In certain embodiments, the compounds and / or compositions of the present invention may be useful for treating galactosemia in a subject. The compounds and / or compositions described herein may be administered to a subject in need thereof to treat PMM2-CDG.

[0204] The compounds and / or compositions described herein can be administered to a subject in need thereof to treat skin aging.Thus, the methods disclosed herein can reduce or delay the signs of skin aging, such as lines, folds, wrinkles and the appearance of crinkled skin, as well as the loss of skin elasticity or firmness.In carrying out the disclosed methods, the aldose reductase inhibitor can be administered topically to the skin, for example, by application to the surface of the skin (e.g., of a topical formulation containing the aldose reductase inhibitor).The aldose reductase inhibitor can be applied to the surface of any desired area of ​​the skin.For example, the aldose reductase inhibitor can be applied to the surface of the skin that is typically exposed in a social environment, such as the skin of the face, neck, chest, arms, hands, or any combination of the above, to reduce or delay skin aging in these areas of the skin.

[0205] In certain embodiments, the compounds and / or compositions of the present invention may be useful for cardiovascular applications.For example, the compounds and / or compositions of the present invention may be used to treat patients undergoing cardiac bypass surgery to improve postoperative recovery.In another example, the compounds and / or compositions of the present invention may be used to inhibit or reduce the accumulation or rapid development of atherosclerotic plaques.In another example, the compounds and / or compositions of the present invention may be used to treat cardiomyopathy.In another example, the compounds and / or compositions of the present invention may be used to treat diabetic cardiomyopathy.

[0206] 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 delay or reduce skin aging.

[0207] In certain embodiments, the compounds disclosed herein may be administered to a subject in need of treatment at dosages ranging from about 0.5 to about 25 mg / kg of the body weight of the subject being treated per day, for example, from about 1.0 to 10 mg / kg, although further variations are within the scope of the invention.

[0208] The compounds disclosed herein may be administered alone or in combination with pharma- ceutically acceptable carriers, such as diluents, fillers, aqueous solutions, and even organic solvents. The compounds and / or compositions of the present invention may be administered as tablets, powders, lozenges, syrups, injections, and the like. Additional ingredients, such as flavorings, binders, excipients, and the like, are within the scope of the present invention.

[0209] In certain embodiments, a pharma- ceutically acceptable composition may contain a compound disclosed herein (e.g., a compound of formula (I)) and / or a pharma- ceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 2% by weight, e.g., 0.01 to about 1% by weight or about 0.05 to about 0.5% by weight. 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-adjusting components, and the like.

[0210] Other modes of administration can be found in US Pat. No. 4,939,140, ​​which is incorporated herein by reference in its entirety.

[0211] In certain embodiments, the present invention provides the use of a pharmaceutical composition and / or medicament comprised of a compound of formula (I) or a pharma- ceutically 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.

[0212] In certain embodiments, the method of treatment comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a compound disclosed herein, or a pharma- ceutically acceptable salt, hydrate, solvate or prodrug thereof; and (iii) administering a therapeutically effective amount of said compound to treat, inhibit and / or prevent a disease state or symptom in the subject in need of such treatment.

[0213] In certain embodiments, the method of treatment comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, hydrate, solvate or prodrug thereof; and (iii) administering a therapeutically effective amount of said composition to treat, inhibit and / or prevent a disease state or symptom in the subject in need of such treatment.

[0214] In certain embodiments, 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, including but 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.

[0215] In certain embodiments, the compound or composition is administered orally. In certain embodiments, the compound or composition is administered intravenously.

[0216] In certain embodiments, the method comprises administering to the subject an effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharma- ceutically acceptable carrier.

[0217] 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. Typically, a pharmaceutically acceptable carrier is 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, and the like. Pharmaceutical carriers may also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants and coloring agents can be used.Other examples of suitable pharmaceutical carriers are described in, for example, Remington's: The Science and Practice of Pharmacy, 22nd Edition (Allen, Loyd V., Jr., ed., Pharmaceutical Press (2012)); Modem Pharmaceutics, 5th Edition (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Edition (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E., ed., Pharmaceutical Press (2012)) (each of which is incorporated herein by reference in its entirety).

[0218] In one embodiment, pharmaceutical composition is a mixture of one or more of the compounds described herein, or their pharmaceutically acceptable salts, solvates, prodrugs or hydrates, and 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.

[0219] In certain embodiments, a method for treating, preventing and / or suppressing a disease state or disorder or symptom associated with aldose reductase comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof; or a composition comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, hydrate or prodrug thereof, and a pharma- ceutically acceptable carrier; and (iii) administering a therapeutically effective amount of said compound or composition to treat, prevent and / or suppress the disease state or disorder or symptom associated with aldose reductase in the subject in need of such treatment.

[0220] "Prodrug" or "prodrug" refers to an agent that is converted to an active drug in vivo. Prodrugs are usually useful because they are easier to administer than the parent drug in some situations. Prodrugs are, for example, bioavailable by oral administration, whereas the parent drug is less bioavailable or not bioavailable. In some embodiments, prodrugs have improved solubility in pharmaceutical compositions than the parent drug. For example, the compound has a protecting group that is removed in vivo, thereby releasing the active compound. The term "prodrug" can be applied to a functional group, such as the acid functional group of the compound of formula (I). Prodrugs can be constructed in structures where the acid 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).

[0221] In certain embodiments, the present invention also encompasses methods that include administration of a prodrug of a compound of formula (I) and / or a pharmaceutical composition thereof. Prodrugs include derivatives of compounds that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound of the present invention. Examples of prodrugs include derivatives and metabolites of the compounds of the present invention that contain a biohydrolyzable moiety, such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogs. Prodrugs may be constructed in structures in which an acid group is masked, for example, as an ester or amide. 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 its entirety). Prodrugs are useful because they are usually easier to administer than the parent drug in some circumstances. A prodrug is, for example, bioavailable by oral administration, whereas the parent drug is less bioavailable or not bioavailable. In some embodiments, the prodrug has improved solubility in pharmaceutical compositions compared to the parent drug. For example, the compound has a protecting group that is removed in vivo, thereby releasing the active compound. The prodrug may, in some cases, provide enhanced permeability through the blood-brain barrier compared to the parent compound. In some embodiments, the prodrug utilizes a transport mechanism to cross the blood-brain barrier.

[0222] In certain embodiments, the prodrugs of compounds having a carboxyl functional group are (C1-C4) alkyl esters of carboxylic acids. Carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule. Prodrugs can typically be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 6th Edition (ed. Donald J. Abraham, 2001, Wiley) and Design and Application of Pro-drugs (ed. H. Bundgaard, 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) can 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) alkyl amines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.

[0223] In some embodiments, the biohydrolyzable portion is an ester that includes a (C1-C6)-alkyl linker, a (C1-C6)-hydroxyalkyl linker, a (C1-C6)-aminoalkyl linker, an aryl linker, a heteroaryl linker, a biaryl linker, or a benzyl linker. In some embodiments, the biohydrolyzable portion is an ester that includes a (C1-C6)-alkyl linker, a (C1-C6)-hydroxyalkyl linker, or a (C1-C6)-aminoalkyl linker. In some embodiments, the biohydrolyzable portion is an ester that includes a (C1-C6)-alkyl linker or a (C1-C6)-hydroxyalkyl linker. In some embodiments, the biohydrolyzable portion is an ester that includes a (C1-C6)-alkyl linker or a (C1-C6)-aminoalkyl linker. In some embodiments, the biohydrolyzable portion is an ester that includes a (C1-C6)-hydroxyalkyl linker or a (C1-C6)-aminoalkyl linker. In some embodiments, the biohydrolyzable moiety is an ester that includes an aryl linker, a heteroaryl linker, a biaryl linker, or a benzyl linker. In some embodiments, the biohydrolyzable moiety is an ester that includes an aryl linker, a heteroaryl linker, or a benzyl linker. In some embodiments, the biohydrolyzable moiety is an ester that includes an aryl linker or a benzyl linker. In some embodiments, the biohydrolyzable moiety is an ester that includes an aryl linker or a heteroaryl linker.

[0224] In some embodiments, the biohydrolyzable portion is an amide that includes a (C1-C6)-alkyl linker, a (C1-C6)-hydroxyalkyl linker, a (C1-C6)-aminoalkyl linker, an aryl linker, a heteroaryl linker, a biaryl linker, or a benzyl linker. In some embodiments, the biohydrolyzable portion is an amide that includes a (C1-C6)-alkyl linker, a (C1-C6)-hydroxyalkyl linker, or a (C1-C6)-aminoalkyl linker. In some embodiments, the biohydrolyzable portion is an amide that includes a (C1-C6)-alkyl linker or a (C1-C6)-hydroxyalkyl linker. In some embodiments, the biohydrolyzable portion is an amide that includes a (C1-C6)-alkyl linker or a (C1-C6)-aminoalkyl linker. In some embodiments, the biohydrolyzable portion is an amide that includes a (C1-C6)-hydroxyalkyl linker or a (C1-C6) aminoalkyl linker. In some embodiments, the biohydrolyzable moiety is an amide that includes an aryl linker, a heteroaryl linker, a biaryl linker, or a benzyl linker. In some embodiments, the biohydrolyzable moiety is an amide that includes an aryl linker, a heteroaryl linker, or a benzyl linker. In some embodiments, the biohydrolyzable moiety is an amide that includes an aryl linker or a benzyl linker. In some embodiments, the biohydrolyzable moiety is an amide that includes an aryl linker or a heteroaryl linker.

[0225] In certain embodiments, the compounds of the present invention are formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for in vivo administration. According to another aspect, the present invention provides pharmaceutical compositions comprising the compounds of formula (I) in admixture with pharma- ceutically acceptable diluents and / or carriers. A pharma-ceutically acceptable carrier is "acceptable" in the sense that it is compatible with other components of the composition and not harmful to its recipient. As used herein, a pharma-ceutically acceptable carrier can be selected from various organic or inorganic materials that are used as materials for pharmaceutical preparations and are incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, bulking agents, lubricants, solubilizers, stabilizers, suspending agents, isotonicity agents, vehicles and thickeners. Pharmaceutical additives such as antioxidants, fragrances, colorants, flavor improvers, 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 "pharmaceutical acceptable" means approved by a regulatory agency of the federal or state government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more particularly in humans.

[0226] 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, polyoxyethylated esters of sorbitol or sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates; anionic surfactants, such as alkaline stearates, especially sodium, potassium or ammonium stearates; 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 those derived from coconut oil; cationic surfactants, such as those of the formula N + Water-soluble quaternary ammonium salts of R'R''R''R''Y-, where the R groups are the same or different, optionally hydroxylated hydrocarbon groups and y- is an anion of a strong acid, such as the halides, sulfates and sulfonates; cetyltrimethylammonium bromide is one cationic surfactant that can be used; amine salts of the formula N+R'R''R''', where the R groups are the same or different, optionally hydroxylated hydrocarbon groups; octadecylamine hydrochloride is one cationic surfactant that can be used; nonionic surfactants, such as the optionally polyoxyethylated esters of sorbitan, in particular 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.

[0227] When administered to subject, the compound of formula (I) and pharmaceutically acceptable carrier can be sterile.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, skimmed milk powder, glycerol, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, etc.The composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

[0228] The pharmaceutical preparation of the present invention is prepared by a method well known in the pharmaceutical field.If necessary, one or more auxiliary components (such as buffers, flavorings, 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.

[0229] Additionally, the compounds and / or compositions of the invention are administered to a human or animal subject by known procedures, including oral, sublingual, or buccal administration, hi one embodiment, the compounds and / or compositions are administered orally.

[0230] For oral administration, the compound of the present invention can be provided in the form of capsule, tablet, powder, granule, or as suspension or solution.Capsule formulation can be gelatin, soft gel or solid.Tablet and capsule formulation can further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers or lubricants, each of which is known in the art.Examples of such include carbohydrates such as lactose or sucrose, anhydrous dibasic calcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearate, silicon dioxide, talc, sodium starch glycolate, acacia, flavorings, preservatives, buffers, disintegrants and colorings. Orally administered compositions may contain one or more optional agents to render the preparation pharma- ceutically palatable, such as, for example, a sweetening agent, such as fructose, aspartame, or saccharin; a flavoring agent, such as peppermint, oil of wintergreen, or cherry; a coloring agent; and a preservative.

[0231] In some embodiments, the composition is in unit dosage form, such as a tablet, capsule, or single dose vial. The appropriate unit dosage, i.e., the therapeutically effective amount, can be determined during appropriately designed clinical trials for each indication for which administration of the selected compound is indicated, and will, of course, vary depending on the desired clinical endpoint.

[0232] According to 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 can be readily determined by one of skill in the art based on known procedures, including analysis of titration curves established in vivo and the methods and assays disclosed herein.

[0233] In certain embodiments, the method comprises administering a therapeutically effective dose of a compound of the invention. In some embodiments, the therapeutically effective dose 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 35 mg / kg body weight, at least about 40 mg / kg body weight, at least about 45 mg / kg body weight, at least about 50 mg / kg body weight, at least about 50 mg / kg body weight, at least about 60 mg / kg body weight, at least about 70 mg / kg body weight, at least about 80 mg / kg body weight, at least about 90 mg / kg body weight, at least about 100 mg / kg body weight, at least about 150 mg / kg body weight, at least about 200 mg / kg body weight, at least about 350 mg / kg body weight, at least about 400 mg / kg body weight, at least about 500 mg / kg body weight, at least about 500 mg / kg body weight, at least about 600 mg / kg body weight, at least about 700 mg / kg body weight, at least about 800 mg / kg body weight, at least 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, 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, and may be combined with any other dosage amounts to constitute a dosage range including upper and lower limits.

[0234] In some embodiments, the methods include a single dose or administration (e.g., as a single injection or depot). Alternatively, the methods include administering to a subject in need thereof once a day, twice a day, three times a day, or four times a day 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 include chronic administration. In still other embodiments, the methods include administration over weeks, months, years, or decades. In still other embodiments, the methods include administration over weeks. In still other embodiments, the methods include administration over months. In still other embodiments, the methods include administration over years. In still other embodiments, the methods include administration over decades.

[0235] The dosage administered may vary depending on known factors such as the pharmacodynamic characteristics 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 the symptoms; the type of concomitant treatment, the frequency of treatment and the desired effect; and the rate of excretion, all of which can be readily determined and used by those skilled in the art to adjust or titrate the dosage and / or administration regimen.

[0236] The exact dose to be used in the composition will also depend on the route of administration and should be determined according to the professional judgment and each patient's circumstances. In certain embodiments of the invention, a suitable dose range for oral administration of the compounds of the invention is generally about 1 mg / day to about 1000 mg / day. In one embodiment, the oral dose is about 1 mg / day to about 800 mg / day. In one embodiment, the oral dose is about 1 mg / day to about 500 mg / day. In another embodiment, the oral dose is about 1 mg / day to about 250 mg / day. In another embodiment, the oral dose is about 1 mg / day to about 100 mg / day. In another embodiment, the oral dose is 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 dose amounts listed herein may constitute an upper or lower dose range, and may be combined with any other dose amount to constitute a dose range that includes the upper and lower limits.

[0237] Any of the compounds and / or compositions of the invention may be provided in a kit comprising the compound and / or composition. Thus, in one embodiment, the compounds and / or compositions of the invention are provided in a kit.

[0238] 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. Such equivalents are intended to be within the scope of this invention.

[0239] The invention is further illustrated by the following non-limiting examples. EXAMPLES

[0240] In order to facilitate a more complete understanding of the present invention, examples are provided below. The following examples serve to illustrate exemplary modes of preparing and carrying out 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.

[0241] Example 1: Preparation of (2R,3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 21): [ka]

[0242] 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound 22) is prepared using the same method as previously described in WO 2017 / 038505.

[0243] (2R,3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 21) (step 1) To a stirred solution of compound 22 and (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (compound 9) in THF is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, NEt3 and DMAP (catalytic amounts). The reaction is stirred at room temperature until completion as monitored by TLC. The reaction mixture is concentrated in vacuo. (Step 2) The crude residue is dissolved in CH2Cl2 and trifluoroacetic acid is added. The reaction mixture is stirred at ambient temperature for 2 h. The reaction mixture is concentrated in vacuo and the residue is partitioned between ether and saturated aqueous NaHCO3. The layers are separated and the ether layer is washed with saturated aqueous NaHCO3 (1x). The ether layers are combined and concentrated in vacuo. The resulting residue is purified by silica gel flash column chromatography to give (2R,3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 21).

[0244] Example 2: Preparation of (2R benzyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 23): [ka]

[0245] (2R Benzyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 23): Benzyl alcohol was reacted with (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole- The first step in the preparation described for compound 21 was repeated except that the reagent used was substituted for 6-ol. The crude residue was purified by silica gel flash column chromatography to give benzyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 23).

[0246] Example 3: Preparation of (2R,3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 2-(8-oxo-7-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-7,8-dihydropyrazino[2,3-d]pyridazin-5-yl)acetate (compound 25): [ka]

[0247] 2-(8-oxo-7-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-7,8-dihydropyrazino[2,3-d]pyridazin-5-yl)acetic acid (compound 24) is prepared using the same method as previously described in U.S. Pat. No. 8,916,563.

[0248] (2R,3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 2-(8-oxo-7-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-7,8-dihydropyrazino[2,3-d]pyridazin-5-yl)acetate (compound 25): To a stirred solution of compound 24 and (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (compound 9) in THF is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, NEt3 and DMAP (catalytic amount). The reaction is stirred at room temperature until completion as monitored by TLC. The reaction mixture is concentrated in vacuo. The crude residue is dissolved in CH2Cl2 and trifluoroacetic acid is added. The reaction mixture is stirred at ambient temperature for 2 h. The reaction mixture is concentrated in vacuo and the residue is partitioned between ether and saturated aqueous NaHCO3. The layers are separated and the ether layer is washed with saturated aqueous NaHCO3 (1x). The ether layers are combined and concentrated in vacuo. The resulting residue is purified by silica gel flash column chromatography to give (2R,3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 2-(8-oxo-7-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-7,8-dihydropyrazino[2,3-d]pyridazin-5-yl)acetate (compound 25).

[0249] Example 4: Preparation of propyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 26):

[0250] [ka]

[0251] R= X=-Cl, -Br, -I, or any leaving group Base = triethylamine (TEA), diisopropylethylamine ( i PrNEt), pyridine Additives: Tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), sodium bromide (NaBr), sodium iodide (NaI) Solvents: dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), tetrahydrofuran (THF)

[0252] [ka]

[0253] Compound 22 (0.150 g, 3.53 × 10) in DMF (3.0 mL) -4 mol), 1-bromopropane (39 μL, 4.24 × 10 -4 mol) and TBAB (0.119 g, 3.70 × 10 -4 A heterogeneous mixture of 100 µL of TEA (4.59 × 10 mol) was added to the mixture. -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.105 g (64% yield) of propyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 26): 1 H NMR (acetone-d6, 400 MHz): δ ppm8.60 (d, J = 3.2Hz, 1H), 8.30 (d, J = 3.2Hz, 1H), 8.29 (s, 1H), 8.26 (d, J = 8.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 5.74 (s, 2H), 4.04 (t, J = 6.4Hz, 2H), 3.97 (s, 2H), 1.61-1.52 (m, 2H), 0.81 (t, J = 7.2Hz, 3H) ); MS ESI (m / z) 468 (M+1) + .

[0254] Example 5: Preparation of isopropyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 27):

[0255] [ka]

[0256] Compound 22 (0.150 g, 3.53 × 10) in DMF (3.0 mL) -4 mol), 2-bromopropane (40 μL, 4.24 × 10 -4 mol) and TBAB (0.119 g, 3.70 × 10 -4 A heterogeneous mixture of 100 µL of TEA (4.59 × 10 mol) was added to the mixture. -4mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.052 g (32% yield) of isopropyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 27): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 3.2Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.83 (d, J = 3.2Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 5.75 (s, 2H), 5.04 (sept, J = 6.4Hz, 1H), 3.84 (s, 2H), 1.21 (d, J = 6.4Hz, 6H); MS ESI (m / z) 468 (M+1) + .

[0257] Example 6: Butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 28):

[0258] Compound 22 (0.150 g, 3.53 × 10) in DMF (3.0 mL) -4 mol), 1-bromobutane (45 μL, 4.24 × 10 -4 mol) and TBAB (0.119 g, 3.70 × 10 -4 A heterogeneous mixture of 100 µL of TEA (4.59 × 10 mol) was added to the mixture. -4mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.103 g (61% yield) of butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 28): 1 H NMR (acetone-d6, 400 MHz): δ ppm 8.60 (d, J = 2.8Hz, 1H), 8.30-8.28 (m, 2H), 8.26 (d, = 8.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 5.74 (s, 2H), 4.08 (t, J = 6.8Hz, 2H), 3.97 (s, 2H), 1.55-1.50 (m, 2H), 1.29-1.21 (m, 2H), 0.81 (t, J = 7.2Hz, 3H); MS ESI (m / z) 482 (M+1) + .

[0259] [ka]

[0260] Example 7: Preparation of sec-butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 29):

[0261] [ka]

[0262] Compound 22 (0.150 g, 3.53 × 10) in DMF (3.0 mL) -4 mol), 2-bromobutane (46 μL, 4.24 × 10 -4 mol) and TBAB (0.119 g, 3.70 × 10 -4 A heterogeneous mixture of 100 µL of TEA (4.59 × 10 mol) was added to the mixture. -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.028 g (17% yield) of sec-butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound IV): 1 H NMR (acetone-d6, 400 MHz): δ ppm 8.60 (d, J = 2.4Hz, 1H), 8.30-8.28 (m, 2H), 8.26 (d, J = 8.4Hz, 1H), 7.74 (d, J = 8.4Hz, 1H), 5.74 (s, 2H), 4.84-4.79 (m, 1H), 3.95 (s, 2H), 1.53-1.46 (m, 2H), 1.13 (d, J = 6.0Hz, 3H), 0.76 (t, J = 8Hz, 3H); MS ESI (m / z) 482 (M+1) + .

[0263] Example 8: Preparation of benzyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 23):

[0264] [ka]

[0265] Compound 22 (0.150 g, 3.53 × 10) in DMF (3.0 mL) -4 mol), benzyl bromide (50 μL, 4.24 × 10 -4 mol) and TBAB (0.119 g, 3.70 × 10 -4 A heterogeneous mixture of 100 µL of TEA (4.59 × 10 mol) was added to the mixture. -4 mol) of benzyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 23) was added. The resulting homogeneous reaction mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.120 g (66% yield) of benzyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 23): 1 H NMR (CDCl3, 400 MHz): δ ppm8.45 (d, J = 2.8Hz, 1H), 8.28 (s, 1H), 7.89 (d, J = 8.4Hz, 1H), 7.73 (d, J = 2.8Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.31-7.27 (m, 5H), 5.73 (s, 2H), 5.16 (s, 2H), 3.92 (s, 2H); MS ESI (m / z) 516 (M+1) + .

[0266] Example 9: Preparation of 2-methoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 30):

[0267] [ka]

[0268] Compound 22 (0.100 g, 2.35 × 10) in DMF (3.0 mL) -4 mol), methyl bromoacetate (25 μL, 2.59 × 10 -4 mol) and TBAB (0.080 g, 2.47 × 10 -4 To a heterogeneous mixture of 100 µL of TEA (3.06 × 10 -4mol) of 2-methoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 30) was added. The resulting homogeneous reaction mixture was stirred overnight at ambient temperature. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.116 g (99% yield) of 2-methoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 30): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 3.2Hz, 1H), 8.29 (s, 1H), 7.97 (d, J = 3.2Hz, 1H), 7.93 (d, J = 8.4Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 5.75 (s, 2H), 4.68 (s, 2H), 4.00 (s, 2H), 3.75 (s, 3H); MS ESI (m / z) 498 (M+1) + .

[0269] Example 10 Preparation of 2-ethoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 31)

[0270] [ka]

[0271] Compound 22 (0.100 g, 2.35 × 10) in DMF (3.0 mL) -4 mol), ethyl bromoacetate (29 μL, 2.59 × 10-4 mol) and TBAB (0.080 g, 2.47 × 10 -4 To a heterogeneous mixture of 100 µL of TEA (3.06 × 10 -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.110 g (92% yield) of 2-ethoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 31): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 3.2Hz, 1H), 8.29 (s, 1H), 7.97 (d, J = 3.2Hz, 1H), 7.93 (d, J = 8.4Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 5.75 (s, 2H), 4.66 (s, 2H), 4.20 (q, J = 7.2Hz, 2H), 4.00 (s, 2H), 1.25 (t, J = 7.2Hz, 3H); MS ESI (m / z) 512 (M+1) + .

[0272] Example 11: Preparation of 2-isopropoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 32):

[0273] [ka]

[0274] Compound 22 (0.100 g, 2.35 × 10) in DMF (3.0 mL) -4 mol), isopropyl bromoacetate (33 μL, 2.59 × 10 -4 mol) and TBAB (0.080 g, 2.47 × 10 -4 To a heterogeneous mixture of 100 µL of TEA (3.06 × 10 -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.102 g (82% yield) of 2-isopropoxy-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 32): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.45 (d, J = 3.2Hz, 1H), 8.29 (s, 1H), 7.98 (d, J = 3.2Hz, 1H), 7.93 (d, J = 8.4Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 5.75 (s, 2H), 5.07 (sept, J = 6.4Hz, 1H), 4.62 (s, 2H), 4.00 (s, 2H), 1.23 (d, J = 6.4Hz, 6H); MS ESI (m / z) 526 (M+1) + .

[0275] Example 12: Preparation of 2-(tert-butoxy)-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 33):

[0276] [ka]

[0277] Compound 22 (0.150 g, 3.53 × 10) in DMF (3.0 mL) -4 mol), tert-butyl bromoacetate (57 μL, 3.88 × 10 -4 mol) and TBAB (0.119 g, 3.70 × 10 -4 A heterogeneous mixture of 100 µL of TEA (4.59 × 10 mol) was added to the mixture. -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in a minimum amount of EtOAc, and then hexanes were added to precipitate a white solid. The solid was collected by vacuum filtration and washed with hexanes. Subsequent drying under vacuum afforded 0.165 g (87% yield) of 2-(tert-butoxy)-2-oxoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 33): 1 H NMR (CDCl3, 400 MHz): δ ppm8.45 (d, J = 2.8Hz, 1H), 8.29 (s, 1H), 7.99 (d, J = 2.8Hz, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 5.75 (s, 2H), 4.55 (s, 2H), 3.99 (s, 2H), 1.45 (s, 9H); MS ESI (m / z) 540 (M+1) + .

[0278] Example 13: Preparation of 2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)acetic acid (compound 34):

[0279] [ka] Acid = HCl, H2SO4, H3PO4, TFA Solvents: Ether, THF, Dioxane, EtOAc

[0280] Compound 33 (0.155 g, 2.87 × 10 -4 To a solution of 2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)acetic acid (compound 34), 0.061 g (44% yield), 2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)acetic acid (compound 34): 1 H NMR (CD3OD, 400 MHz): δ ppm8.58 (d, J = 3.2Hz, 1H), 8.31 (d, J = 3.2Hz, 1H), 8.24(s, 1H), 8.15 (d, J = 8.4Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 5.76 (s, 2H), 4.66 (s, 2H), 4.09 (s, 2H); MS ESI (m / z) 484 (M+1) + .

[0281] Example 14: Preparation of pentan-2-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 35):

[0282] [ka]

[0283] R= X=O, NH, NR 2 Additives: None, 4-dimethylaminopyridine (DMAP) Solvents: dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), tetrahydrofuran (THF)

[0284] [ka]

[0285] Compound 22 (0.050g, 1.18×10 -4 To a solution of 1.5 mL of CDI (23 mg, 1.41 × 10 -4 The reaction mixture was stirred at ambient temperature for 1 h, after which 2-pentanol (18 μL, 1.65×10 -4 mol) and DMAP (7 mg, 5.88 × 10 -5mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature, partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1×), saturated aqueous NaHCO3 (1×), water (1×), 1.0 M HCl (aq) (1×), and brine (1×). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.031 g (53% yield) of pentan-2-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 35): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.76 (s, 2H), MS ESI (m / z) 496 (M+1) + .

[0286] Example 15: Preparation of pentan-3-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 36):

[0287] [ka]

[0288] Compound 22 (0.100g, 2.35×10 -4 To a solution of 1.2×10 mol) in DMF (3.0 mL), CDI (46 mg, 2.82×10 -4 The reaction mixture was stirred at ambient temperature for 1 h, after which 3-pentanol (35 μL, 3.29×10 -4 mol) and DMAP (14 mg, 1.18 × 10 -4 mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature, partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1×), saturated aqueous NaHCO3 (1×), water (1×), 1.0 M HCl (aq) (1×), and brine (1×). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.057 g (49% yield) of pentan-3-yl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 36): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 2.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.76 (s, 2H), 4.77 (pent, J = 6.4Hz, 1H), 3.87 (s, 2H), 1.55-1.45 (m, 4H), 0.76 (t, J = 7.6 Hz, 6H); MS ESI (m / z) 496 (M+1) + .

[0289] Example 16: Preparation of cyclohexyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 37):

[0290] [ka]

[0291] Compound 22 (0.100g, 2.35×10 -4 To a solution of 1.2×10 mol) in DMF (3.0 mL), CDI (46 mg, 2.82×10 -4 The reaction mixture was stirred at ambient temperature for 1 h, after which cyclohexanol (35 μL, 3.29 × 10 -4 mol) and DMAP (14 mg, 1.18 × 10 -4 mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature, partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1×), saturated aqueous NaHCO3 (1×), water (1×), 1.0 M HCl (aq) (1×), and brine (1×). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.084 g (71% yield) of 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 37): 1 H NMR (CDCl3, 400 MHz): δ ppm8.46 (d, J = 3.2 Hz, 1H), 8.29 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 3.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 5.76 (s, 2H), 4.82-4.77 (m, 1H), 3.85 (s, 2H), 1.78-1.73 (m, 2H), 1.61-1.56 (m, 1H), 1.53-1.45 (m, 1H), 1.39-1.24 (m, 5H), 1.20-1.14 (m, 1H); MS ESI (m / z) 508 (M+1) + .

[0292] Example 17: Preparation of methyl (S)-2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)propanoate (Compound 38): [ka]

[0293] Compound 22 (0.300g, 7.06×10 -4 To a solution of 0.137 g, 8.47 × 10 -4 The reaction mixture was stirred at ambient temperature for 1 h, after which L-(-)-methyl lactate (94 μL, 9.88 × 10 -4 mol) and DMAP (43 mg, 3.53 × 10 -4mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature and partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (×1), saturated aqueous NaHCO3 (×1), water (×1), 1.0 M HCl (aq) (×1), and brine (×1). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) eluting with 2:1 (v / v) hexane:ethyl acetate to 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.094 g (26% yield) of methyl (S)-2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)propanoate (compound 38): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 3.2 Hz, 1H), 8.29 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 4.4 MS ESI (m / z) 512 (M+1) + .

[0294] Example 18: Preparation of methyl (R)-2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)propanoate (Compound 39):

[0295] [ka]

[0296] Compound 22 (0.300g, 7.06×10 -4 To a solution of 0.137 g, 8.47 × 10 -4 The reaction mixture was stirred at ambient temperature for 1 h, after which D-(+)-methyl lactate (94 μL, 9.88×10 -4 mol) and DMAP (43 mg, 3.53 × 10 -4 mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature and partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (×1), saturated aqueous NaHCO3 (×1), water (×1), 1.0 M HCl (aq) (×1), and brine (×1). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) eluting with 2:1 (v / v) hexane:ethyl acetate to 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.099 g (27% yield) of methyl (R)-2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)propanoate (compound 39): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 3.2 Hz, 1H), 8.29 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 4.4 MS ESI (m / z) 512 (M+1) + .

[0297] Example 19: Preparation of ethyl (S)-2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)propanoate (Compound 40):

[0298] [ka]

[0299] Compound 22 (0.200g, 4.71×10 -4 To a solution of 0.092 g (5.65 × 10 mol) in DMF (4.0 mL), -4 The reaction mixture was stirred at ambient temperature for 1 h, after which L-(-)-ethyl lactate (74 μL, 6.59 × 10 -4 mol) and DMAP (29 mg, 2.35 × 10 -4 mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature and partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (×1), saturated aqueous NaHCO3 (×1), water (×1), 1.0 M HCl (aq) (×1), and brine (×1). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) eluting with 2:1 (v / v) hexane:ethyl acetate to 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.059 g (24% yield) of ethyl (S)-2-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)propanoate (compound 40): 1 H NMR (CDCl3, 400 MHz): δ ppm8.45 (d, J = 3.2 Hz, 1H), 8.29 (s, 1H), 7.95 (d, J = 3.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 5.6 Hz, 2H), 5.11 (q, J = 7.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.97 (d, J = 8.8 Hz, 2H), 1.48 (d, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); MS ESI (m / z) 526 (M+1) + .

[0300] Example 20: Preparation of 2-(dimethylamino)ethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 41):

[0301] [ka]

[0302] Compound 22 (0.150g, 3.53×10 -4 To a solution of 1.2×10 mol) in DMF (3.0 mL), CDI (63 mg, 3.88×10 -4 The reaction mixture was stirred at ambient temperature for 1 h, and then 2-dimethylaminoethanol (42 μL, 4.24 × 10 -4mol) was added. The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ether and saturated aqueous NaHCO3, the layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 (1x), followed by water (2x). The organic layer was then extracted with 1.0 M HCl (aq) (2x) and the acidic aqueous layers were combined and treated with solid NaHCO3 until a pH of about 9 was reached. At this point the basic aqueous layer was extracted with EtOAc (2x) and the combined EtOAc layers were washed with brine (1x), dried over Na2SO4, filtered, and concentrated in vacuo to provide 0.121 g (69% yield) of 2-(dimethylamino)ethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 41): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.43 (d, J = 3.2 Hz, 1H), 8.28 (s, 1H), 7.92-7.90 (m, 2H), 7.58 (d, J = 9.2 Hz, 1H), 5.73 (s, 2H), 4.21 (t, J = 5.2 Hz, 2H), 3.89 (s, 2H), 2.50 (t, J = 5.2 Hz, 2H), 2.19 (s, 6H); MS ESI (m / z) 497 (M+1) + .

[0303] Example 21: Preparation of 2-((tert-butoxycarbonyl)amino)ethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound 42):

[0304] [ka]

[0305] Compound 22 (0.150g, 3.53×10 -4 To a solution of 1.2×10 mol) in DMF (3.0 mL), CDI (63 mg, 3.88×10-4 The reaction mixture was stirred at ambient temperature for 1 h, after which N-Boc-ethanolamine (71 μL, 4.59×10 -4 mol) was added. The resulting reaction mixture was warmed to 50 °C and stirred overnight. The reaction mixture was cooled to ambient temperature and partitioned between diethyl ether and water, the layers were separated, and the ether layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The ether layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) eluting with 2:1 (v / v) hexane:ethyl acetate to 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.109 g (55% yield) of 2-((tert-butoxycarbonyl)amino)ethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound 42): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.47 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 7.95-7.92 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 5.75 (s, 2H), 4.20 (t, J = 5.6 Hz, 2H), 3.90 (s, 2H), 3.39-3.36 (m, 2H), 1.43 (s, 9H); MS ESI (m / z) 569 (M+1) + .

[0306] Example 22: Preparation of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoate (Compound 43):

[0307] [ka]

[0308] Compound 22 (0.143g, 3.36×10 -4 To a solution of 0.065 g, 4.04 × 10 -4 The reaction mixture was stirred at ambient temperature for 1 h, after which ethyl (tert-butoxycarbonyl)-L-tyrosinate (0.104 g, 3.36×10 -4 mol) and DMAP (21 mg, 1.68 × 10 -4 mol) was added. The resulting reaction mixture was warmed to 40° C. and stirred overnight. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (×1), saturated aqueous NaHCO3 (×1), water (×1), 1.0 M HCl (aq) (×1), and brine (×1). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) eluting with 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.079 g (33% yield) of ethyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoate (compound 43): 1 H NMR (CDCl3, 400 MHz): δ ppm8.50 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 7.92-7.90 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.78 (s, 2H), 4.98-4.96 (m, 1H), 4.54-4.52 (m, 1H), 4.14 (q, J = 6.8 Hz, 2H), 4.10 (s, 2H), 3.08-3.03 (m, 2H), 1.41 (s, 9H), 1.22 (t, J = 6.8Hz, 3H); MS ESI (m / z) 717 (M+1) + .

[0309] Example 23: Preparation of ethyl (S)-2-amino-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoate hydrochloride (Compound 44):

[0310] [ka]

[0311] Acid = HCl, H2SO4, H3PO4, TFA Solvents: Ether, THF, Dioxane, EtOAc

[0312] [ka]

[0313] Compound 43 (0.079g, 1.10×10 -4To a solution of (S)-2-amino-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoate hydrochloride (compound 44), 0.053 g (74% yield): 1 H NMR (DO, 400 MHz): δ ppm 8.54 (d, J = 2.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 8.00 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.8 MS ESI (m / z) 617 (M+1) + .

[0314] Example 24: Preparation of 2-aminoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate hydrochloride (Compound 45):

[0315] [ka]

[0316] Acid = HCl, H2SO4, H3PO4, TFA Solvents: Ether, THF, Dioxane, EtOAc

[0317] [ka]

[0318] Compound 42 (0.113g, 1.99×10 -4 To a solution of 2-aminoethyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate hydrochloride (compound 45), 0.089 g (89% yield): 1 H NMR (CD3OD, 400 MHz): δ ppm 8.62 (d, J = 3.2 Hz, 1H), 8.26 (d, J = 3.2 Hz, 1H), 8.24 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 5.76 (s, 2H), 4.38 (t, J = 4.8 Hz, 2H), 4.07 (s, 2H), 3.25 (t, J = 4.8 Hz, 2H); MS ESI (m / z) 469 (M+1) + .

[0319] Example 25: Preparation of methyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycinate (Compound 46):

[0320] [ka]

[0321] R= X=O, NH, NR 2 Additives: None, N-hydroxysuccinimide (NHS), 4-dimethylaminopyridine (DMAP), hydroxybenzotriazole (HOBT) Base = triethylamine (TEA), diisopropylethylamine ( i PrNEt), pyridine Solvents: dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), tetrahydrofuran (THF)

[0322] [ka]

[0323] Compound 22 (0.100g, 2.35×10 -4 mol), EDC·HCl (59 mg, 3.06×10 -4 mol), NHS (35 mg, 3.06 × 10 -4 mol) and glycine methyl ester hydrochloride (38 mg, 3.06 × 10 -4 To a heterogeneous solution of 1.2×10 mol) in DMF (4.0 mL), -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) eluting with 2:1 (v / v) hexane:ethyl acetate to 19:1 (v / v) CHCl2:methanol. Evaporation of collected fractions afforded 0.028 g (24% yield) of methyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycinate (compound 46): 1 H NMR (CDCl3, 400 MHz): δ ppm8.47 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.71 (br s, 1H), 5.77 (s, 2H), 4.00 (d, J = 5.2 Hz, 2H), 3.84 (s, 2H), 3.68 (s, 3H); MS ESI (m / z) 497 (M+1) + .

[0324] Example 26: Preparation of ethyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycinate (Compound 47):

[0325] [ka]

[0326] Compound 22 (0.100g, 2.35×10 -4 mol), EDC·HCl (59 mg, 3.06×10 -4 mol), NHS (35 mg, 3.06 × 10 -4 mol) and glycine ethyl ester hydrochloride (42 mg, 3.06 × 10 -4 To a heterogeneous solution of 1.2×10 mol) in DMF (4.0 mL), -4mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (monitored by thin layer chromatography) eluting with 19:1 (v / v) CH2Cl2:methanol. Collected fractions were evaporated to give a solid that was suspended in ether and collected by vacuum filtration. The collected solid was washed with ether and dried in vacuum to give 0.018 g (15% yield) of ethyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycinate (compound 47): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 6.69 (br s, 1H), 5.77 (s, 2H), 4.12 (q, J = 6.8 Hz, 2H), 3.98 (d, J = 4.8 Hz, 2H), 3.84 (s, 2H), 1.22 (t, J = 6.8 Hz, 3H); MS ESI (m / z) 511 (M+1) + .

[0327] Example 27: Preparation of isopropyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycinate (Compound 48):

[0328] [ka]

[0329] Compound 22 (0.100g, 2.35×10 -4 mol), EDC·HCl (59 mg, 3.06×10 -4 mol), NHS (35 mg, 3.06 × 10 -4 mol) and glycine isopropyl ester hydrochloride (47 mg, 3.06 × 10 -4 To a heterogeneous solution of 1.2×10 mol) in DMF (4.0 mL), -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 1:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.021 g (17% yield) of isopropyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycinate (compound 48): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.66 (br s, 1H), 5.77 (s, 2H), 4.97 (sept, J = 6.4 Hz, 1H), 3.94 (d, J = 5.2 Hz, 2H), 3.84 (s, 2H), 1.19 (d, J = 6.4 Hz, 6H); MS ESI (m / z) 525 (M+1) + .

[0330] Example 28: Preparation of methyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)-L-alaninate (Compound 49):

[0331] [ka]

[0332] Compound 22 (0.300g, 7.06×10 -4 mol), EDC·HCl (0.176g, 9.18×10 -4 mol), NHS (0.106 g, 9.18 × 10 -4 mol) and L-alanine methyl ester hydrochloride (0.128 g, 9.18 × 10 -4 To a heterogeneous solution of 2.82 × 10 mol) in DMF (10 mL), -3 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 1:1 (v / v) hexane:ethyl acetate. Evaporation of collected fractions afforded 0.101 g (28% yield) of methyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)-L-alaninate (compound 49): 1 H NMR (CDCl3, 400 MHz): δ ppm8.46 (d, J = 3.2 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 3.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 6.70 (br s, 1H), 5.77 (s, 2H), 4.52 (m, 1H), 3.80 (s, 2H), 3.65 (s, 3H), 1.32 (d, J = 7.6 Hz, 3H); MS ESI (m / z) 511 (M+1) + .

[0333] Example 29: Preparation of ethyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)-L-alaninate (Compound 50):

[0334] [ka]

[0335] Compound 22 (0.100g, 2.35×10 -4 mol), EDC·HCl (59 mg, 3.06×10 -4 mol), NHS (35 mg, 3.06 × 10 -4 mol) and L-alanine ethyl ester hydrochloride (47 mg, 3.06 × 10 -4 To a heterogeneous solution of 1.2×10 mol) in DMF (4.0 mL), -4mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (monitored by thin layer chromatography) eluting with 1:1 (v / v) hexane:ethyl acetate. Collected fractions were evaporated to give a solid that was suspended in cold (0°C) ether and collected by vacuum filtration. The collected solid was washed with cold (0° C.) ether and dried in vacuum to give 0.037 g (30% yield) of ethyl (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)-L-alaninate (compound 50): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.46 (d, J = 2.8 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.69 (br s, 1H), 5.77 (s, 2H), 4.49 (m, 1H), 4.09 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 1.31 (d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); MS ESI (m / z) 525 (M+1) + .

[0336] Example 30: Preparation of 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetamide (Compound 51):

[0337] [ka]

[0338] Compound 22 (0.100g, 2.35×10 -4 mol), EDC·HCl (59 mg, 3.06×10 -4 mol), NHS (35 mg, 3.06 × 10 -4 mol) and ammonium acetate (24 mg, 3.06 × 10 -4 To a heterogeneous solution of 1.18 × 10 mol) in DMF (3.0 mL), -3 mol) of 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetamide (compound 51) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography) and eluted with 19:1 (v / v) CHCl2:methanol. Evaporation of collected fractions afforded 0.071 g (71% yield) of 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetamide (compound 51): 1 H NMR (CD3OD, 400 MHz): δ ppm 8.58 (d, J = 2.8 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 8.23 ​​(s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 5.77 (s, 2H), 3.82 (s, 2H); MS ESI (m / z) 425 (M+1) + .

[0339] Example 31: Preparation of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoate (Compound 52):

[0340] [ka]

[0341] Compound 22 (0.100g, 2.35×10 -4 mol), EDC·HCl (59 mg, 3.06×10 -4 mol), NHS (35 mg, 3.06 × 10 -4 mol) and tert-butyl (tert-butoxycarbonyl)-L-tyrosinate (0.103 g, 3.06 × 10 -4 To a heterogeneous solution of 1.2×10 mol) in DMF (4.0 mL), -4 mol) was added. The resulting homogeneous reaction mixture was stirred at ambient temperature overnight. The reaction mixture was then partitioned between EtOAc and water, the layers were separated, and the organic layer was washed successively with water (1x), saturated aqueous NaHCO3 (1x), water (1x), 1.0 M HCl (aq) (1x), and brine (1x). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography (monitored by thin layer chromatography), eluting with 4:1 (v / v) hexane:ethyl acetate to 1:1 (v / v) hexane:ethyl acetate. Evaporation of the collected fractions gave 0.049 g (28% yield) of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoate (compound 52): 1 H NMR (CDCl3, 400 MHz): δ ppm8.50 (d, J = 3.2 Hz, 1H), 8.28 (s, 1H), 7.92-7.90 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, MS ESI (m / z) 745 (M+1) + .

[0342] Example 32: Preparation of (S)-2-amino-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoic acid hydrochloride (Compound 53):

[0343] [ka]

[0344] Acid = HCl, H2SO4, H3PO4, TFA Solvents: Ether, THF, Dioxane, EtOAc

[0345] [ka]

[0346] Compound 52 (0.049g, 6.58×10 -5To a solution of (S)-2-amino-3-(4-(2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetoxy)phenyl)propanoic acid hydrochloride (compound 53), 0.032 g (78% yield): MS ESI (m / z) 589 (M+1). + .

[0347] Example 33: Preparation of (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycine (Compound 54):

[0348] [ka]

[0349] Base = NaOH, LiOH, KOH Solvent = Water, MeOH, EtOH, i PrOH, THF

[0350] [ka]

[0351] Compound 46 (0.096 g, 1.94 × 10 -4To a heterogeneous mixture of 1.0 M NaOH(aq) (0.5 mL) was added. The reaction mixture was stirred at ambient temperature overnight. The resulting homogeneous reaction mixture was partitioned between ether and water, the layers were separated, and the aqueous layer was washed with ether (2x). The basic aqueous layer was acidified to pH ~2 by addition of 1.0 M HCl(aq). The acidic aqueous layer was extracted with EtOAc (3x) and the organic layer was washed with brine (1x), then dried over Na2SO4, filtered, and concentrated in vacuo. The resulting solid was suspended in ether and stirred for 5 min. The solid was collected by vacuum filtration and washed with ether. The resulting solid was dried under vacuum to give 0.069 g (75% yield) of (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)glycine (compound 54): 1 H NMR (CD3OD, 400 MHz): δ ppm 8.56 (d, J = 3.2 Hz, 1H), 8.34 (d, J = 3.2 Hz, 1H), 8.23 ​​(s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 5.77 (s, 2H), 3.92 (s, 2H), 3.90 (s, 2H); MS ESI (m / z) 483 (M+1) + .

[0352] Example 34: Preparation of (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)-L-alanine (Compound 55):

[0353] [ka]

[0354] Base = NaOH, LiOH, KOH Solvent = Water, MeOH, EtOH, i PrOH, THF

[0355] [ka]

[0356] Compound 49 (0.101 g, 1.98 × 10 -4 To a heterogeneous mixture of 1.0 M NaOH(aq) (0.5 mL) was added. The reaction mixture was stirred at ambient temperature overnight. The resulting homogeneous reaction mixture was partitioned between ether and water, the layers were separated, and the aqueous layer was washed with ether (2x). The basic aqueous layer was acidified to pH ~2 by addition of 1.0 M HCl(aq). The acidic aqueous layer was extracted with EtOAc (3x) and the organic layer was washed with brine (1x), then dried over Na2SO4, filtered, and concentrated in vacuo. The resulting solid was suspended in ether and stirred for 5 min. The solid was collected by vacuum filtration and washed with ether. The resulting solid was dried under vacuum to give 0.085 g (87% yield) of (2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetyl)-L-alanine (compound 55): 1 H NMR (CDCl3, 400 MHz): δ ppm 8.47 (d, J = 2.8 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 6.87-6.84 (br s, MS ESI (m / z) 497 (M+1) + .

[0357] Example 35: Characterization of Aldose Reductase Inhibitor Compounds

[0358] The compounds are characterized for physical properties (solubility and LogD).

[0359] Equilibrium solubility in phosphate buffer, pH 7.4: The equilibrium solubility of the test articles is measured in pH 7.4 aqueous buffer. The pH 7.4 buffer is prepared by combining 50 mL of 0.2 M KH2PO4 with 150 mL of H2O and then adjusting to pH 7.4 with 10 N NaOH. At least 1 mg of powder for each test article is combined with 1 mL of buffer to create a mixture of 1 mg / mL or greater. These samples are shaken overnight at room temperature on a Thermomixer®. The samples are then centrifuged at 10,000 rpm for 10 minutes. The supernatant is sampled and diluted 10x, 100x, and 100 millionx in duplicate in a 1:1 buffer:acetonitrile (ACN) mixture prior to analysis. All samples are 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.

[0360] Octanol / Buffer Partition Coefficients at pH 7.4 (LogD): The octanol / buffer partition coefficients of the three test articles are measured at pH 7.4. The pH 7.4 buffer is 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 (100 μM) of each test article is added to a test tube containing 0.75 mL of octanol and 0.75 mL of pH 7.4 phosphate buffer. Testosterone is also introduced into each tube as an internal control, at a dose concentration of 100 μM. The samples are mixed gently on a benchtop rotator for 1 hour at room temperature. The tubes are then removed from the rotator and the aqueous and organic phases are allowed to separate for 1 hour. An aliquot of the organic layer is taken and diluted 200-fold in a 1:1 buffer:acetonitrile (ACN) mixture. Take an aliquot of the aqueous layer and dilute 2x, 10x, and 200x into a mixture of 1:1 buffer:ACN. Assay all samples by LC-MS / MS using electrospray ionization. Utilize testosterone as a positive control (published / known LogD of 3.0-3.4).

[0361] Example 36: In Vitro Testing: Aldose Reductase Enzyme Inhibition

[0362] The compounds are characterized for biochemical characteristics, such as the ability to inhibit aldose reductase enzyme activity in vitro. The reductase activity of the compounds of the present invention is spectrophotometrically assayed according to the reduction of NADPH at 25° C. for 4 minutes, as described in Sato, S. (1992), "Rat kidney aldose reductase and aldehyde reductase and polyolproduction in rat kidney," Am.J Physiol.263, F799.F805, which is incorporated herein by reference in its entirety.

[0363] The reaction mixture (total volume 1 ml) contains 0.1 mM NADPH, 100 mM substrate (DL-glyceraldehyde or L-xylose) and human recombinant aldose reductase (100 mU) in 0.1 M phosphate buffer, pH 6.2. Experiments are performed in a microplate assay for AR inhibition using D-glyceraldehyde and NADPH, the absorbance change is monitored at 340 nm, and the % inhibition is calculated for ARl at concentrations ranging from 0.1 nM to 100 μM. The reaction is initiated by adding the substrate (glyceraldehyde or xylose) as well as the same reaction mixture used as a control with the substrate replaced with deionized water. One enzyme unit (U) is defined as the activity that consumes 1 μmol of NADPH in 1 minute at 25° C. The enzyme inhibition assay is performed as described in WO 2012 / 009553, which is incorporated herein by reference in its entirety.

[0364] Example 37: Ex vivo studies

[0365] Rat studies are performed with the approval of the Animal Care and Use Committee of Columbia University, New York. This investigation complies with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85-23, 1996; incorporated herein by reference in its entirety).

[0366] Experiments are performed using isovulic isolated rat heart preparations as described in Hwang YC, Sato S, Tsai JY, Yan S, Bakr S, Zhang H, Oates PJ, Ramasamy R (2002), "Aldose reductase activation is a key component of myocardial response to ischemia", Faseb J. 16, 243-245 and Ramasamy R, Hwang YC, Whang J, Bergmann SR (2001), "Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4", American Journal of Physiology. 281, H290-297, each of which is incorporated herein by reference in its entirety.

[0367] Male Wistar rats (300.350 g, 3-4 months old) are anesthetized with a mixture of ketamine (80 mg / kg) and xylazine (10 mg / kg). After deep anesthesia is achieved, the heart is rapidly excised, placed in ice-cold saline, and perfused retrogradely at 37 °C in non-recirculating mode through the aorta at a rate of 12.5 ml / min. The heart is perfused with modified Krebs-Henseleit buffer containing (in mM): NaCl 118, KCl 4.7, CaCl 2.5, MgCl 2 1.2, NaHCO 3 25, glucose 5, palmitate 0.4, bovine serum albumin 0.4, and 70 mU / L insulin. The perfusate is equilibrated with a mixture of 95% 02 and 5% CO2, which allows the perfusate P O2is maintained above 600 mmHg. Maximal left ventricular pressure (LVDP) and left ventricular end diastolic pressure (LVEDP) are measured using a latex balloon in the left ventricle. LVDP, heart rate, and coronary perfusion pressure are continuously monitored with an ADI recorder. All rat hearts are subjected to 20 min of zero-flow ischemia and 60 min of reperfusion (I / R).

[0368] In studies involving the use of aldose reductase inhibitors, hearts are perfused with modified Krebs-Henseleit buffer containing a compound of the invention at a final concentration of 100 nM 10 min prior to ischemia and continued throughout the perfusion protocol. Creatine kinase (CK) release, a marker of myocardial I / R injury, is measured as described in Hwang YC, Sato S, Tsai JY, Yan S, Bakr S, Zhang H, Oates PJ, Ramasamy R (2002), "Aldose reductase activation is a key component of myocardial response to ischemia", Faseb J. 16, 243-245 and Ramasamy R, Hwang YC, Whang J, Bergmann SR (2001), "Protection of ischemic hearts by high glucose is mediated, in part, by GLUT-4", American Journal of Physiology. 281, H290-297, each of which is incorporated by reference in its entirety.

[0369] The isolated perfused heart is subjected to ischemia-reperfusion (1 / R) injury, and the scale of cardiac injury and cardiac function are monitored.The release of creatine kinase (CK) during reperfusion, which is a marker of cardiac ischemic injury, is measured in the rat heart treated with the compound of the present invention and in the untreated heart.The maximum left ventricular pressure (LVDP) is measured in the rat heart treated with the compound of the present invention and in the untreated heart after I / R.

[0370] While the invention has been described and illustrated in the foregoing exemplary embodiments, it will be understood that the disclosure is made by way of example only, and that numerous changes in the details of the implementation of the invention may be made without departing from the spirit and scope of the invention, which is limited only by the following claims. The features of the disclosed embodiments can be combined and rearranged in various ways within the scope and spirit of the invention.

[0371] All patents, patent applications, and publications cited herein are incorporated herein by reference in their entireties. The disclosures of these publications are incorporated herein by reference in their entireties in order to more fully describe the prior art known to those skilled in the art as of the date of the invention described and claimed herein.

[0372] 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 the patent disclosure as it appears in the U.S. Patent and Trademark Office patent files or records, but otherwise reserves any and all copyright rights whatsoever. The present invention provides, for example, the following items. (Item 1) Compounds of formula (I) [ka] (In the formula, X 1 is N or CR 1 and; X 2 N, CR 2 or S; X 3 N, CR 3 or a combination; X 4 is N or CR 4 where X 2 If S, then X1 is CR 1 and X 4 is CR 4 and X 3 is a single bond; or X 1 、X 2 、X 3 or X 4 Two or three of these are N; Y is a bond, C=O, C=S, C=NH, or C=N(C 1 ~C 4 )-alkyl; Z is

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Claims

1. Compounds of formula (I) 【Chemistry 154】 (In the formula, X １ is CR １ and X ２ is S; X ３ is a bond; X ４ is CR ４ and Y is C=O; Z is 【Chemistry 157】 and A １ is S; A ２ is N; R １ ~R ８ 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; or R １ ~R ４ Two of the following, or R ５ ~R ８ Two of them together form (C １ ~C ４ )-alkylenedioxy; X ５ Q-R １０ and Q is O, NH, O-(C １ ~C ６ )-alkyl, O—(C １ ~C ６ )-hydroxyalkyl, O—(C １ ~C ６ )-aminoalkyl, O-aryl, O-heteroaryl, O-biaryl, O-benzyl, NH—(C １ ~C ６ )-alkyl, NH-(C １ ~C ６ )-hydroxyalkyl, NH—(C １ ~C ６ )-aminoalkyl, NH-aryl, NH-heteroaryl, NH-biaryl, NH-benzyl, or a bond; R １０ teeth 【Chemistry 156】 Aryl, heteroaryl, biaryl, benzyl, heterocycle, or C(O)OR １１ with the proviso that when Q is not a bond, then R １０ can be bonded to any substitutable atom in Q, and when Q is NH, R １０ may be H or OH; R １１ and R １２ are independently H or OR １３ , N.H.R. １３ , S.R. １３ , CO ２ R １３ , C.O.N.R. １３ , aryl, hydroxyaryl, indolyl, imidazolyl, and NH(CNH)NH ２ (C １ ~C ６ )-alkyl; Or R １１ and R １２ together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring; R １３ is H or (C １ ~C ６ )-alkyl; n is 0, 1, or 2. or a pharma- ceutically acceptable salt thereof.

2. The compound is represented by formula (I-4): 【Chemistry 158】 (In the formula, R ５ , R ６ , R ７ , R ８ and X ５ is as defined in formula (I). The compound of claim 1 ,

3. X ５ but 【Chemistry 159】 3. The compound according to claim 1 or 2, selected from the group consisting of:

4. R ５ , R ７ and R ８ are each H; R ６ The compound according to any one of claims 1 to 3, wherein is halogen or haloalkyl.

5. R ６ The compound according to any one of claims 1 to 4, wherein is trifluoromethyl. 【Request 6】 【Chemical 164】 2. A compound selected from the group consisting of: and pharma- ceutically acceptable salts thereof.

7. 【Chemical 165】 2. A compound selected from the group consisting of: and pharma- ceutically acceptable salts thereof.

8. 8. The compound of claim 7, wherein the pharma- ceutically acceptable salt thereof is the hydrochloride salt.

9. 【Chemical 166】 2. A compound selected from the group consisting of: and pharma- ceutically acceptable salts thereof.

10. 10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharma- ceutically acceptable carrier.

11. 10. A composition comprising a compound according to any one of claims 1 to 9 for use in a method for inhibiting aldose reductase activity in a subject.

12. The composition of claim 11 , wherein the subject is a human.

13. 10. A composition comprising a compound according to any one of claims 1 to 9 for use in a method of treating a disorder in a subject.

14. The composition of claim 13, wherein the disorder is stroke.

15. The composition of claim 13, wherein the disorder is ischemic stroke.

16. The composition of claim 13 , wherein the injury is tissue damage.

17. The composition of claim 13, wherein the injury is brain injury.

18. The composition of claim 13, wherein the injury is nerve damage.

19. The composition of claim 13, wherein the disorder is an autoimmune disease.

20. The composition of claim 13, wherein the disorder is galactosemia.

21. The composition of claim 13, wherein the disorder is Phosphomannomutase 2-Congenital Glycosylation Disorder (PMM2-CDG).

22. The composition of claim 13, wherein the disorder is a diabetic complication.

23. 23. The composition of claim 22, wherein the diabetic complication is diabetic cardiomyopathy, diabetic retinopathy, diabetic neuropathy or diabetic nephropathy.

24. The composition of claim 13, wherein the disorder is neuropathy, retinopathy, or nephropathy.

25. The composition of claim 13, wherein the disorder is a cardiovascular disorder.

26. 26. The composition of claim 25, wherein the cardiovascular disorder is a cardiomyopathy.

27. 10. A composition comprising a compound according to any one of claims 1 to 9 for use in a method for treating skin aging.

28. The composition of claim 27, wherein the composition is administered topically to the skin.

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