WO2011140078A1 - Synthetic triterpenoid derivatives - Google Patents

Abstract

The present invention provides compounds of formula (A), and pharmaceutically acceptable salts thereof. This invention also provides compositions thereof the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering bardoxolone or bardoxolone methyl.

Description

Synthetic Triterpenoid Derivatives

Related Applications

[1] This application claims the benefit of U.S. Application No. 61/330,962, filed May 4, 2010. The entire teachings of the above application are incorporated herein by reference.

Background of the Invention

[2] Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches have important limitations and often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment. A rapidly metabolized drug may also expose patients to undesirable toxic or reactive metabolites.

[3] Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites. As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent. In certain cases, modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.

[4] In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. The FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect. Quinidine, however, has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L et al., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67; and FDA label for quinidine at www.accessdata.fda.gov).

[5] In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme's activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.

[6] A potentially attractive strategy for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow metabolism of a drug or reduce the formation of undesirable metabolites by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.

[7] Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, MI et al, J Pharm Sci, 1975, 64:367-91; Foster, AB, Adv Drug Res 1985, 14: 1-40 ("Foster"); Kushner, DJ et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, MB et al, Curr Opin Drug Discov Devel, 2006, 9: 101-09 ("Fisher")). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism (see Foster at p. 35 and Fisher at p. 101).

[8] The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its non-deuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.

[9] This invention relates to novel dioxooleandienoic acids, esters and

pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering

bardoxolone.

[10] Bardoxolone, also known as CDDO or 2-cyano-3,12-dioxoolean- 1,9(1 l)-dien-28- oic acid, is a triterpenoid derivative originally of interest as an anti-cancer agent. The activities displayed by bardoxolone are complex and are believed to be mediated, at least in part, by induction of the transcription factor Nrf2, which mediates production of numerous enzymes with anti-oxidant and Phase 2 metabolic activities. Bardoxolone methyl, the methyl ester of bardoxolone, has been demonstrated to improve estimated glomerular filtration rate (eGFR), a measure of renal function, in patients with stage 3 or 4 chronic kidney disease, in a dose-dependent manner during a 28 day study.

[11] Bardoxolone was in phase I clinical trials for metastatic and unresectable solid tumors and lymphoma. Bardoxolone methyl is currently in clinical trials for diabetic nephropathy, chronic kidney disesase, pancreatic cancer and lymphoma. Bardoxolone methyl is also being developed for inflammation and to treat cancer-related indications (such as multiple myeloma, pancreatic cancer and melanoma) that involve immune - mediated inflammation, as well as the treatment of chronic kidney disease.

[12] Despite the beneficial activities of bardoxolone or bardoxolone methyl, there is a continuing need for new compounds to treat the aforementioned diseases and conditions.

Definitions

[13] The term "treat" means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.

[14] "Disease" means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.

[15] "The term "alkyl" refers to a monovalent saturated hydrocarbon group. Ci-C ₆ alkyl is an alkyl having from 1 to 6 carbon atoms. An alkyl may be linear or branched. Examples of alkyl groups include methyl; ethyl; propyl, including n-propyl and isopropyl; butyl, including n-butyl, isobutyl, sec-butyl, and t-butyl; pentyl, including, for example, n-pentyl, isopentyl, and neopentyl; and hexyl, including, for example, n-hexyl and 2-methylpentyl.

[16] The term "alkenyl" refers to a monovalent unsaturated hydrocarbon group where the unsaturation is represented by at least one double bond. C₂-C₆ alkenyl is an alkenyl having from 2 to 6 carbon atoms. An alkenyl group may be linear or branched.

Examples of alkenyl groups include CH₂=CH-, CH₂=C(CH₃)-, CH₂=CH-CH₂-,

CH₃-CH=CH-CH₂-, CH₃-CH=C(CH₃)- and CH₃-CH=CH-CH(CH₃)-CH₂-. Where double bond stereoisomerism is possible, the stereochemistry of an alkenyl may be (E), (Z), or a mixture thereof.

[17] As used herein, the term "bivalent Ci_g (or C_1-6) saturated or unsaturated, straight or branched, hydrocarbon chain", refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[18] Unless otherwise specified, "alkylene" by itself or as part of another substituent refers to a saturated straight-chain or branched bivalent group having the stated number of carbon atoms and derived from the removal of two hydrogen atoms from the corresponding alkane. Examples of straight chained and branched alkylene groups include -CH₂- (methylene), -CH₂-CH₂- (ethylene), -CH₂-CH₂-CH₂- (propylene), -C(CH₃)₂-, -CH₂-CH(CH₃)-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-CH₂- (pentylene), -CH₂-CH(CH₃)-CH₂-, and -CH₂-C(CH₃)₂-CH₂.

[19] The term "alkenylene refers to an unsaturated straight-chain or branched bivalent group having at least one double bond and derived from the removal of two hydrogen atoms from the corresponding alkene. Examples of straight chained and branched alkenylene groups include -CH=CH- and -CH=C(CH₃)-, and the like. The

stereochemistry of an alkenylene may be (E), (Z), or a mixture thereof.

[20] The term "alkynylene refers to an unsaturated straight-chain or branched bivalent group having at least one triple bond and derived from the removal of two hydrogen atoms from the corresponding alkyne. Examples of straight chained and branched alkynylene groups include -C≡C- and -C≡C-CH₂-CH(CH₃)-, and the like.

[21] The term "carbocyclyl" refers to a 3-6 membered monocyclic hydrocarbon ring that is saturated, partially unsaturated, or aromatic. Carbocyclic groups include cycloalkyl, cycloalkenyl, and phenyl.

[22] The term "cycloalkyl" refers to a 3-6 membered monocyclic monovalent saturated hydrocarbon ring. The term "C₃-C₆ cycloalkyl" refers to a cycloalkyl wherein the number of ring carbon atoms is from 3 to 6. More particular examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[23] The term "cycloalkenyl" refers to a 3-6 membered monocyclic monovalent unsaturated hydrocarbon ring having at least one double bond. The term "C₃-C₆ cycloalkenyl" refers to a cycloalkyl wherein the number of ring carbon atoms is from 3 to 6. More particular examples of cycloalkenyl groups include cyclopropenyl, cyclobuten- 2-yl, etc.

[24] The term "heterocyclyl" refers to a 3-6 membered monocyclic ring that is saturated, partially unsaturated, or aromatic, having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heterocyclyl groups include heterocycloalkyl and heteroaryl.

[25] The term "heterocycloalkyl" refers to a 3-6 membered monocyclic monovalent saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The term "3- to 6-membered heterocycloalkyl" refers to a

heterocycloalkyl wherein the total number of ring atoms is from 3 to 6. More particular examples of heterocycloalkyl groups include oxiranyl, thiooxiranyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl and

tetrahydrofuranyl.

[26] The term "heteroaryl" refers to a 5-6 membered monocyclic monovalent aromatic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. The term "5- to 6-membered heteroaryl" refers to a heteroaryl wherein the total number of ring atoms is from 5 to 6. More particular examples of heteroaryl groups include furanyl, pyrrolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

[27] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[28] It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending upon the origin of chemical materials used in the synthesis. Thus, a preparation of bardoxolone or bardoxolone methyl will inherently contain small amounts of deuterated isotopologues. The concentration of naturally abundant stable hydrogen and carbon isotopes, notwithstanding this variation, is small and immaterial as compared to the degree of stable isotopic substitution of compounds of this invention. See, for instance, Wada, E et al, Seikagaku, 1994, 66: 15; Gannes, LZ et al, Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[29] In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as "D" or "deuterium", the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium). [30] The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[31] In other embodiments, a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium

incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5%) deuterium incorporation).

[32] The term "isotopologue" refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.

[33] The term "compound," when referring to a compound of this invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules. Thus, it will be clear to those of skill in the art that a compound represented by a particular chemical structure containing indicated deuterium atoms, will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure. The relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compound.

[34] The invention also provides salts of the compounds of the invention.

[35] A salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another

embodiment, the compound is a pharmaceutically acceptable acid addition salt. [36] The term "pharmaceutically acceptable," as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A

"pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention. A "pharmaceutically acceptable counterion" is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.

[37] Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[38] The pharmaceutically acceptable salt may also be a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;

N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[39] The compounds of the present invention (e.g., compounds of Formula I), may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers. Accordingly, a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer. The term "substantially free of other stereoisomers" as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present. Methods of obtaining or synthesizing an individual stereoisomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[40] Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[41] The term "stable compounds," as used herein, refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).

[42] "D" and "d" both refer to deuterium. "Stereoisomer" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to tertiary. "US" refers to the United States of America.

[43] "Substituted with deuterium" refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[44] Throughout this specification, a variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R¹, R², R³, etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.

Therapeutic Compounds

The present invention provides a compound of Formula A:

, or a pharmaceutically acceptable salt thereof, wherein:

each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is independently selected from -CH₃, -CH₂D, -CHD₂ and -CD₃;

G is selected from hydrogen, halo, -OR⁶, -NHR⁶ and -R⁷,

R⁶ is selected from hydrogen; Ci-C₆ alkyl; C₂-C₆ alkenyl; and -Co-C₃

alkylene-C₃-C₆ carbocyclyl or -Co-C₃ alkylene-3-6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein any carbocyclyl or heterocyclyl portion of R⁶ is optionally substituted with a single -Ci-C₃ alkyl or -C₂-C₃ alkenyl substituent, and wherein R⁶ is optionally substituted with deuterium;

R⁷ is C₃-C₆ carbocyclyl or 3 to 6-membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein R⁷ is optionally substituted with deuterium;

each of Y^la, Y^lb, Y^2a, Y^2b, Y^3a and Y^3b is independently selected from hydrogen and deuterium; provided that when each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is -CH₃ and each Y is hydrogen, then G is selected from -OR⁶, -NHR⁶, and R⁷, wherein R⁶ is other than hydrogen, and G comprises deuterium.

[46] In one embodiment, R⁷ is phenyl. In another embodiment, R⁷ is C₃-C₆ cycloalkyl.

[47] In another embodiment, R⁷ is 5- to 6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another embodiment, R⁷ is 3-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[48] In one embodiment the compound of Formula A is a compound of Formula I:

Formula I or a pharmaceutically acceptable salt thereof, wherein:

each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is independently selected from -CH₃, -CH₂D, -CHD₂ and -CD₃;

R⁶ is defined as in Formula A; and

each of Y^la, Y^lb, Y^2a, Y^2b, Y^3a and Y^3b is independently selected from hydrogen and deuterium;

provided that when each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is -CH₃ and each Y is hydrogen, then R⁶ is other than hydrogen and R⁶ comprises deuterium.

[49] In one embodiment of the compound of Formula A and Formula I, each of Y^la and Y^lb is the same; each of Y^2a and Y^2b is the same; each of Y^3a and Y^3b is the same; and each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is independently selected from -CH₃ and -CD₃. In one aspect each of Y^la and Y^lb is hydrogen. In another aspect, each of Y^la and Y^lb is deuterium. In one aspect each of Y^2a and Y^2b is hydrogen. In another aspect, each of Y^2a and Y^2b is deuterium. In one aspect each of Y^3a and Y^3b is hydrogen. In another aspect, each of Y^3a and Y^3b is deuterium. In one aspect R^la and R^lb are the same. In a further aspect R^la and R^lb are -CH₃. In another further aspect R^la and R^lb are -CD₃. In one aspect R^5a and R^5b are the same. In a further aspect R^5a and R^5b are -CH₃. In another further aspect R^5a and R^5b are -CD₃. In one aspect R² is -CH₃. In another aspect R² is -CD₃. In one aspect R³ is -CH₃. In another aspect R³ is -CD₃. In one aspect R⁴ is -CH₃. In another aspect R⁴ is -CD₃. In one aspect R⁶ is selected from hydrogen, cyclopropyl, cyclopropenyl, C₁-C₃ alkyl, and C₂-C₃ alkenyl, wherein R⁶ is optionally substituted with deuterium. In a further aspect R⁶ is -CH₃. In another further aspect R⁶ is -CD₃. In another further aspect R⁶ is H. In another aspect, at least one of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is -CD₃. In a more particular aspect, Y^la and Y^lb are the same; Y^2a and Y^2b are the same; Y^3a and Y^3b are the same; each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is independently selected from -CH₃ and -CD₃; R^la and R¹ are the same; and R^5a and R^5b are the same.

[50] In one embodiment of the compound of Formula A and Formula I, at least one of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is -CD₃. In one aspect of this embodiment each of R^la and R^lb is -CD₃. In one aspect of this embodiment each of R^5a and R^5b is -CD₃. In one aspect R² is -CD₃. In one aspect R³ is -CD₃. In one aspect R⁴ is -CD₃.

[51] In another set of embodiments, any atom not designated as deuterium in any of the embodiments set forth above for a compound of Formula I or Formula A is present at its natural isotopic abundance.

2] In one embodiment the compound of Formula I is a compound of Formula II:

Formula 11 _? wherein Y^la and Y^lb are the same; Y^2a and Y^2b are the same; Y^3a and Y^3b are the same; and the compound is selected from any one of the compounds set forth in Table 1 : TABLE 1 : Examples of Compounds of Formula II.

and pharmaceutically acceptable salts thereof, wherein any atom not designated as deuterium in Formula II is present at its natural isotopic abundance. In another embodiment the compound of Formula I is a compound of Formula III

, wherein Y^la and Y¹ are the same; Y^2a and Y^2b are the same; Y ^a and

are the same; and the compound is selected from any one of the compounds set forth in Table 2:

TABLE 2: Examples of Compounds of Formula III.

Compound # R⁶ Y^la and Y^lb Y^2a and Y^2b Y ^a and Y ^b

139 CD₃ H D H

140 CDs H H D

141 CDs D D H

142 CDs H D D

143 CDs D H D

144 CDs D D D

145 CDs H H H and pharmaceutically acceptable salts thereof, wherein, any atom not designated as deuterium in Formula III is present at its natural isotopic abundance.

54] In one embodiment the compound of Formula I is a compound of Formula IV:

Formu la IV _? wherein R^la and R^lb are the same; R^5a and R^5b are the same; and the compound is selected from any one of the compounds set forth in Table 3, below:

TABLE 3: Examples of Compounds of Formula IV.

and pharmaceutically acceptable salts thereof, wherein, any atom not designated as deuterium in Formula IV is present at its natural isotopic abundance.

[55] The synthesis of compounds of Formula I - IV may be readily achieved by synthetic chemists of ordinary skill by reference to the Exemplary Synthesis and Examples disclosed herein. Relevant procedures analogous to those of use for the preparation of compounds of Formula I - IV and intermediates thereof are disclosed, for instance in U.S. Patent No. 6,326,507.

[56] Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.

Exemplary Synthesis

[57] A convenient method for synthesizing compounds of Formula I, II, III and IV is depicted in Schemes 1-6.

Scheme 1 : General Route to Compounds of Formula I.

benzene

[59] Scheme 1 depicts a general route to preparing compounds of Formula I. In a manner analogous to that described in Honda, T. et al, Bioorg. Med. Chem. Lett., 1998, 8: 2711-2714, and in Honda, T. et al, J. Med. Chem., 2000, 43: 4233-4246, compound 10 is esterified, then acetylated with acetic anhydride, and finally oxidized with hydrogen peroxide to afford compound 11. For example, in the first step, esterification with diazomethane produces an ester wherein R⁶ is CH₃. Use of known reagent

diazomethane-d2 (see Prakash, G. K. S. et al., J. Am. Chem. Soc, 1986, 1341-1342, or Parsons, E. J. et al, J. Am. Chem. Soc, 1987, 3973-3977) produces an ester wherein R⁶ is CD₃. Similarly, CD₃I and K₂CO₃ (see Zhao, L. et al., Liaoning Shifan Daxue Xuebao, Ziran Kexueban, 2007, 30(4): 476-479; or see Chinese patent CN1682740) or (CD₃)₂S0₄ and NaOH (see Zaprutko, L. et al, Bioorg. Med. Chem. Lett., 2004, 14(18): 4723-4726) may be used to afford an ester wherein R⁶ is CD₃.

[60] Treatment of compound 11 with bromine and HBr in AcOH affords enone 12. Hydrolysis with aqueous KOH in MeOH followed by Jones oxidation provides ketone 13. Treatment with NaOMe and ethyl formate provides compound 14. Cyclization with hydroxylamine hydrochloride provides compound 15. Treatment either with NaOMe followed by phenyl selenium chloride and then hydrogen peroxide, or with NaOMe followed by oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), affords compounds of Formula I wherein R⁶ is other than H. Treatment with lithium iodide in DMF provides compounds of Formula I wherein R⁶ is H.

[61] Scheme 2: Preparation of Compound 10.

[62] Compound 10, for use in Scheme 1 above, may be prepared from compound 16 (see Scheme 3, below) following the same chemical transformation route described in Corey, E.J. et al, J. Am. Chem. Soc, 1993, 8873-8874, particularly the work disclosed on page 8874 in Scheme II.

[63] Scheme 3: Preparation of Compound 16.

17 18



[64] Scheme 3 depicts a preparation of compound 16, which is a useful starting material for Scheme 2. In an analogous manner to the work disclosed in Corey, E. J. et al, J. Am. Chem. Soc, 1993, 8873-8874, an appropriately deuterated form of compound 17 is treated with potassium tert-butoxide and an appropriately deuterated electrophile (R^5a/b-I), followed by reduction with either NaBH₄ or NaBD₄. Treatment with acetyl chloride, followed by reduction with Et₃SiH or Et₃SiD, affords compound 18. Birch reduction with lithium and ammonia affords compound 19, and treatment with tBuLi and appropriately deuterated electrophile 20 provides compound 21. Treatment with

2-mercaptoethanol and TFA, followed by treatment with silver nitrate and silver oxide yields compound 22. Treatment with KHMDS and t-amyl alcohol followed by N-phenyl triflimide provides compound 23. Treatment with NBS affords compound 24. Treatment with potassium carbonate in MeOH followed by a Gilman cuprate prepared from an appropriately deuterated R⁴-Li reagent (for example, CH₃Li or CD₃Li) affords compound 25. Treatment with perfluorosilane and DIEA, followed by oxidation with

DMSO/TFAA/Et₃N provides compound 26. Enantioselective reduction with the

(i?)-oxazaborolidine catalyst and catecholborane affords compound 27, and treatment with NaOiPr in isopropanol provides compound 16.

[65] Scheme 4: Preparation of Compound 17.

28 29 30

[66] Scheme 4 depicts a preparation of compound 17, which is a useful starting material for Scheme 3. Anisole 28 and appropriately deuterated succinic acid 29 are subjected to Friedel-Crafts conditions, either using AlCl₃/dichloroethane in a manner analogous to that in Srinivas, C. et al, Organic Process Research & Development, 2004, 8(2): 291-292; or using AlCl₃/nitropropane in a manner analogous to that in Shang, G. et al, Chemistry—A European Journal, 2007, 13(27): 7780-7784. For example, commercially available succinic anhydride -2,2,3, 3-d4 may be used as compound 29 to afford compound 30 wherein all Y² are deuterium. DC1 and D₂0 may be used in place of HCI and H₂0 when appropriate to maintain desired levels of deuteration. Reduction of ketone 30 to afford 31 is effected via treatment with either zinc/HCl in a manner analogous to Shang, G. et al, Chemistry—A European Journal, 2007, 13(27):

7780-7784; or hydrazine/KOH in a manner analogous to Aisa, H. A. et al., Chinese Journal of Chemistry, 2003, 21(7): 720-722, and to Chattopadhyay, S. et al. Journal of the Indian Chemical Society, 2002, 79(11): 906-907. DC1, D₂0, N₂D₄, and KOD may all be used to provide desired levels of deuteration. Compound 31 is cyclized to afford compound 17 via treatment with either H₃PO₄ and P₂0₅ in a manner analogous to that in Aisa, H. A. et al, Chinese Journal of Chemistry, 2003, 21(7): 720-722; or Bi(NTf₂)₃ in a manner analogous to that in Cui, D.-M. et al., Tetrahedron Letters, 2003, 44(21): 4007-4010. D₃PO₄ and D₂0 may be used when appropriate to maintain desired levels of deuteration.

[67] Scheme 5: Preparation of Compound 20.

[68] Scheme 5 depicts a preparation of compound 20, which is a useful intermediate for Scheme 3. In a manner analogous to that described in Kocienski, P. et al., Journal of Organic Chemistry, 1989, 54(5): 1215-1217, (4,5-dihydrofuran-2-yl)lithium 32 is treated with appropriately deuterated iodide 33 to afford compound 34. Treatment with nickel and an appropriately deuterated Grignard reagent affords alcohol 35. For example, use of commercially available CD₃MgI provides compounds wherein R² is CD₃. The alcohol is converted to iodide 36 in two steps via treatment with methanesulfonyl chloride followed by sodium iodide. Treatment of 36 with

(4,5-dihydrofuran-2-yl)lithium provides compound 37. Treatment with nickel and an appropriately deuterated Grignard reagent affords alcohol 38. For example, use of commercially available CD₃MgI provides compounds wherein R³ is CD₃. The alcohol is converted to iodide 20 in two steps via treatment with methanesulfonyl chloride followed by sodium iodide. [69] Scheme 6: Preparation of Compound 33.

39 (X = CI, Br, I) 40 33

[70] Scheme 6 depicts a preparation of compound 33, which is a useful intermediate for Scheme 5. In a manner analogous to that described in Argenti, L. et al., Synthetic Communications, 1994, 24(22): 3167-88, ketone 39 is treated with an appropriately deuterated Grignard reagent to afford alcohol 40. For example, use of known

cyclopropyl methyl-d3 ketone (see Nishida, S. et al, Journal of Organic Chemistry, 1989, 54(16): 3859-68) provides compounds wherein R^la is CD₃. Alcohol 40 is then treated with zinc iodide to afford compound 33 in a manner analogous to that described in Ismail, Z. M. et al, Journal of Organic Chemistry, 1981, 46(17): 3549-50.

[71] The specific approaches and compounds shown above are not intended to be limiting. The chemical structures in the schemes herein depict variables that are hereby defined commensurately with chemical group definitions (moieties, atoms, etc.) of the corresponding position in the compound formulae herein, whether identified by the same variable name (i.e., R¹, R², R³, etc.) or not. The suitability of a chemical group in a compound structure for use in the synthesis of another compound is within the knowledge of one of ordinary skill in the art.

[72] Additional methods of synthesizing compounds of Formula A, I, II, III and IV and their synthetic precursors, including those within routes not explicitly shown in schemes herein, are within the means of chemists of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the applicable compounds are known in the art and include, for example, those described in Larock R, Comprehensive Organic Transformations, VCH Publishers (1989); Greene, TW et al, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley and Sons (1999); Fieser, L et al., Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and Paquette, L, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[73] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds.

Compositions

[74] The invention also provides pharmaceutical compositions comprising an effective amount of a compound of any one of Formulae A, I, II, III or IV, or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[75] In some embodiments, the present invention provides pyrogen-free

pharmaceutical compositions comprising an effective amount of a compound of any one of Formulae A, I, II, III or IV, or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.

[76] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene -block polymers, polyethylene glycol and wool fat.

[77] If required, the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art. One method includes the use of lipid excipients in the formulation. See "Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences)," David J. Hauss, ed. Informa Healthcare, 2007; and "Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.

[78] Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.

[79] The pharmaceutical compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. In certain embodiments, the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques). Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).

[80] Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[81] In certain embodiments, the compound is administered orally. Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.

[82] In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. [83] Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[84] Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[85] Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[86] The pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

[87] The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.

[88] Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For topical application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,

2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.

[89] Application of the subject therapeutics may be local, so as to be administered at the site of interest. Various techniques can be used for providing the subject

compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access. [90] Thus, according to yet another embodiment, the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters. Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer,

polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.

[91] According to another embodiment, the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.

[92] According to another embodiment, the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention. Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.

[93] According to another embodiment, the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.

[94] According to another embodiment, the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.

[95] Where an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.

[96] In another embodiment, a composition of this invention further comprises a second therapeutic agent. The second therapeutic agent may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as bardoxolone or bardoxolone methyl. Such agents include those indicated as being useful in combination with bardoxolone or bardoxolone methyl, including but not limited to, those described in PCT publication WO2009089545.

[97] In one embodiment, the second therapeutic agent is selected from a cholesterol lowering drug, an anti-hyperlipidemic, a calcium channel blocker, an anti hypertensive, or an HMG-CoA reductase inhibitor. Non-limiting examples of second therapeutic agents are amlodipine, aspirin, ezetimibe, felodipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine and nitrendipine. Further non-limiting examples of second therapeutic agents are atenolol, bucindolol, carvedilol, clonidine, doxazosin, indoramin, labetalol, methyldopa, metoprolol, nadolol, oxprenolol, phenoxybenzamine, phentolamine, pindolol, prazosin, propranolol, terazosin, timolol and tolazoline.

[98] In some embodiments, the second therapeutic agent is a statin. Non-limiting examples of statins are atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

[99] In some embodiments, the second therapeutic agent is a dipeptidyl peptidase-4 (DPP-4) inhibitor. Non- limiting examples of DPP-4 inhibitors are sitagliptin, vildagliptin, SYR-322, BMS 4771 18 and GSK 823093.

[100] In some embodiments, the second therapeutic agent is a biguanide. For example, the biguanide can be metformin.

[101] In some embodiments, the second therapeutic agent is a thiazolidinedione (TZD). Non- limiting examples of TZDs are pioglitazone, rosiglitazone and troglitazone.

[102] In some embodiments, the second therapeutic agent is a sulfonylurea derivative. Non-limiting examples of sulfonyl urea derivatives are tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide, glyburide, glimepiride and gliclazide. [103] In some embodiments, the second therapeutic agent is a meglitinide. Non- limiting examples of meglitinides include repaglinide, mitiglinide and nateglinide.

[104] In some embodiments, the second therapeutic agent is insulin.

[105] In some embodiments, the second therapeutic agent is an alpha-glucosidase inhibitor. Non-limiting examples of alpha-glucosidase inhibitors are acarbose, miglitol and voglibose.

[106] In some embodiments, the second therapeutic agent is a glucagon-like peptide- 1 analog. Non-limiting examples of glucagon-like peptide- 1 analogs are exenatide and liraglutide.

[107] In some embodiments, the second therapeutic agent is a gastric inhibitory peptide analog.

[108] In some embodiments, the second therapeutic agent is a GPR40 agonist.

[109] In some embodiments, the second therapeutic agent is a GPR1 19 agonist.

[110] In some embodiments the second therapeutic agent is a GPR30 agonist. In some embodiments the second therapeutic agent is a glucokinase activator.

[Ill] In some embodiments the second therapeutic agent is a glucagon receptor antagonist. In some embodiments the second therapeutic agent is an amylin analog. A non- limiting example of an amylin analog is pramlintide.

[112] In some embodiments the second therapeutic agent is an IL-1 β receptor antagonist. A non-limiting examples of a IL-I β receptor antagonist is anakinra.

[113] In some embodiments the second therapeutic agent is an endocannabinoid receptor antagonist or inverse agonist. A non-limiting example of a endocannabinoid receptor antagonist or inverse agonist is rimonabant.

[114] In some embodiments the second therapeutic agent is Orlistat. In some embodiments the second therapeutic agent is Sibutramine.

[115] In some embodiments the second therapeutic agent is a growth factor. Non- limiting examples of growth factors are TGF-βΙ , TGF-P2, TGF-pi.2, VEGF, insulin-like growth factor I or II, BMP2, BMP4, BMP7, a GLP-I analog, a GIP analog, a DPP-IV inhibitor, a GPR1 19 agonist, a GPR40 agonist, gastrin, EGF, betacellulin, KGF, NGF, insulin, growth hormone, HGF, an FGF, an FGF homologue, PDGF, Leptin, prolactin, placental lactogen, PTHrP, activin, inhibin, and INGAP. Further non-limiting examples of growth factors are parathyroid hormone, calcitonin, interleukin-6, and interleukin-1 1.

[116] In some embodiments the second therapeutic agent is an anti-cancer compound, more specifically a chemotherapeutic agent and even more specifically a nucleoside analog. In one specific embodiment, the second therapeutic agent is gemcitabine.

[117] In another embodiment, the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another. The term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).

[118] In the pharmaceutical compositions of the invention, the compound of the present invention is present in an effective amount. As used herein, the term "effective amount" refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.

[119] The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described in Freireich et al, Cancer Chemother. Rep, 1966, 50: 219. Body surface area may be approximately determined from height and weight of the subject. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970, 537.

[120] In one embodiment, an effective amount of a compound of this invention can range from about 0.1 mg to about 500 mg per day. In some embodiments, the daily dose is from about 1 mg to about 300 mg of the compound. In some embodiments, the daily dose is from about 10 mg to about 200 mg of the compound. In some embodiments, the daily dose is about 25 mg of the compound. In other embodiments, the daily dose is about 75 mg of the compound. In still other embodiments, the daily dose is about 150 mg of the compound. In further embodiments, the daily dose is from about 0.1 mg to about 30 mg of the compound. In some embodiments, the daily dose is from about 0.5 mg to about 20 mg of the compound. In some embodiments, the daily dose is from about 1 mg to about 15 mg of the compound. In some embodiments, the daily dose is from about 1 mg to about 10 mg of the compound. In some embodiments, the daily dose is from about 1 mg to about 5 mg of the compound.

[121] In some embodiments, the pharmaceutically effective amount is a daily dose of 0.01 - 25 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.05 - 20 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.1 - 10 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.1 - 5 mg of compound per kg of body weight. In some embodiments, the daily dose is 0.1 - 2.5 mg of compound per kg of body weight.

[122] Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician.

[123] For pharmaceutical compositions that comprise a second therapeutic agent, an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent. Preferably, an effective amount is between about 70% and 100% of the normal monotherapeutic dose. The normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al, eds., Pharmacotherapy Handbook, 2nd Edition,

Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.

[124] It is expected that some of the second therapeutic agents referenced above will act synergistically with the compounds of this invention. When this occurs, it will allow the effective dosage of the second therapeutic agent and/or the compound of this invention to be reduced from that required in a monotherapy. This has the advantage of minimizing toxic side effects of either the second therapeutic agent of a compound of this invention, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall expense of compound preparation or formulation. Methods of Treatment

[125] In another embodiment, the invention provides a method of reducing the activity of nitric oxide synthase in a cell, comprising contacting a cell with one or more compounds of any of Formulae A, I, II, III or IV herein or a pharmaceutically acceptable salt thereof.

[126] In another embodiment, the invention provides a method of reducing the activity of cyclooxygenase in a cell, comprising contacting a cell with one or more compounds of any of Formulae A, I, II, III or IV herein or a pharmaceutically acceptable salt thereof.

[127] In another embodiment, the invention provides a method of increasing the activity of cytoprotective enzymes in a cell, comprising contacting a cell with one or more compounds of any of Formulae A, I, II, III or IV herein or a pharmaceutically acceptable salt thereof. In one aspect the cytoprotective enzyme is selected from one or more of NAD(P)H quinine oxidoreductase and hemeoxygenase-1.

[128] In another embodiment, the invention provides a method of reducing the levels of pSTAT3 in a cell, comprising contacting a cell with one or more compounds of any of Formulae A, I, II, III or IV herein or a pharmaceutically acceptable salt thereof.

[129] In another aspect of the invention, a method is provided for improving glomerular filtration rate or creatinine clearance in a subject comprising, administering to said subject a pharmaceutically effective amount of a compound of any of Formulae A, I, II, III or IV herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compound

[130] According to another embodiment, the invention provides a method of treating a disease selected from renal/kidney disease (RKD) (including diabetic nephropathy, RKD resulting from toxic insult, RKS resulting from ischemia/reperfusion injury, RKD resulting from hypertension, RDK resulting from autoimmune disease, chronic RKD and acute RKD), insulin resistance, diabetes, endothelial dysfunction, fatty liver disease, cardiovascular disease (CVD), inflammation, autoimmune disease, and cancer.

[131] In one particular embodiment, the method of this invention is used to treat diabetic nephropathy in a subject in need thereof.

[132] In another particular embodiment, the method of this invention is used to treat metastatic tumors, unresectable solid tumors or lymphoma in a subject in need thereof. In one aspect, the metastatic or unresectable solid tumor is selected from pancreatic cancer, small intestinal cancer and melanoma.

[133] In another particular embodiment the method of this invention is used to treat inflammatory bowel disease in a subject in need thereof.

[134] In another particular embodiment the method of this invention is used to treat autoimmune disease in a subject in need thereof.

[135] Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g.

measurable by a test or diagnostic method).

[136] In another embodiment, any of the above methods of treatment comprises the further step of co-administering to the subject in need thereof one or more second therapeutic agents. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent.

[137] In particular, the combination therapies of this invention include a method of treating unresectable pancreatic cancer or melanoma comprising the step of

co-administering a compound of any one of Formulae A, I, II, III or IV herein or a pharmaceutically acceptable salt thereof and gemcitabine to a subject in need thereof.

[138] The term "co-administered" as used herein means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods. The administration of a composition of this invention, comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.

[139] Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy

Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR

Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.

[140] In one embodiment of the invention, where a second therapeutic agent is administered to a subject, the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not

administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.

[141] In yet another aspect, the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above. Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof delineated herein.

Example 1. Evaluation of Metabolic Stability

[142] Microsomal Assay: Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). β -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.

[143] Determination of Metabolic Stability: 7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5 mM stock solutions are diluted to 12.5-50 μΜ in acetonitrile (ACN). The 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate. A 10 aliquot of the 12.5-50 μΜ test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution. The final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 μΜ test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures are incubated at 37 °C, and 50 μΐ, aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μΐ_^ of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 μΐ_^ of water is added to the wells of the plate before centrifugation to pellet precipitated proteins. Supernatants are transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio-systems API 4000 mass spectrometer. The same procedure is followed for the non-deuterated counterpart of the compound of Formula I and the positive control, 7-ethoxycoumarin (1 μΜ). Testing is done in triplicate.

[144] Data analysis: The in vitro ti/₂s for test compounds are calculated from the slopes of the linear regression of % parent remaining (In) vs incubation time relationship,

in vitro t _½ = 0.693/k

k = -[slope of linear regression of % parent remaining(ln) vs incubation time]

[145] Data analysis is performed using Microsoft Excel Software.

[146] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those of ordinary skill in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.

Claims

A compound of Formula I

Formula I or a pharmaceutically acceptable salt thereof, wherein:

each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is independently selected from -CH₃, -CH₂D, -CHD₂ and -CD₃;

R⁶ is selected from hydrogen; Ci-C₆ alkyl; C₂-C₆ alkenyl; and -C0-C3

alkylene-C₃-C₆ carbocyclyl or -Co-C₃ alkylene-3-6 membered heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein any carbocyclyl or heterocyclyl portion of R⁶ is optionally substituted with a single -Ci-C₃ alkyl or -C₂-C₃ alkenyl substituent, and wherein R⁶ is optionally substituted with deuterium; and

each of Y^la, Y^lb, Y^2a, Y^2b, Y^3a and Y^3b is independently selected from hydrogen and deuterium;

provided that when each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is -CH₃ and each Y is hydrogen, then R⁶ is other than hydrogen and R⁶ comprises deuterium.

2. A compound of claim 1, wherein R⁶ is selected from hydrogen; Ci-C₆ alkyl; C₂-C₆ alkenyl; and -Co-C₃ alkylene-C₃-C₆ carbocyclyl, wherein any carbocyclyl portion of R⁶ is optionally substituted with a single -Ci-C₃ alkyl or -C₂-C₃ alkenyl substituent, and wherein R⁶ is optionally substituted with deuterium.

3. The compound of claim 1 or 2, wherein Y^la and Y¹ are the same; Y^2a and Y² are the same; Y^3a and Y^3b are the same; each of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is independently selected from -CH₃ and -CD₃; R^la and R^lb are the same; and R^5a and R^5b are the same.

4. The compound of claim 1, 2 or 3, wherein at least one of R^la, R^lb, R², R³, R⁴, R^5a and R^5b is -CD₃.

5. The compound of claim 4, wherein each of R^la and R^lb is -CD₃.

6. The compound of claim 4 or 5, wherein each of R^5a and R^5b is -CD₃.

7. The compound of any one of claims 1-6, wherein R⁶ is Ci-C₃ alkyl or C₂-C₃ alkenyl; and R⁶ is optionally substituted with deuterium.

8. The compound of claim 7 wherein R⁶ is -CH₃ or -CD₃.

9. The compound of any one of claims 1-8, wherein any atom not designated as deuterium in Formula I is present at its natural isotopic abundance.

The compound of claim 3, having the Formula II

Formula II and being selected from any one of the compounds set forth in the table below: Compound # R⁶ Y^la and Y^lb Y^2a and Y^2b Y ^a and Y ^b

100 H D H H

101 H H D H

102 H H H D

103 H D D H

104 H H D D

105 H D H D

106 H D D D

107 CH₃ D H H

108 CH₃ H D H

109 CH₃ H H D

110 CH₃ D D H

111 CH₃ H D D

112 CH₃ D H D

113 CH₃ D D D

114 CD₃ D H H

115 CD₃ H D H

116 CD₃ H H D

117 CD₃ D D H

118 CD₃ H D D

119 CD₃ D H D

120 CD₃ D D D

121 CD₃ H H H and a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium in Formula II is present at its natural isotopic abundance.

11. The compound of claim 3, having the Formula III:

Formula I II ^ _an(j b_eing selected from any one of the compounds set forth in the table below:

Compound # R⁶ Y^la and Y^lb Y^2a and Y^2b Y ^a and Y ^b

143 CD₃ D H D

144 CDs D D D

145 CDs H H H and a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium in Formula III is present at its natural isotopic abundance.

The com ound of claim 3, having the Formula IV

, and being selected from any one of the compounds set forth in the table below:

and a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium in Formula I in claim 1 is present at its natural isotopic abundance.

13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

14. The composition of claim 13, additionally comprising a second therapeutic agent selected from a cholesterol lowering drug, an anti-hyperlipidemic, a calcium channel blocker, an anti hypertensive, an HMG-CoA reductase inhibitor, a statin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a biguanide, a thiazolidinedione, a sulfonylurea derivative, a meglitinide, insulin, an alpha- glucosidase inhibitor, a glucagon- like peptide- 1 analog, a gastric inhibitory peptide analog, a GPR40 agonist, a GPR1 19 agonist, a GPR30 agonist, a glucokinase activator, a glucagon receptor antagonist, an IL-1 β receptor antagonist, an endocannabinoid receptor antagonist or inverse agonist, a growth factor, and an anti-cancer compound.

15. A method for improving glomerular filtration rate or creatinine clearance in a subject comprising administering to the subject in need thereof the pharmaceutical composition of claim 13.

16. A method of treating a disease or condition selected from renal/kidney disease (RKD), insulin resistance, diabetes, endothelial dysfunction, fatty liver disease, cardiovascular disease (CVD), inflammation, autoimmune disease, and cancer in a subject comprising administering to the subject in need thereof the pharmaceutical composition of claim 13.

17. The method of claim 16, wherein the disease or condition is diabetic

nephropathy.

18. The method of claim 16, wherein the disease or condition is selected from metastatic tumors, unresectable solid tumors and lymphoma.

19. The method of any one of claims 16-18, comprising the additional step of coadministering to the subject in need thereof a second therapeutic agent selected from a cholesterol lowering drug, an anti-hyperlipidemic, a calcium channel blocker, an anti hypertensive, an HMG-CoA reductase inhibitor, a statin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a biguanide, a

thiazolidinedione, a sulfonylurea derivative, a meglitinide, insulin, an alpha- glucosidase inhibitor, a glucagon- like peptide- 1 analog, a gastric inhibitory peptide analog, a GPR40 agonist, a GPR1 19 agonist, a GPR30 agonist, a glucokinase activator, a glucagon receptor antagonist, an IL-1 β receptor antagonist, an endocannabinoid receptor antagonist or inverse agonist, a growth factor, and an anti-cancer compound.

20. The method of claim 19, wherein the disease or condition is metastatic or non- resectable pancreatic cancer or melanoma, and wherein the second therapeutic agent is gemcitabine.