RU2795195C2 - Aldose reductase inhibitors and methods of their application - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to a heterocyclic compound of formula (I) or a pharmaceutically acceptable salt thereof, where R¹ represents CO₂R²; R² is H, (C₁-C₆)-alkyl or (C₁-C₆)-aminoalkyl; X¹ and X² are H; Y is C=O; Z represents

or

; A¹ is S; A² is N; A³ is O; and R³-R⁶ are independently hydrogen, halogen or haloalkyl. The invention also relates to specific compounds and a pharmaceutical composition based on a compound of formula (I) or a specific compound.

EFFECT: effective inhibition of aldoreductase activity in the treatment of such diseases as diabetes, neuropathy, retinopathy, nephropathy and cardiomyopathy.

38 cl, 1 tbl, 17 ex

Description

[0001] This application claims priority to U.S. Provisional Application No. 62/352,784, filed June 21, 2016, which is hereby incorporated by reference in its entirety.

[0002] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. The disclosure of these publications, in their entirety, is incorporated herein by reference in this application for a more complete description of the state of the art known to those skilled in the art as of the date of the invention described and claimed herein.

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to anyone's facsimile reproduction of the patent document or patent disclosure as it appears in the patent register or registered in the US Patent and Trademark Office, but otherwise retains all copyright.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0004] The present invention relates to novel compounds and pharmaceutical compositions thereof, as well as methods for promoting healthy skin aging, treating skin diseases, treating cardiovascular diseases, treating kidney disorders, treating angiogenesis disorders such as cancer, treating tissue damage such as damage to non-cardiac tissue, treatment of developing myocardial infarction, treatment of ischemic injury, and treatment of various other disorders, such as complications arising from diabetes, with the compounds and compositions of the invention. Other disorders may include, without limitation, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, skin infections, peripheral vascular disease, stroke, asthma, and the like.

BACKGROUND OF THE INVENTION

[0005] Diabetes is one of the most common chronic diseases in which high blood glucose leads to a stop in insulin production and/or loss of insulin sensitivity. People with high blood glucose levels have a higher glucose metabolism by converting glucose to sorbitol and then to fructose in insulin-insensitive cells such as lenses, peripheral nerves, and glomeruli. This leads to an excess of sorbitol in the cells, which hardly diffuses through the cell membrane. An increased concentration of sorbitol causes an influx of water into the cells, causing them to swell and potentially damage.

[0006] Aldose reductase (AP, AR) is a monomeric NADPH-dependent oxidoreductase from the aldoket reductase family of enzymes. It is an enzyme that is present in many parts of the body. Aldose reductase catalyzes the reduction of saturated and unsaturated aldehydes, including aldosaccharides and monosaccharides, as well as a wide variety of other substrates. Primarily, aldose reductase catalyzes the reduction of glucose to sorbitol, one of the steps in the sorbitol pathway that is responsible for the formation of fructose from glucose. Aldose reductase activity increases as glucose concentration rises in diabetic conditions, when tissues are no longer insulin sensitive. These tissues include, for example, lenses, peripheral nerves, and renal glomeruli. Sorbitol hardly diffuses through cell membranes and therefore accumulates, causing osmotic damage, which in turn leads to the development of retinopathy, neuropathy, nephropathy and cardiomyopathy. The mechanism of damage is also associated with an increase in oxidative stress and damage, as well as an increased amount of advanced advanced glycation end products. Therefore, inhibition of aldose reductase can prevent the accumulation of sorbitol in insulin-insensitive cells in diabetics and represents a new way to prevent macrovascular and microvascular complications in diabetic patients. In addition, aldose reductase inhibitors such as zopolrestat may help treat or attenuate such effects and have been shown to be effective in wound healing in the corneal epithelium in diabetic animal models. Finally, AR has recently been used in a wide range of therapeutic areas, including cancer, myocardial infarction and ischemic injury, asthma, and transplantation.

[0007] Previous clinical trials have shown that although aldose reductase inhibitors are well tolerated by patients, their effectiveness in controlling disease is minimal. These failures have been attributed to current aldose reductase inhibitors, which have low potency and a short half-life, resulting in reduced efficacy. In addition, some aldose reductase inhibitors are toxic. Thus, there is a need for new compounds, inhibitors of aldose reductase.

SUMMARY OF THE INVENTION

[0008] It is understood that any of the embodiments described below may be combined in any desired manner and that any embodiment or combination of embodiments may apply to each of the aspects described below unless the context indicates otherwise.

[0009] In one aspect, the invention relates to a compound of formula (I)

(I),

(I)

Where

R ¹ is CO ₂ R ² or CO ₂ ^- X ⁺ ;

R ² is H, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-hydroxyalkyl or (C ₁ -C ₆ )-aminoalkyl;

X ¹ represents H or halogen;

X ² represents H or halogen;

Y represents a bond, C=O, C=S, C=NH or C=N(C ₁ -C ₄ )-alkyl;

или

Z represents

or

A ¹ is NR ⁷ , O, S or CH ₂ ;

A ² is N or CH;

A ³ is NR ⁷ , O or S;

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl;

R ⁷ represents hydrogen, C ₁ -C ₄ alkyl or C(O)O-(C ₁ -C ₄ )-alkyl; And

X ⁺ is a counterion; or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, R ² is hydrogen or (C ₁ -C ₆ )-alkyl;

Y is C=O;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S; And

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (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 a pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, R ² is hydrogen or t-butyl;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, Z is

[0013] In some embodiments, R ² is hydrogen or (C ₁ -C ₆ )-alkyl;

Y is C=O;

A ¹ is NR ⁷ , O or S;

A ² is N;

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )- alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ alkyl or C(O)O-(C ₁ -C ₄ )-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0014] In some embodiments, R ² is hydrogen or tert-butyl;

Y is C=O;

A ¹ is NR ⁷ , O or S;

A ² is N;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; a pharmaceutically acceptable salt or solvate thereof.

[0015] In some embodiments, R ² is hydrogen or tert-butyl;

Y is C=O;

A ¹ is NR ⁷ , O or S;

A ² is N;

R ³ -R ⁶ independently represent hydrogen, halogen or CF ₃ ; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, R ² is hydrogen;

X ¹ is H;

X ² is H;

Y is C=O;

A ¹ is S;

A ² is N;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0017] In some embodiments, R ² is hydrogen;

X ¹ is H;

X ² is H;

Y is C=O;

A ¹ is S;

A ² is N;

R ³ , R ⁵ and R ⁶ are hydrogen;

R ⁴ is hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; a pharmaceutically acceptable salt or solvate thereof.

[0018] In some embodiments, a compound of formula (I) is represented by the formula

или его фармацевтически приемлемую соль или сольват.

or a pharmaceutically acceptable salt or solvate thereof.

[0019] In some embodiments, R ² is hydrogen;

X ¹ represents Cl;

X ² represents Cl;

Y is C=O;

A ¹ is S;

A ² is N;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, R ² is hydrogen;

X ¹ represents Cl;

X ² represents Cl;

Y is C=O;

A ¹ is S;

A ² is N;

R ³ , R ⁵ and R ⁶ are hydrogen;

R ⁴ is hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0021] In some embodiments, a compound of formula (I) is represented by the formula

или его фармацевтически приемлемую соль или сольват.

or a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, Z is

[0023] In some embodiments, R ² is hydrogen or (C ₁ -C ₆ )-alkyl;

Y is C=O;

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )- alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ alkyl or C(O)O-(C ₁ -C ₄ )-alkyl; or a pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, R ² is hydrogen or tert-butyl;

Y is C=O;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0025] In some embodiments, R ² is hydrogen or tert-butyl;

Y is C=O;

R ³ -R ⁶ independently represent hydrogen or halogen; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0026] In some embodiments, R ² is hydrogen;

X ¹ is H;

X ² is H;

Y is C=O;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0027] In some embodiments, R ² is hydrogen;

X ¹ is H;

X ² is H;

Y is C=O;

R ³ , R ⁵ and R ⁶ are hydrogen;

R ⁴ is hydrogen or halogen; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0028] In some embodiments, a compound of formula (I) is represented by the formula

,

или

, или его фармацевтически приемлемую соль или сольват.

,

or

, or a pharmaceutically acceptable salt or solvate thereof.

[0029] In some embodiments, R ² is hydrogen;

X ¹ represents Cl;

X ² represents Cl;

Y is C=O;

R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0030] In some embodiments, R ² is hydrogen;

X ¹ represents Cl;

X ² represents Cl;

Y is C=O;

A ³ is NR ⁷ , O or S; And

R ³ , R ⁵ and R ⁶ are hydrogen;

R ⁴ is hydrogen or halogen; And

R ⁷ is hydrogen, (C ₁ -C ₄ )-alkyl or C(O)O-tert-butyl; or a pharmaceutically acceptable salt or solvate thereof.

[0031] In some embodiments, the compound of formula (I) is selected from the group consisting of:

,

,

,

,

,

,

,

и

.

,

,

,

,

,

,

,

And

.

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

[0033] In some embodiments, the counterion is selected from the group consisting of:

[0034] В другом аспекте изобретение относится к фармацевтической композиции, содержащей соединение формулы (I) и фармацевтически приемлемый носитель.

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

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

[0036] In some embodiments, the subject is diabetic.

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

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

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

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

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

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

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

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

[0045] In some embodiments, the implementation of the disorder is a violation of angiogenesis.

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

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

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

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

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

[0051] The present invention, in particular, is based on certain discoveries, which are described in more detail in the present application section "Examples". For example, the present invention is based in particular on the discovery of compounds of formula (I) and their aldose reductase inhibitory activity.

[0052] These and other embodiments of the invention are described in the following sections of the application, including a detailed description, examples and claims. Other objects and advantages of the invention will become apparent to those skilled in the art from the disclosure in this application, which is purely illustrative and not restrictive. Thus, other embodiments of the invention will be apparent to those skilled in the art without departing from the scope and without changing the spirit of the invention.

DETAILED DESCRIPTION

[0053] Aldose reductase inhibitors are described, for example, in US Patent Nos. 8,916,563; 5677342; 5304557; 5155259; 4954629; 4939140; U.S. Patent Application Publication 2006/0293265; Roy et al., in Diabetes Research and Clinical Practice 1990, 10(1), 91-97; CN101143868A; and Chatzopoulou et al., in Expert Opin. Ther. Pat. 2012, 22, 1303 ; and links provided in it; each of which is incorporated herein in its entirety by reference. Aldose reductase inhibitors include, for example, zopolrestat, epalrestat, ranirestat, berberine and sorbinil. A new family of aldose reductase inhibitors have been discovered and are described in this application. Surprisingly, this new family includes compounds that have significantly improved properties such as, for example, binding affinity, solubility and polarity compared to other aldose reductase inhibitors, such as, for example, zopolrestat. Compounds such as zopolrestat are described, for example, in US Pat. Nos. 4,939,140; 6159976; and 6570013; each of which is incorporated herein in its entirety by reference.

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

Abbreviations and definitions

[0055] 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 reduction of aldose. Examples of aldoses include, without limitation, glucose or galactose and their respective polyols such as sorbitols and galactitols. Examples of aldose reductase inhibitors can be found in US Pat. Nos. 8,916,563; 5677342; 5304557; 5155259; 4954629; 4939140; U.S. Patent Application Publication 2006/0293265; and Roy et al., in Diabetes Research and Clinical Practice 1990, 10(1), 91-97; each of which is incorporated herein in its entirety by reference.

[0056] As used herein, the term "compound of the invention" means a compound of formula (I). The term also includes their salts, hydrates, prodrugs and solvates.

[0057] As used herein, the term "composition(s)" means compositions containing a compound of the invention, as well as salts, hydrates, prodrugs, or solvates thereof. The compositions of the invention may additionally contain other agents such as, for example, excipients, stabilizers, lubricants, solvents, and the like.

[0058] As used herein, the term “alkyl”, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon radical having a straight chain, a branched chain, a monocyclic group, or a polycyclic group, or combinations thereof, where the radical is optionally substituted with one or more carbon atoms. straight chain, branched chain, monocyclic portion or polycyclic portion, or combinations thereof with one or more substituents on each carbon, where one or more substituents are independently C ₁ -C ₁₀ alkyl. Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0059] Used in the present description, the term "solvate" means a compound or its pharmaceutically acceptable salt, where the molecules of a suitable solvent are included in the crystal lattice. A suitable solvent is physiologically well tolerated at the doses administered. Examples of suitable solvents are ethanol, water, and the like. When the solvent is water, the molecule is referred to as a "hydrate".

[0060] The term "pharmaceutically acceptable salt" includes salts derived from inorganic or organic acids, including, for example, hydrochloric, hydrobromic, sulfuric, nitric, chloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic , salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic and other acids; and salts derived from inorganic or organic bases, including, for example, sodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine, histidine, polyhydroxylated amines, or tetrafluoroborate. Examples of pharmaceutically acceptable salts are given, for example, in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and US Pat. Nos. 6,570,013 and 4,939,140; (each of which is incorporated herein by reference). Pharmaceutically acceptable salts also include hemi-salts in which the ratio of the compound is: the acid is respectively 2: 1. Typical hemi-salts are salts derived from acids containing two carboxyl groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary semi-salts are salts derived from dibasic mineral acids such as sulfuric acid Examples of preferred semi-salts include, without limitation, semi-maleate, semi-fumarate, and semi-succinate.

[0061] The term "acid" encompasses all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic and hydrochloric acids, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are linear or branched, saturated or unsaturated C ₁ -C ₂₀ aliphatic carboxylic acids which are optionally substituted with halogen or hydroxyl groups, or C ₆ -C ₁₂ aromatic 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, tartaric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylstearic acid. Other acids include gluconic acid, glycoheptonic acid and lactobionic acid.

[0062] As used herein, the term "about" is used to mean about, about, about, or in the region. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending its boundaries above and below the stated numerical values. As a rule, the term "about" is used in the present description to increase or decrease the numerical value of the specified value by 20% up or down (higher or lower).

[0063] An "effective amount", "sufficient amount", or "therapeutically effective amount", as used herein, is an amount of a compound that is sufficient to produce beneficial or desired results, including clinical results. Thus, an effective amount may be sufficient, for example, to reduce or improve the severity and/or duration of disorders associated with aldose reductase, or one or more symptoms that prevent improvement of the condition, or symptoms associated with diseases associated with aldose reductase, or increase or otherwise improving the prophylactic(s) or therapeutic(s) effect(s) of another therapy. An effective amount also includes an amount of the compound that prevents or substantially reduces unwanted side effects.

[0064] As used herein and well known in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include (without limitation) alleviation or improvement of one or more symptoms or conditions, reduction in the severity of a disease or disorder, a stabilized (i.e., not worsening) state of a disease or disorder, prevention of the spread of a disease or disorder, delay or slowing down progression of the disease or disorder, improvement or amelioration of the severity of the disease or disorder, and remission (whether partial or total), whether detectable or non-detectable. "Treatment" can also mean prolonging survival compared to expected survival without treatment.

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

[0066] In one embodiment, the aldose reductase inhibitors described herein include compounds of formula (I) or pharmaceutically acceptable salts, prodrugs, and solvates thereof,

(I),

(I)

Where

R ¹ is CO ₂ R ² or CO ₂ ^- X ⁺ ;

R ² is H, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-hydroxyalkyl or (C ₁ -C ₆ )-aminoalkyl;

X ¹ represents H or halogen;

X ² represents H or halogen;

Y represents a bond, C=O, C=S, C=NH or C=N(C ₁ -C ₄ )-alkyl;

или

Z represents

or

A ¹ is NR ⁷ , O, S or CH ₂ ;

A ² is N or CH;

A ³ is NR ⁷ , O or S;

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl;

R ⁷ represents hydrogen, C ₁ -C ₄ alkyl or C(O)O-(C ₁ -C ₄ )-alkyl; And

X ⁺ is a counterion.

[0067] Those skilled in the art will appreciate that the notation

, или Z представляет собой

означает, что Z представляет собой

, соединения формулы (I) включают

(I-1); и когда Z представляет собой

, соединения формулы (I) включают

(I-2) и

(I-3).Z represents

, or Z is

means Z is

, compounds of formula (I) include

(I-1); and when Z is

, compounds of formula (I) include

(I-2) and

(I-3).

[0068] In some embodiments, R ¹ is CO ₂ R ² or CO ₂ ^- X ⁺ . In some embodiments, R ¹ is CO ₂ R ² . In some embodiments, R1 is CO ₂ ^- X ⁺ .

[0069] In some embodiments, R ² is hydrogen or (C ₁ -C ₆ )-alkyl. In some embodiments, R ² is hydrogen or (C ₁ -C ₄ )-alkyl. In some embodiments, R ² is hydrogen or (C ₁ -C ₃ )-alkyl. In some embodiments, R ² is hydrogen, methyl, or ethyl. In some embodiments, R ² is hydrogen or methyl. In some embodiments, R ² is methyl or ethyl. In some embodiments, R ² is methyl. In some embodiments, R ² is hydrogen. In some embodiments, R ² is (C ¹ -C ⁶ )-alkyl. In some embodiments, R ² is (C ₁ -C ₆ )-n-alkyl. In some embodiments, R ² is (C ₁ -C ₂ )-alkyl. In some embodiments, R ² is (C ₁ -C ₃ )-alkyl. In some embodiments, R ² is (C ₁ -C ₄ )-alkyl. In some embodiments, R ² is tert-butyl.

[0070] In some embodiments, R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (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.

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

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

[0073] In some embodiments, R ⁴ is hydrogen, halogen, or haloalkyl. In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is haloalkyl. In some embodiments, R ⁴ is CF ₃ .

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

[0075] In some embodiments, Y is C=O, C=S, C=NH, or C=N(C ₁ -C ₄ )-alkyl. In some embodiments, Y is C=O or C=S. In some embodiments, Y is C=O. In some embodiments, Y is C=S. In some embodiments, Y is C=NH or C=N(C ₁ -C ₄ )-alkyl.

[0076] In some embodiments, A ¹ is NR ⁷ , O, S, or CH ₂ . In some embodiments, A ¹ is NR ⁷ , O, or S. In some embodiments, A ¹ is NR ⁷ , S, or CH ₂ . In some embodiments, A ¹ is NR ⁷ or O. In some embodiments, A ¹ is NR ⁷ or S. In some embodiments, A ¹ is NR ⁷ . In some embodiments, A ¹ is O. In some embodiments, A ¹ is S.

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

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

[0079] In some embodiments, X ¹ and X ² are hydrogen.

[0080] In some embodiments, X ¹ and X ² are halogen. In some embodiments, X ¹ and X ² are Cl.

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

.[0082] In some embodiments, Z is

.

.[0083] In some embodiments, Z is

.

[0084] In some embodiments, R ⁷ is hydrogen, C ₁ -C ₄ alkyl, or C(O)O-(C ₁ -C ₄ ) alkyl. In some embodiments, R ⁷ is hydrogen. In some embodiments, R ⁷ is C ₁ -C ₄ alkyl. In some embodiments, R ⁷ is C ₁ -C ₃ alkyl. In some embodiments, R ⁷ is C ₁ -C ₂ alkyl. In some embodiments, R ⁷ is C ₁ -C ₄ -n -alkyl. In some embodiments, R ⁷ is C ₁ -C ₃ - n -alkyl. In some embodiments, R ⁷ is C(O)O-(C ₁ -C ₄ )-alkyl. In some embodiments, R ⁷ is C(O)O-(C ₁ -C ₃ )-alkyl. In some embodiments, R ⁷ is C(O)O-(C ₁ -C ₂ )-alkyl. In some embodiments, R ⁷ is C(O)O-(C ₁ -C ₄ ) -n -alkyl. In some embodiments, R ⁷ is C(O)O-(C ₁ -C ₃ ) -n -alkyl.

[0085] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or (C ₁ -C ₆ )-alkyl;

X ¹ is H;

X ² is H;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

[0086] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or tert-butyl;

X ¹ is H;

X ² is H;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ⁶ -R ⁶ are independently hydrogen, halogen, haloalkyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

[0087] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or tert-butyl;

X ¹ is H;

X ² is H;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ³ , R ⁵ and R ⁶ are hydrogen;

R ⁴ is hydrogen, halogen or haloalkyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

[0088] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or (C ₁ -C ₆ )-alkyl;

X ¹ is halogen;

X ² is halogen;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ³ -R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

[0089] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or tert-butyl;

X ¹ is halogen;

X ² is halogen;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ³ -R ⁶ are independently hydrogen, halogen, haloalkyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

[0090] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or tert-butyl;

X ¹ represents Cl;

X ² represents Cl;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ³ -R ⁶ are independently hydrogen, halogen, haloalkyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

[0091] In some embodiments, R ¹ is CO ₂ R ² ;

R ² is H or tert-butyl;

X ¹ represents Cl;

X ² represents Cl;

Y is C=O;

или

;Z represents

or

;

A ¹ is NR ⁷ , O or S;

A ² is N;

A ³ is O or S;

R ³ , R ⁵ and R ⁶ are hydrogen;

R ⁴ is hydrogen, halogen or haloalkyl; And

R ⁷ represents hydrogen, C ₁ -C ₄ -alkyl or C(O)O-(C ₁ -C ₄ )-alkyl.

,

,

,

,

,

,

,

и

.[0092] In some embodiments, the compound of formula (I) is selected from the group consisting of:

,

,

,

,

,

,

,

And

.

или его фармацевтически приемлемую соль.[0093] In some embodiments, the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

или его фармацевтически приемлемую соль.[0094] In some embodiments, the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, X ⁺ is a counterion. In some embodiments, the counterion is sodium, lithium, potassium, calcium, ammonium, or tetrafluoroborate. In some embodiments, the counterion is sodium, lithium, potassium, calcium, ammonium, or a protonated amino acid. In some embodiments, the counterion is sodium, lithium, potassium, ammonium, or a protonated amino acid. In some embodiments, the counterion is sodium or ammonium. In some embodiments, the counterion is lithium or potassium. In some embodiments, the counterion is sodium, ammonium, or an amino acid. In some embodiments, the counterion is potassium, ammonium, or an amino acid. In some embodiments, the counterion is sodium or calcium. In some embodiments, the counterion is lithium, potassium, or calcium. In some embodiments, the counterion is sodium. In some embodiments, the counterion is lithium. In some embodiments, the counterion is potassium. In some embodiments, the counterion is calcium. In some embodiments, the counterion is ammonium. In some embodiments, the counterion is a tetrafluoroborate. In some embodiments, the compound of formula (I) is highly water soluble when X ⁺ is a counterion. It is well known in the art that highly water-soluble drugs, when administered orally, provide efficient absorption of such drugs from the gastrointestinal tract into the systemic circulation. Another hallmark of such drugs is the rapid rate at which they are absorbed into the systemic circulation, resulting in a high blood concentration of the active agent. In addition, water-soluble preparations are particularly suitable for parenteral administration, eg intravenous administration.

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

,

,

,

,

,

или

. В некоторых вариантах осуществления противоион представляет собой

. В некоторых вариантах осуществления противоион представляет собой

. В некоторых вариантах осуществления противоион представляет собой

. В некоторых вариантах осуществления противоион представляет собой

. В некоторых вариантах осуществления противоион представляет собой

. В некоторых вариантах осуществления противоион представляет собой

. В некоторых вариантах осуществления противоион представляет собой

.[0097] In some embodiments, the counterion is

,

,

,

,

,

or

. In some embodiments, the counterion is

. In some embodiments, the counterion is

. In some embodiments, the counterion is

. In some embodiments, the counterion is

. In some embodiments, the counterion is

. In some embodiments, the counterion is

. In some embodiments, the counterion is

.

Synthesis

[0098] The compounds described in this application can be obtained by known methods. Schemes 1-4 are general synthetic schemes for the preparation of compounds of formula (I). These schemes are illustrative and are not intended to limit the possible methods that can be used by a person skilled in the art to obtain the compounds disclosed in this application. Various methods will be apparent to those skilled in the art. Those skilled in the art may use various modifications of these methods to achieve similar results to those set forth below. For example, optional protective groups can be used as described in, for example, Greene et al., Protective Groups in Organic Synthesis ( ^4th ed., 2006).

[0099] Compounds of formula (I-1) can generally be prepared, for example, according to Scheme 1:

Scheme 1,

where X ¹ , X ² , R ¹ , A ¹ , A ² , R ² , R ³ -R ⁷ are as defined above, and Q is a halogen such as Cl, Br, I, and the like. or any other leaving group such as OSO ₂ Me, OMs, OTs, OTf, and the like.

[0100] Compounds of formula (I-2) can generally be prepared, for example, according to Scheme 2:

Scheme 2,

where X ¹ , X ² , R ¹ , A ¹ , A ² , R ² , R ³ -R ⁷ are as defined above, and Q is a halogen such as Cl, Br, I, and the like. or any other leaving group such as OSO ₂ Me, OMs, OTs, OTf, and the like.

[0101] Compounds of formula (I-2) can generally be prepared, for example, according to Scheme 3:

Scheme 3,

where X ¹ , X ² , R ¹ , A ¹ , A ² , R ² , R ³ -R ⁷ are as defined above, and Q is a halogen such as Cl, Br, I, and the like. or any other leaving group such as OSO ₂ Me, OMs, OTs, OTf, and the like.

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

[0103] In some embodiments, the reaction can be carried out using aprotic solvents such as DMF, THF, NMP, and the like. In some embodiments, the reaction can be carried out using alcoholic solvents such as methanol, ethanol, and the like.

[0104] In some embodiments, the implementation of the reaction can be carried out at temperatures from about 5°C to about 80°C, for example from 20°C to 30°C.

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

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

Scheme 4

(2) на

(3). Аналогично, соединения формулы (I-3) также могут быть получены в соответствии со схемой 4 путем замены

(2) на

(4).[0107] The compounds of formula (I-2) can also be obtained in accordance with scheme 4 by replacing

( 2 ) on

( 3 ). Similarly, the compounds of formula (I-3) can also be obtained in accordance with scheme 4 by replacing

( 2 ) on

( 4 ).

[0108] Other suitable reactions are possible, such as hydrolysis of a compound of formula (I) to give various forms of a compound of formula (I-1), (I-2) or (I-3). For example, compounds containing t-butoxy, methoxy, ethoxy and the like as R ² can be hydrolyzed by reaction with a suitable reagent such as trifluoroacetic acid (TFA), HCl, KOH or the like. to obtain a compound of Formula (I) containing hydrogen as R ² .

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

Scheme 5

[0110] In some other embodiments where Y is C=O, subsequent reactions may be carried out to replace C=O with C=S or C=N, or the like.

Compounds of formula (2)

[0111] There are various ways to obtain the compounds of formula (2). Compounds of formula (2) can be synthesized by various reactions such as the condensation reaction shown schematically in Scheme 6 below. The reaction can be carried out in various solvents such as ethanol, methanol, DMF, ACOOH, and the like. The reaction can be carried out at a temperature ranging from about 5°C to about 80°C, for example, from 55°C to 65°C.

Scheme 6

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

Compounds of formula (1)

[0113] There are various ways to obtain the compounds of formula (1). For example, compounds of formula (1) can be synthesized according to Scheme 7 below. For example, to obtain a compound of formula (1) in which Y is C=O, a compound of formula (13) can be reacted with a reagent that an addition-cyclization reaction such as hydrazine as shown in Scheme 7. The reaction can be carried out using various solvents such as ethanol, methanol, THF, and the like. The reaction can be carried out at temperatures from about 20°C to about 100°C, for example from 60 to 80°C.

Scheme 7

[0114] Compounds of formula (13) can be prepared, for example, by reacting an anhydride with a reagent that causes a Wittig reaction, such as (tert-butoxycarbonylmethylene)triphenylphosphorane, and the like, as shown in Scheme 8. Reactions can be carried out using aprotic solvents such as CH ₂ Cl ₂ , THF, 1,4-dioxane, toluene, and the like. The reaction can be carried out at a temperature of from about 20°C to about 110°C, for example from 55°C to 70°C.

[0115] In some embodiments, the reaction of an anhydride, such as compound 15 , with a Wittig reactant may result in the formation of a mixture of specific compounds represented by 16 and 17 as shown below (Scheme 9). In such cases, if necessary, the mixture can be separated and purified to obtain specific compounds of interest (for example, compounds 16 or 17 ).

Scheme 9

[0116] In some embodiments, compounds of formula (13) can be prepared by a Perkins reaction as shown in Scheme 10. KOAc/Ac ₂ O can be used in the Perkins reaction as shown in Scheme 10. However, other temperatures and other bases can be used. such as K ₂ CO ₃ and the like. Further information on the Perkins reaction can be found in WO 03/061660, the contents of which are incorporated herein in their entirety by reference.

Scheme 10

[0117] Compounds of formula ( 14 ) can be prepared by reacting a dicarboxylic acid derivative represented by formula ( 18 ) with a suitable anhydride reagent such as dicyclohexylcarbodiimide (DCC) or acetic anhydride to give compounds of formula ( 14 ) as schematically as shown below (Scheme 11). The reaction can be carried out using non-nucleophilic solvents such as acetic anhydride, THF, and the like. The reaction can be carried out at a temperature of from about 20°C to about 100°C, for example from 60 to 80°C.

Scheme 11

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

[0119] Compounds of formula ( 18 ) are commercially available, for example from Sigma-Aldrich. Alternatively, compounds of formula ( 18 ) can be prepared by reacting a suitable precursor represented by formula ( 19 ) or formula ( 20 ) with a suitable dicarboxylic acid derivatizer such as NaMnO ₄ and/or NaOH to give compounds of formula ( 18 ), as shown schematically below (schemes 12 and 13). The reaction can be carried out using aqueous solvents such as water. The reaction can be carried out at a temperature of from about 50°C to about 100°C, for example, from 85°C to 95°C.

Scheme 12

Scheme 13

[0120] Compounds of formula ( 18 ) in which X ¹ and X ² are Cl can be prepared as described by Ayres et al. in Tetrahedron, 1975, 31, 1755-1760 (incorporated herein in its entirety by reference) as shown in Scheme 14. Bis-iodination of compound 34 followed by transmetallization and carboxylation provides compound 36 . Other halogenated derivatives can also be used as starting materials for obtaining compounds of formula ( 18 ). Subsequent conversion of the dicarboxylic acid functional groups of compounds of formula ( 18 ) to form a cyclic anhydride as described above gives compounds of formula ( 14 ). Compounds of formula ( 14 ) can be converted to compounds of formula (I) by known methods. Typical methods are described in US Pat. No. 8,916,563 (which is incorporated herein in its entirety by reference).

Additional Schemes for the Synthesis of a Compound of Formula (I)

[0121] The synthesis schemes described above for the preparation of compounds of formula (I) are illustrative and are not intended to limit the possible methods that can be used by a person skilled in the art for the compounds disclosed in this application. Various methods will be apparent to those skilled in the art. Additional reactions may be performed to synthesize further embodiments of the compounds represented by formula (I).

[0122] To obtain compounds of formula (I), in which Y represents C=S, the following synthesis can be carried out (scheme 15). Treatment of compound 21 with Lawesson's reagent provides the corresponding thiocarbonyl derivative 22 . Subsequent deprotection or hydrolysis gives compound 23 .

Scheme 15

[0123] To obtain compounds of formula (I), in which Y represents C=NR*, where R* represents hydrogen or an alkyl substituent, for example, the following synthesis can be carried out (scheme 16).

Scheme 16

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

[0125] As will be apparent to those skilled in the art, other substitutions and modifications are possible. For example, in Scheme 17, KOH can be used instead of NaOH. In Scheme 18 below, KOtBu can be used instead of NaH. Also, NMP or THF can be used instead of DMF.

Scheme 17

Scheme 18

[0126] In some embodiments, the following alternative synthesis can be carried out (Scheme 19).

Scheme 19

[0127] The compounds or compositions of the invention may be useful in applications that promote inhibition of aldose reductase enzymes. For a typical benefit of aldeoreductase inhibition, see, for example, US Pat. Nos. 8,916,563; 5677342; 5155259; 4939140; U.S. Patent Application Publication 2006/0293265; and Roy et al., in Diabetes Research and Clinical Practice 1990, 10(1), 91-97; and references cited in those documents; each of which is incorporated herein in its entirety by reference. Inhibition of aldose reductase Prevents Colon Cancer Metastasis, Carcinogenesis 2011, doi: 10.1093/carcin /bgr102 published online: June 3, 2011 Angiogenesis 2011 May 14(2):209-21 and Mol Cancer Ther 2010 Apr 9(4):813-824 each of which is incorporated herein in its entirety as a reference).

[0128] In some embodiments, the compounds and/or compositions of the invention may be useful in promoting healthy skin aging, treating skin disorders, treating angiogenesis disorders such as cancer, including colon cancer, treating tissue damage other than heart tissue, treatment of cardiovascular diseases, treatment of renal dysfunction, treatment of developing myocardial infarction, treatment of ischemic injury, and treatment of various other diseases such as complications arising from diabetes. Such disorders may include, without limitation, atherosclerosis, coronary artery disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, skin infections, peripheral vascular disease, stroke, asthma, and the like.

[0129] In some embodiments, the compounds and/or compositions of the invention may be useful in cardiovascular disorders. For example, the compounds and/or compositions of the invention may be used to treat patients undergoing heart bypass surgery to speed recovery from surgery. In another example, the compounds and/or compositions of the invention can be used to suppress or reduce the accumulation or rapid appearance of atherosclerotic plaques.

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

[0131] In some embodiments, the compounds of formula (I) can be administered to a subject in need of treatment at doses ranging from about 0.5 to about 25 mg/kg body weight of the patient to be treated per day, for example from about 1.0 to 10 mg/kg. However, additional options are within the scope of the invention.

[0132] The compound of formula (I) can be administered alone or in combination with pharmaceutically acceptable carriers such as diluents, excipients, aqueous solution, and even organic solvents. The compound and/or compositions of the invention may be administered as a tablet, powder, lozenge, syrup, injection, and the like. Additional ingredients such as flavor, binder, excipients, and the like are within the scope of the invention.

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

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

[0135] In one embodiment, the present invention relates to the use of pharmaceutical compositions and/or medicaments consisting of a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, in a method of treating a disease state and/or a condition caused by or associated with aldose reductase.

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

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

[0138] In one embodiment, the subject in need is an animal. In another embodiment, the patient in need is an animal. Animals include all members of the animal kingdom, without limitation, humans, mice, rats, cats, monkeys, dogs, horses and pigs. In some embodiments, the subject in need is a human. In some embodiments, the subject in need is a mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the patient in need is a human. In some embodiments, the patient in need is a mouse, rat, cat, monkey, dog, horse, or pig.

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

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

[0141] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants, and carriers. 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 a forming agent. Often the pharmaceutically acceptable carrier is chemically inert to the active compounds 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 petroleum, animal, vegetable, or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Pharmaceutical carriers can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea, and the like. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used. Other examples of suitable pharmaceutical carriers are described, for example, in Remington's: The Science and Practice of Pharmacy, ^22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, ^7th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which is incorporated herein in its entirety by reference).

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

[0143] In another embodiment, a method for treating, preventing, and/or suppressing an aldose reductase-associated condition comprises the steps of: (i) identifying a subject in need of such treatment; (ii) providing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; or a composition containing a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and a pharmaceutically acceptable carrier; and (iii) administering said compound or composition in a therapeutically effective amount for the treatment, prevention and/or suppression of a disease or aldose reductase related condition in a subject in need of such treatment.

[0144] The term "prodrug" or "prodrug" refers to an agent that is converted in vivo to an active drug. Prodrugs are often useful because they are easier to administer than the parent drug in some situations. They are bioavailable, for example, when administered orally, while the parent drug is either 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 contains protecting groups that are removed in vivo, thus releasing the active agent. The term "prodrug" may be applied to functional groups such as, for example, acidic functional groups of compounds of formula (I). Prodrugs may consist of structures in which the acid group is masked, for example as an ester or amide. Other examples of prodrugs are discussed in this application and, for example, Alexander et al., J. Med. Chem. 1988, 31, 318 (included herein in its entirety by reference).

[0145] In one embodiment, the present invention also encompasses methods containing prodrugs of compounds of formula (I) and/or pharmaceutical compositions thereof. Prodrugs include derivatives of compounds that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to form the active compound of the invention. Examples of prodrugs include, without limitation, derivatives and metabolites of a compound of the invention, which include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable phosphate analogs. Prodrugs may consist of structures in which the acid group is masked, for example as an ester or amide. Additional examples of prodrugs are discussed, for example, Alexander et al., J. Med. Chem. 1988, 31, 318; and in The Practice of Medicinal Chemistry (Camille Wermuth, ed., 1999, Academic Press; incorporated herein in its entirety by reference). Prodrugs are often useful because they are easier to administer than the parent drug in some situations. They are bioavailable, for example, when administered orally, while the parent drug is either 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 bears protecting groups that are removed in vivo , thus releasing the active compound.

[0146] In some embodiments, the implementation of the prodrugs of compounds with carboxyl functional groups are (C ₁ -C ₄ )-alkyl carboxylic acid esters. Esters of carboxylates are conveniently prepared by esterification of any of the carboxylic acid moieties present in the molecule. Prodrugs can generally be prepared by well known methods such as those described in Burger's Medicinal Chemistry and Drug Discovery ^6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Pro-drugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh; each of which is hereby incorporated by reference in its entirety). Biohydrolyzable fragments of a compound of formula (I) (i) do not affect the biological activity of the compound, but may confer useful in vivo properties on the compound, such as uptake, duration of action, or onset of action; or (ii) may be biologically inactive but converted in vivo to a biologically active compound. Examples of biohydrolysable esters include, without limitation, (C ₁ -C ₄ )alkyl esters, alkoxyacyloxyesters, alkylacylaminoalkyl esters, and choline esters. Examples of biohydrolysable amides include, without limitation, (C ₁ -C ₄ )alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable carbamates include, without limitation, (C ₁ -C ₄ )alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyesteramines. In some embodiments, the biohydrolysable moiety is a C ₁ -C ₄ alkyl ester, alkoxyacyloxy ester, alkyl acylamino alkyl ester, or choline ester. In some embodiments, the biohydrolysable moiety is a C ₁ -C ₄ alkyl ester, alkoxyacyloxy ester, or alkyl acylamino alkyl ester. In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkyl ester or alkoxyacyloxy ester. In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkyl ester. In some embodiments, the biohydrolyzable moiety is a (C ₁ -C ₃ )alkyl ester. In some embodiments, the biohydrolysable moiety is a methyl ester or an ethyl ester. In some embodiments, the biohydrolyzable moiety is a tert-butyl ether. In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkylamide, α-amino acid, alkoxyacylamide, or alkylaminoalkylcarbonylamide. In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkylamide, an α-amino acid, or an alkoxyacylamide. In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkylamide or amino acid amide. In some embodiments, the biohydrolyzable moiety is a (C ₁ -C ₄ )alkylamide.

[0147] In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkylamine, substituted ethylenediamine, amino acid, hydroxyalkylamine, heterocyclic amine, heteroaromatic amine, or polyetheramine. In some embodiments, the biohydrolysable moiety is a (C ₁ -C ₄ )alkylamine, an amino acid, a hydroxyalkylamine, a heterocyclic amine, a heteroaromatic amine, or a polyetheramine. In some embodiments, the biohydrolyzable moiety is a (C ₁ -C ₄ )alkylamine, amino acid, hydroxyalkylamine, or polyetheramine. In some embodiments, the biohydrolyzable moiety is a (C ₁ -C ₄ )alkylamine, amino acid, or hydroxyalkylamine. In some embodiments, the biohydrolyzable moiety is a (C ₁ -C ₄ )alkylamine.

[0148] In one embodiment, the compounds of the invention are formulated into pharmaceutical compositions for administration to subjects in a biocompatible form suitable for in vivo administration. According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) in admixture with a pharmaceutically acceptable diluent and/or carrier. A pharmaceutically acceptable carrier is "acceptable" in the sense that it is compatible with the other ingredients of the composition and is not harmful to the recipient. Used in this application, pharmaceutically acceptable carriers can be selected from various organic or inorganic materials that are used as materials for the preparation of pharmaceutical compositions and which include as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, fillers, glidants , solubilizers, stabilizers, suspending agents, adjusting tonicity agents, carrier media and viscosity increasing agents. Pharmaceutical additives such as antioxidants, flavoring agents, colorants, flavor enhancers, preservatives and sweeteners may also be added. Examples of acceptable pharmaceutical carriers include, but are not limited to, carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powders, saline, sodium alginate, sucrose, starch, talc, and water. In one embodiment, the term "pharmaceutically acceptable" means approved for use in animals, and more particularly in humans, by a federal or state government regulatory agency, or listed in the USP or other generally recognized pharmacopeia.

[0149] Surfactants, such as, for example, detergents, are also suitable for use in drug formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerin, sorbitol, or polyoxyethylene esters of sorbitol; lecithin or sodium carboxymethylcellulose; or acrylic derivatives such as methacrylates and other anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctylsulfosuccinate; or fatty acids, in particular acids derived from coconut oil, cationic surfactants such as water-soluble quaternary ammonium salts of the formula N ⁺ R'RʺRʺ'RʺʺY-, in which the R radicals are the same or different optionally hydroxylated hydrocarbon radicals, and Y ^- represents the anion of a strong acid, such as halide, sulfate and sulfonate anion; cetyltrimethylammonium bromide, which is one of the cationic surfactants that can be used, amine salts of the formula N ⁺ R'R'R'R'', in which the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride, which is one of the cationic surfactants that can be used, non-ionic surfactants such as optionally polyoxyethylene sorbitan esters, in particular polysorbate 80, or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, polyglycerol esters, polyoxyethylene fatty alcohols, polyoxyethylene fatty acids or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants such as substituted lauryl compounds of betaine.

[0150] When administered to a subject, the compound of formula (I) and pharmaceutically acceptable carriers may be sterile. Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, polyethylene glycol 300 glycol, water, ethanol, polysorbate 20, etc. The present compositions, if necessary, may also contain minor amounts of wetting or emulsifying agents or pH buffering agents.

[0151] The pharmaceutical compositions of the present invention are prepared by methods well known in the pharmaceutical field. Optionally, one or more accessory ingredients (eg, buffers, flavors, surfactants, etc.) are also added. The choice of carrier is determined by the solubility and chemical nature of the compounds, the chosen route of administration and standard pharmaceutical practice.

[0152] In addition, the compounds and/or compositions of the present invention is administered to a human or animal using known procedures, including oral administration, sublingual or buccal administration. In one embodiment, the compound and/or composition is administered orally.

[0153] For oral administration, the formulation of the compounds of the invention may be presented in dosage forms such as capsules, tablets, powders, granules, or as a suspension or solution. Capsules as a dosage form can be gelatinous, soft or hard. Tablets and capsules may additionally contain one or more adjuvants, binders, diluents, disintegrants, excipients, excipients or lubricants, each of which is known in the art. Examples of such substances include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, gum arabic, flavorings, preservatives, buffering agents, disintegrants and colorants. Orally administered compositions may contain one or more optional agents such as, for example, sweeteners such as fructose, aspartame or saccharin; flavorings such as peppermint, oil of wintergreen or cherry; dyes; and preservatives, thus providing a pharmaceutical preparation with a pleasant taste.

[0154] In some embodiments, the composition is in unit dose form, such as a tablet, capsule, or single dose vial. Suitable unit doses, ie, therapeutically effective amounts, may be determined during clinical trials designed as appropriate for each of the conditions for which administration of the selected compound is indicated, and will, of course, vary depending on the desired clinical end point.

[0155] In accordance with the methods of the present invention, the compounds of the invention are administered to a subject in a therapeutically effective amount, for example, to reduce or alleviate symptoms associated with aldose reductase activity in the subject. This amount can be readily determined by one of skill in the art based on known procedures, including analysis of in vivo titration curves and the methods and assays disclosed herein.

[0156] In one embodiment, the methods include administering a therapeutically effective dose of the compounds 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 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 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 kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg 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 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 body. It will be understood that any of the doses listed herein may constitute an upper or lower dose range and may be combined with any other dose, thus constituting a dose range including an upper and lower limit.

[0157] In some embodiments, the implementation of the methods include a single dose or administration (for example, in the form of a single injection or deposition). Alternatively, the methods include administering to a subject in need once a day, twice a day, three times a day, or four times a day for a period of about 2 to about 28 days, or about 7 to about 10 days, or from about 7 to 15 days, or longer. In some embodiments, the methods include long-term administration. In other embodiments, the methods include administration over weeks, months, years, or decades. In other embodiments, the methods include administration over several weeks. In other embodiments, the methods include administration over several months. In other embodiments, the methods include administration over several years. In other embodiments, the methods include administration over several decades.

[0158] The dose administered may vary depending on known factors such as the pharmacodynamic characteristics of the active ingredient, regimen and route of administration; the time of administration of the active ingredient; age, gender, health status and weight of the recipient; the nature and severity of symptoms; type of concomitant treatment, frequency of treatment and desired effect; and withdrawal speed. All of these parameters are easily determined and can be used by the skilled artisan to adjust or titrate doses and/or dosing regimens.

[0159] The exact dose to be used in the compositions will also depend on the route of administration and should be determined by the practitioner and the circumstances of each patient. In specific embodiments, suitable dosage ranges for oral administration of the compounds of the invention are typically from about 1 mg/day to about 1000 mg/day. In one embodiment, the oral dose is from about 1 to about 800 mg/day. In one embodiment, the oral dose is from about 1 mg/day to about 500 mg/day. In another embodiment, the oral dose is from about 1 mg/day to about 250 mg/day. In another embodiment, the oral dose is from about 1 mg/day to about 100 mg/day. In another embodiment, the oral dose is from about 5 mg/day to about 50 mg/day. In another embodiment, the oral dose is about 5 mg/day. In another embodiment, the oral dose is about 10 mg/day. In another embodiment, the oral dose is about 20 mg/day. In another embodiment, the oral dose is about 30 mg/day. In another embodiment, the oral dose is about 40 mg/day. In another embodiment, the oral dose is about 50 mg/day. In another embodiment, the oral dose is about 60 mg/day. In another embodiment, the oral dose is about 70 mg/day. In another embodiment, the oral dose is about 100 mg/day. It will be understood that any of the doses listed herein may constitute an upper or lower dose range and may be combined with any other dose, thus constituting a dose range including an upper and lower limit.

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

[0161] Those skilled in the art will recognize, or will be able to identify, using routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Such equivalents are within the scope of the present invention.

[0162] the Invention is further described using the following non-limiting examples.

EXAMPLES

[0163] The following are examples to help you better understand the invention. The following examples serve to illustrate exemplary methods for making and using the invention. However, the scope of the invention should not be construed as being limited to the specific embodiments disclosed in these examples, which are illustrative only.

Example 1 : Preparation of Compound VII.

[0164] Compound VII was prepared according to the scheme shown below.

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

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

[0167] 2,5-Dichloro-4-(methoxycarbonyl)thiophene-3-carboxylic acid (compound III ): 0.495 g (2.22 mmol) solution of 4,6-dichloro-1H,3H-thieno[3,4- c]furan-1,3-dione (compound II ) in 4.0 ml MeOH was treated with TFA (1 drop) and heated to 65° C. overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. Ether was added to the resulting residue, followed by a saturated aqueous solution of NaHCO ₃ . The layers were separated and the aqueous layer was extracted with ether (1x). Then the aqueous layer was acidified to pH=2 by adding conc. HCl. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers from the second extraction were washed with brine (1x). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 0.537 g (95% crude yield) of 2,5-dichloro-4-(methoxycarbonyl)thiophene-3-carboxylic acid (compound III ) as white solid used without further purification: ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 3.91 (s, 3H); ¹³ C NMR (CDCl ₃ , 100 MHz): δ ppm. 165.6, 162.0, 133.9, 131.0, 129.6, 128.1, 53.0.

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

[0169] tert-Butyl 2-(5,7-dichloro-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound V ): K 0.170 g (0.482 mmol) compound IV in 4.0 ml of MeOH was added 17 μl (0.530 mmol) of hydrazine. The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by silica gel flash column chromatography (monitored by thin layer chromatography) and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave 0.091 g (57% yield) tert-Butyl 2-(5,7-dichloro-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound V ) as a white solid: ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 9.15 (br s, 1H), 3.89 (s, 2H), 1.46 (s, 9H).

[0170] Tert-butyl 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benz[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4 -d]pyridazin-1-yl)acetate (compound VI ). To a solution of 0.091 g (0.271 mmol) of compound V in 3.0 ml of DMF was added 0.037 g (0.326 mmol) of KOtBu. The resulting dark mixture was stirred at ambient temperature for 10 minutes, after which 0.082 g (0.326 mmol) of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]thiazole (compound IS ) was added. After stirring the reaction mixture at ambient temperature for 2 hours, the reaction mixture was partitioned between water and ether, the layers were separated, and the aqueous layer was extracted with ether (2x). The combined ether layers were washed successively with saturated aqueous NaHCO ₃ (1x), water (1x), 1.0 M aqueous HCl (1x) and brine (1x). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 4:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave 0.072 g (48% yield) tert-butyl 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)- 3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound VI ): ¹ H NMR (CDCl ₃ , 400 MHz): δm.d. 8.28 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 5.63 (s, 2H), 3.92 (s, 2H), 1.45 (s, 9H); MS ESI (m/z) 550 (M+1) ⁺ .

[0171] 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydro[3,4-d] pyridazin-1-yl)acetic acid (compound VII ). To a solution of 0.072 g (0.131 mmol) of compound VI in 1.0 ml of THF was added 5.0 ml of formic acid (88% in water) and 0.5 ml of water. The reaction mixture was stirred for 12 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue partitioned between ether and saturated aqueous NaHCO ₃ . The layers were separated and the aqueous layer was acidified to pH 2 by adding conc. HCl. The precipitated solid was collected by filtration to give 8 mg (12% yield) 2-(5,7-dichloro-4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)- 3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound VII ) as a white solid: mp=205-207° C. (not recrystallized); ¹ H NMR (acetone, 400 MHz): δ ppm 8.32-8.28 (m, 2H), 7.75 (d, J=7.6 Hz, 1H), 5.67 (s, 2H), 4.04 (s, 2H); MS ESI (m/z) 494 (M+1) ⁺ .

Example 2 : Preparation of Compound XII.

[0172] Compound XII was prepared according to the scheme shown below.

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

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

[0175] tert-Butyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound X ): to a solution of 8.04 g (28.31 mmol) crude compound IX in 70 ml of MeOH at 0° C. was added 2.7 ml (42.46 mmol) of hydrazine hydrate (50-60% in H ₂ O). The resulting reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was diluted with water and the precipitated solid was collected by filtration to give 2.99 g (40% overall yield of the two steps) tert-butyl 2-(4-oxo-3,4-dihydrothieno[3,4-d]pyridazine- 1-yl)acetate (compound X ) as white solid: ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 9.29 (br s, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 3.76 (s, 2H ), 1.44 (s, 9H); ¹³ C NMR (CDCl ₃ , 100 MHz): δ ppm. 168.5, 158.0, 139.2, 133.3, 130.7, 129.3, 123.9, 82.1, 40.9, 27.9; ESI (m/z) 308 (M+MeCN) ⁺ .

[0176] Tert-butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[3,4-d]pyridazin-1 -yl)acetate (compound XI ). To a solution of 0.100 g (0.376 mmol) of compound X in 2.5 ml of DMF was added 0.044 g (0.391 mmol) of KOtBu. The resulting dark mixture was stirred at ambient temperature for 15 minutes after which 0.104 g (0.414 mmol) of compound IS was added. After stirring the reaction mixture at ambient temperature for 2 hours, the reaction mixture was partitioned between water and ether, the layers were separated and the aqueous layer was extracted with ether (2x). The combined ether layers were washed successively with 1.0 M NaOH (1x), water (1x), 1.0 M aqueous HCl (1x) and brine (1x). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave 0.058 g (32% yield) tert-butyl 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydrothieno[ 3,4-d]pyridazin-1-yl)acetate (compound XI ): ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 8.45 (d, J=3.2 Hz, 1H), 8.29 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.83 (d, J=3 .2 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 5.75 (s, 2H), 3.78 (s, 2H), 1.41 (s, 9H); ESI (m/z) 482 (M+H) ⁺ .

[0177] 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3,4-dihydro[3,4-d]pyridazin-1-yl) acetic acid (compound XII ). A solution of 0.058 g (0.121 mmol) of compound XI in 1.0 ml of trifluoroacetic acid and 1.0 ml of CH ₂ Cl ₂ was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between ether and saturated aqueous NaHCO ₃ . The layers were separated and the ether layer was washed with saturated aqueous NaHCO ₃ (1x). The aqueous layer was acidified to pH=2 by adding conc. HCl and the precipitated solid was collected by filtration to give 20 mg (39% yield) 2-(4-oxo-3-((5-(trifluoromethyl)benzo[d]thiazol-2-yl)methyl)-3.4 -dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XII ) as a white solid: mp=174-176° C. (not recrystallized); ¹ H NMR (acetone, 400 MHz): δ ppm 8.60 (d, J=3.2 Hz, 1H), 8.33 (d, J=3.2 Hz, 1H), 8.29 (s, 1H), 8.26 (d, J=8 .8 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 5.74 (s, 2H), 3.96 (s, 2H); MS ESI (m/z) 426 (M+1) ⁺ .

Example 3 : Preparation of Compound XIII.

[0178] Compound XIII shown above was prepared as follows. The method of preparation described for compound XI was repeated except that 2-(bromomethyl)-5-fluorobenzo[d]thiazole was used as a reagent instead of compound IS in the same molar proportions as above. In this case, the resulting end product was tert-butyl 2-(3-((5-fluorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin- 1-yl)acetate (compound XIII ) which was used in crude form after filtration through a pad of silica, washing with 2:1 (v/v) hexanes:ethyl acetate.

Example 4 : Preparation of Compound XIV.

[0179] Compound XIV shown above was prepared as follows. The method of preparation described for compound XII was repeated, except that instead of compound XI , compound XIII was used as starting material. In this case, the final product was 2-(3-((5-fluorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl) acetic acid (compound XIV ) in 25% yield: mp=172-173°C (not recrystallized); ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 8.47 (d, J=3.2 Hz, 1H), 7.85 (d, J=3.2 Hz, 1H), 7.75-7.69 (m, 2H), 7.13 (dt , J=8.8, 2.8 Hz, 1H), 5.72 (s, 2H), 3.93 (s, 2H); ESI (m/z) 376 (M+H) ⁺ .

Example 5 : Receiving Compound XV.

[0180] Compound XV shown above was prepared as follows. The method of preparation described for compound XI was repeated, except that instead of compound IS , 2-(bromomethyl)benzo[d]thiazole was used as the reagent in the same molar proportions as above. In this case, the resulting end product was tert-butyl 2-(3-(benzo[d]thiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (compound XV ), which was used in the crude form after filtration through a plug of silica gel, washing with a mixture of 3:1 (v/v) hexanes:ethyl acetate.

Example 6 : Preparation of Compound XVI.

[0181] Compound XVI shown above was prepared as follows. The preparation method described for Compound XII was repeated except that Compound XV was used as starting material instead of Compound XI . In this case, the final product was 2-(3-(benzo[d]thiazol-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XVI ) with 7% yield: mp=172-173°C (non-recrystallized); ¹ H NMR (acetone, 400 MHz): δ ppm 8.58 (d, J=2.8 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H), 7.99-7.94 (m, 2H), 7.49 (t , J=8.0 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 5.68 (s, 2H), 3.94 (s, 2H); ESI (m/z) 358 (M+H) ⁺ .

Example 7 : Preparation of Compound XVII.

[0182] Compound XVII shown above was prepared as follows. The preparation method described for compound XI was repeated except that instead of compound IS , 3-(bromomethyl)-5-chlorobenzo[b]thiophene was used as the reagent in the same molar proportions as above. In this case, the resulting end product was tert-butyl 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin- 1-yl)acetate (compound XVII ). The resulting product was purified by silica gel flash column chromatography (monitored by thin layer chromatography) and eluted with 3:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave 18% yield of compound XVII : ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 8.38 (d, J=3.2 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.75 (d, J=3.2 Hz, 1H), 7. 72 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.30-7.27 (m, 1H), 5.48 (s, 2H), 3.76 (s , 2H) 1.40 (s, 9H); ESI (m/z) 447 (M+H) ⁺ .

Example 8 : Preparation of Compound XVIII.

[0183] Compound XVIII shown above was prepared as follows. The method of preparation described for compound XII was repeated, except that instead of compound XI , compound XVII was used as starting material. In this case, the final product was 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl) acetic acid (compound XVIII ) in 25% yield: ¹ H NMR (acetone, 400 MHz): δ ppm. 8.53 (d, J=2.8 Hz, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.23 (d, J=2.8 Hz, 1H), 7, 95 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.37 (dd, J=8.8, 2.0 Hz, 1H), 5.51 (s, 2H ) 3.92 (s, 2H); ESI (m/z) 391 (M+H) ⁺ , 389 (M-H) ^- .

Example 9 : Preparation of Compound XIX.

[0184] Compound XIX shown above was prepared as follows. The method of preparation described for compound XI was repeated except that instead of compound IS , 5-chloro-2-(chloromethyl)benzo[d]thiazole was used as the reagent in the same molar proportions as above. In this case, the resulting end product was tert-butyl 2-(3-((5-chlorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin- 1-yl)acetate (compound XIX ). The resulting product was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 4:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave a 47% yield of compound XIX : ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 8.44 (d, J=3.2 Hz, 1H), 8.00 (s, 1H), 7.82 (d, J=3.2 Hz, 1H), 7.70 (d, J=8 .4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 5.72 (s, 2H), 3.77 (s, 2H), 1.40 (s, 9H); ESI (m/z) 448 (M+H) ⁺ .

Example 10 : Receive connection XX.

[0185] Compound XX shown above was prepared as follows. The method of preparation described for compound XII was repeated, except that instead of compound XI , compound XIX was used as starting material. In this case, the final product was 2-(3-((5-chlorobenzo[d]thiazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl) acetic acid (compound XX ) in 61% yield: mp=184-185° C. (not recrystallized); ¹ H NMR (acetone, 400 MHz): δ ppm 8.59 (d, J=2.8 Hz, 1H), 8.32 (d, J=2.8 Hz, 1H), 8.03-7.99 (m, 2H), 7.45 (d , J=8.8 Hz, 1H), 5.69 (s, 2H), 3.95 (s, 2H); ESI (m/z) 392 (M+H) ⁺ .

Example 11 : Obtaining connection XXI.

[0186] Compound XXI shown above was prepared as follows. The method of preparation described for compound XI was repeated except that 2-(chloromethyl)-6-fluorobenzo[d]oxazole was used as the reagent instead of compound IS in the same molar proportions as above. In this case, the resulting end product was tert-butyl 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin- 1-yl)acetate (compound XXI ). The resulting product was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 4:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave a 30% yield of compound XXI : ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 8.44 (d, J=3.2 Hz, 1H), 7.81 (d, J=3.2 Hz, 1H), 7.60 (dd, J=8.8, 4.8 Hz, 1H ), 7.19 (dd, J=7.6, 2.0 Hz, 1H), 7.05 (dt, J=8.8, 2.0 Hz, 1H), 5.58 (s, 2H) , 3.75 (s, 2H), 1.40 (s, 9H); ESI (m/z) 416 (M+H) ⁺ .

Example 12 : Preparation of compound XXII.

[0187] Compound XXII shown above was prepared as follows. The method of preparation described for compound XII was repeated, except that instead of compound XI , compound XXI was used as starting material. In this case, the final product was 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl) acetic acid (compound XXII ) in 40% yield: ¹ H NMR (acetone, 400 MHz): δ ppm. 8.57 (d, J=3.2 Hz, 1H), 8.30 (d, J=3.2 Hz, 1H), 7.65 (dd, J=8.8, 5.2 Hz, 1H ), 7.45 (dd, J=8.0, 2.4Hz, 1H), 7.17 (dt, J=8.8, 2.4Hz, 1H), 5.57 (s, 2H) , 3.91 (s, 2H); ESI (m/z) 360 (M+H) ⁺ .

Example 13 : Preparation of compound XXIII.

[0188] Compound XXIII shown above was prepared as follows. The method of preparation described for compound XI was repeated except that instead of compound IS , 5-chloro-2-(chloromethyl)benzofuran was used as the reagent in the same molar proportions as above. In this case, the resulting end product was tert-butyl 2-(3-((5-chlorobenzofuran-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl) acetate (compound XXIII ). The resulting product was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave a 33% yield of compound XXIII: mp=117-118° C. (non-recrystallized); ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm 8.40 (d, J=3.2 Hz, 1H), 7.78 (d, J=3.2 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7. 33 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 2.4 Hz, 1H), 6.65 (s, 1H), 5.44 (s, 2H ), 3.76 (s, 2H), 1.41 (s, 9H); ESI (m/z) 431 (M+H) ⁺ .

Example 14 : Preparation of compound XXIV.

[0189] Compound XXIV shown above was prepared as follows. The method of preparation described for compound XII was repeated, except that instead of compound XI , compound XXIII was used as starting material. In this case, the final product obtained was 2-(3-((5-chlorobenzofuran-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XXIV ) in 54% yield: mp=154-155°C (non-recrystallized); ¹ H NMR (acetone, 400 MHz): δ ppm 8.54 (d, J=3.2 Hz, 1H), 8.26 (d, J=3.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7. 47 (d, J=8.8 Hz, 1H), 7.26 (dd, J=8.8, 2.0 Hz, 1H), 6.77 (s, 1H), 5.44 (s, 2H ), 3.91 (s, 2H); ESI (m/z) 375 (M+H) ⁺ .

Example 15 : Obtain connection XXV.

[0190] Compound XXV shown above was prepared as follows. The method of preparation described for compound XI was repeated, except that instead of compound IS , 2-(chloromethyl)benzofuran was used as a reagent in the same molar proportions as indicated above. In this case, the resulting end product was tert-butyl 2-(3-(benzofuran-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetate (Compound XXV ) . The resulting product was purified by flash column chromatography on silica gel (monitored by thin layer chromatography) and eluted with 2:1 (v/v) hexanes:ethyl acetate. Evaporation of the collected fractions gave a 44% yield of compound XXV: ¹ H NMR (CDCl ₃ , 400 MHz): δ ppm. 8.40 (d, J=3.2 Hz, 1H), 7.76 (d, J=3.2 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7. 41 (d, J=8.0, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 6.70 (s , 1H) 5.45 (s, 2H), 3.76 (s, 2H), 1.40 (s, 9H); ESI (m/z) 397 (M+H) ⁺ .

Example 16 : Obtain connection XXVI.

[0191] Compound XXVI shown above was prepared as follows. The method of preparation described for compound XII was repeated, except that instead of compound XI , compound XXV was used as starting material. In this case, the final product was 2-(3-(benzofuran-2-ylmethyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazin-1-yl)acetic acid (compound XXVI ) with a yield of 28 %: mp=158-159°C (non-recrystallized); ¹ H NMR (acetone, 400 MHz): δ ppm 8.54 (d, J=3.2 Hz, 1H), 8.26 (d, J=3.2 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7. 45 (d, J=8.4 Hz, 1H), 7.26 (t, J=8.4 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 6.76 ( s, 1H), 5.44 (s, 2H), 3.91 (s, 2H); ESI (m/z) 341 (M+H) ⁺ .

Example 17 : Physical, chemical and biological methods of analysis and results.

[0192] Characterization of aldose reductase inhibitor compounds : Compounds were synthesized as described above and physical characteristics (solubility and LogD) as well as biochemical characteristics, in particular their ability to inhibit aldose reductase enzymatic activity in vitro , were determined. The methods of these assays and the results are shown below.

[0193] Equilibrium solubility in phosphate buffer, pH 7.4: The equilibrium solubility of test articles was measured in aqueous buffers at pH 7.4. Buffer pH 7.4 was prepared by combining 50 ml 0.2 M KH ₂ PO ₄ with 150 ml H ₂ O and then adjusting the pH to 7.4 using 10N. NaOH. At least 1 mg of powder for each test article was combined with 1 ml of buffer to obtain a mixture with a concentration of ≥1 mg/ml. These samples were shaken on the ThermoMixer® overnight at room temperature. The samples were then centrifuged for 10 minutes at 10,000 rpm. The supernatant was collected and diluted, in duplicate, 10, 100, and 10,000-fold in 1:1 buffer:acetonitrile (ACN) before analysis. All samples were analyzed by LC-MS/MS with electrospray ionization against standards prepared in a mixture of 1:1 assay buffer:ACN. Standard concentrations ranged from 1.0 μM to 1.0 nM.

[0194] Octanol/buffer partition coefficient (LogD) at pH 7.4 : The octanol/buffer partition coefficient of the three test articles was measured at pH 7.4. A pH 7.4 buffer was prepared by combining 50 ml of a 0.2 M KH ₂ PO ₄ solution with 150 ml of dH ₂ O and then adjusting the pH to 7.4 using 10 N hydrochloric acid. NaOH. In one incubation, 15 μl of a 10 mM DMSO solution of each test article (100 μM) was added to tubes that contained 0.75 ml of octanol and 0.75 ml of phosphate buffer pH 7.4. As an internal control, testosterone was also injected into each tube at a dosed concentration of 100 μM. These samples were gently mixed on a tabletop rotary shaker for 1 hour at room temperature. The tubes were then removed from the rotary shaker and allowed to stand for 1 hour to separate the aqueous and organic phases. An aliquot of the organic layer was removed and diluted 200-fold with 1:1 buffer:acetonitrile (ACN). An aliquot of the aqueous layer was taken and diluted 2, 10 and 200 times in a mixture of 1:1 buffer:ACN. All samples were analyzed by LC-MS/MS with electrospray ionization. Testosterone was used as a positive control (with a published/known LogD of 3.0-3.4).

[0195] Aldose Reductase Enzyme Inhibition : All compounds and zopolrestat were tested individually in a microplate AR inhibition assay using D-glyceraldehyde and NADP as substrate, and absorbance changes at 340 nm were monitored. Percent inhibition was calculated for AP at concentrations ranging from 0.1 to 10 μM. An enzyme inhibition assay was performed as described in WO 2012/009553, which is hereby incorporated by reference in its entirety.

Table 1. Results of physical, chemical and biological analysis:

Compound Structure Mol. mass (AMU) Solubility (mg/ml) LogD Aldose reductase suppression (IC50) XIV

375 0.65 -0.87 60 nM VI

357 0.81 -1.01 190 nM XX

391 0.59 -0.35 35 nM XII

425 0.97 -0.09 0.1 nM XXVI

340 0.79 -0.86 57 nM XIV

374 0.76 -0.01 64 nM

[0196] While the invention has been described and illustrated in the above exemplary embodiments, it is to be understood that the present disclosure is provided by way of example only, and that numerous changes may be made to the details of the invention without departing from the spirit and scope of the invention, which is limited only by what is given. below the claims. The features of the disclosed embodiments may be combined and rearranged in various ways within the scope and spirit of the invention.

Claims (106)

1. Compound of formula (I)

Where R ¹ is CO ₂ R ² ; R ² is H, (C ₁ -C ₆ )-alkyl or (C ₁ -C ₆ )-aminoalkyl; X ¹ is H; X ² is H; Y is C=O; Z represents

or

A ¹ is S; A ² is N; A ³ is O; And R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; or a pharmaceutically acceptable salt thereof. 2. Connection according to claim 1, where R ² is hydrogen or (C ₁ -C ₆ )-alkyl; Y is C=O; A ¹ is S; A ² is N; A ³ is O; And R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, where Z is

or a pharmaceutically acceptable salt thereof. 4. Connection according to claim 3, where R ² is hydrogen or (C ₁ -C ₆ )-alkyl; Y is C=O; A ¹ is; A ² is N; And R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; or a pharmaceutically acceptable salt thereof. 5. Connection according to claim 3, where R ² is hydrogen or (C ₁ -C ₆ )-alkyl; X ¹ is H; X ² is H; Y is C=O; A ¹ is S; A ² is N; R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; or a pharmaceutically acceptable salt thereof. 6. Connection according to claim 1, where Z represents

or a pharmaceutically acceptable salt thereof. 7. Connection according to claim 6, where R ² is hydrogen or (C ₁ -C ₆ )-alkyl; Y is C=O; And R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; or a pharmaceutically acceptable salt thereof. 8. Connection according to claim 1, where: R ² is hydrogen; X ¹ is hydrogen; X ² is hydrogen; Y is C=O; A ³ is O; And R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, selected from the group consisting of:

,

,

,

,

And

or a pharmaceutically acceptable salt of any of the above compounds. 10. The compound according to claim 1, which is a pharmaceutically acceptable salt, where the counterion is selected from the group consisting of: sodium, lithium, potassium, calcium, magnesium, zinc, ammonium and tetrafluoroborate. 11. The compound according to claim 1, which is a pharmaceutically acceptable salt, where the counterion is selected from the group consisting of:

12. Connection according to claim 1, where R ¹ is CO ₂ R ² ; R ² is H, (C ₁ -C ₆ )-alkyl or (C ₁ -C ₆ )-aminoalkyl; X ¹ is H; X ² is H; Y is C=O; Z represents

A ¹ is S; A ² is N; And R ³ -R ⁶ are independently hydrogen, halogen or haloalkyl. 13. A compound according to claim 12, wherein R ² is (C ₁ -C ₆ )-alkyl. 14. A compound according to claim 12 wherein R ² is (C ₁ -C ₆ )-aminoalkyl. 15. The compound according to claim 12, where R ² is H. 16. The compound according to claim 12, where each of R ³ , R ⁵ and R ⁶ represents hydrogen; and R ⁴ is hydrogen, halogen or haloalkyl. 17. The compound according to claim 13, where each of R ³ , R ⁵ and R ⁶ represents hydrogen; and R ⁴ is hydrogen, halogen or haloalkyl. 18. The compound according to claim 14, where each of R ³ , R ⁵ and R ⁶ represents hydrogen; and R ⁴ is hydrogen, halogen or haloalkyl. 19. The compound according to claim 15, where each of R ³ , R ⁵ and R ⁶ represents hydrogen; and R ⁴ is hydrogen, halogen or haloalkyl. 20. A compound that is

or a pharmaceutically acceptable salt thereof. 21. A compound that is

or a pharmaceutically acceptable salt thereof. 22. A compound that is

or a pharmaceutically acceptable salt thereof. 23. A compound that is

or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition for inhibiting aldose reductase activity in a subject, comprising an effective amount of a compound according to any one of claims 1-23 and a pharmaceutically acceptable carrier. 25. A pharmaceutical composition according to claim 24, including a compound according to claim 20. 26. A pharmaceutical composition according to claim 24, including a compound according to claim 21. 27. A pharmaceutical composition according to claim 24, including a compound according to claim 22. 28. A pharmaceutical composition according to claim 24, including a compound according to claim 23. 29. The pharmaceutical composition of claim 24, wherein the subject is diabetic. 30. The pharmaceutical composition of claim 24 wherein the subject suffers from neuropathy, retinopathy, nephropathy, or cardiomyopathy. 31. The pharmaceutical composition of claim 25, wherein the subject is diabetic. 32. The pharmaceutical composition of claim 25, wherein the subject suffers from neuropathy, retinopathy, nephropathy, or cardiomyopathy. 33. The pharmaceutical composition of claim 26 wherein the subject is diabetic. 34. The pharmaceutical composition of claim 26 wherein the subject suffers from neuropathy, retinopathy, nephropathy, or cardiomyopathy. 35. The pharmaceutical composition of claim 27, wherein the subject is diabetic. 36. The pharmaceutical composition of claim 27, wherein the subject suffers from neuropathy, retinopathy, nephropathy, or cardiomyopathy. 37. The pharmaceutical composition of claim 28, wherein the subject is diabetic. 38. The pharmaceutical composition of claim 28, wherein the subject suffers from neuropathy, retinopathy, nephropathy, or cardiomyopathy.