WO2017210261A1 - Deuterated fevipiprant - Google Patents

Abstract

This invention relates to novel pyrrolo[2,3-b]pyridine compounds, and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted pyrrolo[2,3-b]pyridine compounds that are structurally related to fevipiprant. This invention also provides pharmaceutical 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 a prostaglandin D2 receptor 2 antagonist (e.g., a CRTH2, GPR44, or PTGDR2 antagonist).

Description

DEUTERATED FEVIPIPRANT CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims priority to U.S. Provisional Application Serial No. 62/343,634, filed on May 31, 2016. The disclosure of the prior application is considered part of the disclosure of this application, and is incorporated in its entirety into this application.

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 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 the CYP-mediated metabolism of a drug or to 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. SUMMARY OF THE INVENTION

[9] This invention relates to deuterated forms of pyrrolo[2,3-b]pyridine compounds, and pharmaceutically acceptable salts thereof. For example, this invention relates to novel deuterated pyrrolo[2,3-b]pyridine compounds that are structurally related to fevipiprant.

[10] Certain aspects of the present invention provide a compound of Formula I:

(I), or a pharmaceutically acceptable salt thereof, wherein each of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is hydrogen or deuterium; each of R¹ and R² is independently selected from the group consisting of CH3, CH2D, CHD2, and CD₃; R³ is H or C₁-C₈ alkyl; provided that at least one of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, R¹, and R² comprises deuterium.

[11] Certain aspects of the present invention also provide compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Certain aspects of the present invention provide the use of such compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a prostaglandin D₂ receptor 2 antagonist (e.g., a CRTH2, GPR44, or PTGDR2 antagonist). Some exemplary embodiments include a method of antagonizing the prostaglandin D2 receptor 2 in a cell, comprising contacting the cell with a compound of Formula I or a composition comprising a compound of Formula I. Some exemplary embodiments include a method of treating a disease or condition selected from the group consisting of asthma, allergic rhinitis, and atopic dermatitis, comprising the step of administering to a subject in need thereof a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I. In some exemplary embodiments, wherein the subject is suffering from allergic rhinitis, the method further comprises co- administering montelukast to the subject in need thereof. DETAILED DESCRIPTION OF THE INVENTION

[12] Fevipiprant, also known as NVP-QAW039 or QAW-039, and by the chemical name 2-[2-methyl-1-[4-(methylsulfonyl)-2-(trifluoromethyl)benzyl]-1H-pyrrolo[2,3- b]pyridin-3-yl]acetic acid, is a selective antagonist of the prostaglandin D2 receptor 2 CRTH2. Prostaglandin D₂ receptor 2 (CRTH2) is a receptor also known as G protein- coupled receptor 44 (GPR44) that mediates chemotaxis of inflammatory cells in response to prostaglandin D2 (PGD2) binding. PGD2 is produced by T helper type 2 (Th2) cells and is an important mediator in allergic inflammatory diseases. Thus, CRTH2 antagonists may be beneficial in the treatment of allergic disorders including atopic dermatitis, allergic rhinitis, and asthma.

[13] Fevipiprant is currently in Phase II clinical trials for atopic dermatitis and Phase III clinical trials for asthma. Phase II clinical trials are also ongoing for treatment of allergic rhinitis with fevipiprant as monotherapy or in combination with montelukast (Singulair).

[14] Despite the beneficial activities of fevipiprant, there is a continuing need for new compounds to treat the aforementioned diseases and conditions. Definitions

[15] 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.

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

[17] As used herein, the term“subject” includes humans and non-human mammals. Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc.

[18] “The term“alkyl” refers to a monovalent saturated hydrocarbon group. C1-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.

[19] Unless otherwise specified,“alkylene” by itself or as part of another substituent refers to a saturated straight-chain or branched divalent 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-.

[20] The term“alkenyl” refers to a monovalent unsaturated hydrocarbon group where the unsaturation is represented by a double bond. C2-C6 alkenyl is an alkenyl having from 2 to 6 carbon atoms. An alkenyl 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.

[21] The term "alkynyl" refers to a monovalent unsaturated hydrocarbon group where the unsaturation is represented by a triple bond. C₂-C₆ alkynyl is an alkenyl having from 2 to 6 carbon atoms. An alkynyl may be linear or branched. Examples of alkynyl groups include CH≡C-, -C≡C-CH3, CH3-C≡C-CH2-, CH3-C≡C-CH2-CH2 and CH₃-C≡C-CH(CH₃)-CH₂-.

[22] The term "cycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C3-C10 cycloalkyl” refers to a cycloalkyl wherein the number of ring carbon atoms is from 3 to 10.

Examples of C₃-C₁₀ cycloalkyl include C₃-C₆ cycloalkyl. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More particular examples of cycloalkyl groups include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cis- and trans-decalinyl, norbornyl, and spiro[4.5]decanyl.

[23] The term "carbocyclyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated hydrocarbon ring system. The term "C3-C10 carbocyclyl” refers to a carbocyclyl wherein the number of ring carbon atoms is from 3 to 10. Examples of C₃-C₁₀ carbocyclyl include C₃-C₆ carbocyclyl. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More particular examples of carbocyclyl groups include, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cis- and trans-decalinyl, norbornyl, norbornenyl, and spiro[4.5]decanyl.

[24] The term "heterocycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated ring system wherein from 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of O, N and S. The term "3 to 10-membered heterocycloalkyl" refers to a heterocycloalkyl wherein the number of ring atoms is from 3 to 10. Examples of 3 to 10-membered

heterocycloalkyl include 3 to 6-membered heterocycloalkyl. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More particular examples of heterocycloalkyl groups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, and thiomorpholinyl.

[25] In the above heterocycloalkyl substituents, the nitrogen, phosphorus, carbon or sulfur atoms can be optionally oxidized to various oxidation states. In a specific example, the group -S(O)_0-2-, refers to -S-(sulfide), -S(O)-(sulfoxide), and -SO₂- (sulfone) respectively. For convenience, nitrogens, particularly but not exclusively, are meant to include their corresponding N-oxide form, although not explicitly defined as such in a particular example. Thus, for a compound of the invention having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another compound of the invention. In addition, annular nitrogen atoms can be optionally quaternized; and the ring substituent can be partially or fully saturated or aromatic.

[26] “Aryl” by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon group having the stated number of carbon atoms (i.e., C5-C14 means from 5 to 14 carbon atoms). Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octophene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthylene, and the like. In a specific embodiment, the aryl group is cyclopentadienyl, phenyl or naphthyl. In a more specific embodiment, the aryl group is phenyl or naphthyl.

[27] “Arylalkyl” by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp₃ carbon atom, is replaced with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2- naphthophenylethan-1-yl and the like. In one embodiment, the alkyl moiety of the arylalkyl group is (C1-C6) and the aryl moiety is (C5-C14). In a more specific embodiment the alkyl group is (C1-C3) and the aryl moiety is (C5-C10), such as (C6- [28] The term“heteroaryl” refers to a monovalent aromatic monocyclic

ring system wherein at least one ring atoms is a heteroatom independently selected from the group consisting of O, N and S. The term 5-membered heteroaryl refers to a heteroaryl wherein the number of ring atoms is 5. Examples of 5-membered heteroaryl groups include pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furazanyl, imidazolinyl, and triazolyl.

[29] “Heteroarylalkyl” by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, is replaced with a heteroaryl group. In one embodiment, the alkyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and the heteroaryl moiety is a 5-14-membered heteroaryl. In a more specific embodiment, the alkyl moiety is (C₁- C3) alkyl and the heteroaryl moiety is a 5-10 membered heteroaryl.

[30] “Halogen” or“Halo” by themselves or as part of another substituent refers to fluorine, chlorine, bromine and iodine, or fluoro, chloro, bromo and iodo.

[31] 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 fevipiprant 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.

[32] 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).

[33] The term“isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[34] 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).

[35] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 52.5%.

[36] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 60%.

[37] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 67.5%.

[38] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 75%.

[39] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 82.5%.

[40] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 90%. [41] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 95%.

[42] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 97.5%.

[43] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 99%.

[44] In some embodiments, in a compound of this invention, each designated deuterium atom has deuterium incorporation of least 99.5%.

[45] The term“isotopologue” refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.

[46] 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.

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

[48] 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 one embodiment, the compound is a pharmaceutically acceptable acid addition salt. In one embodiment the acid addition salt may be a deuterated acid addition salt.

[49] 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.

[50] 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-1,4-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, methanesu1fonate, 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. In one embodiment, the acids commonly employed to form pharmaceutically acceptable salts include the above- listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.

[51] 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-(C₁-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.

[52] 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.“Stereoisomer” refers to both enantiomers and diastereomers. 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 enantiomer for a given compound are known in the art and may be applied as practicable to final compounds or to starting material or intermediates.

[53] 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.

[54] 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).

[55] “D” and“d” both refer to deuterium.“Tert” and“t-” each refer to tertiary. “US” refers to the United States of America.

[56] “Substituted with deuterium” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[57] 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

[58] Certain aspects of the present invention provide a compound of Formula I:

, or a pharmaceutically acceptable salt thereof, wherein each of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is independently hydrogen or deuterium;

each of R¹ and R² is independently selected from the group consisting of CH₃, CH2D, CHD2, and CD3; and

R³ is H or C₁-C₈ alkyl;

provided that at least one of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, R¹, and R² comprises deuterium.

[59] In some embodiments, R¹ is CH3 or CD3. In some embodiments, R² is CH3 or CD₃. In some embodiments, each of R¹ and R² is CH₃. In some embodiments, each of R¹ and R² is CD3. In some embodiments, R¹ is CH3 and R² is CD3. In some embodiments, R¹ is CD3 and R² is CH3.

[60] In some embodiments, each Y¹ is the same. In some embodiments, each Y¹ is hydrogen. In some embodiments, each Y¹ is deuterium. In some embodiments, each Y² is the same. In some embodiments, each Y² is hydrogen. In some embodiments, each Y² is deuterium.

[61] In some embodiments, Y³ is hydrogen. In some embodiments, Y³ is deuterium. In some embodiments, Y⁴ is hydrogen. In some embodiments, Y⁴ is deuterium. In some embodiments, Y⁵ is hydrogen. In some embodiments, Y⁵ is deuterium. In some embodiments, Y⁶ is hydrogen. In some embodiments, Y⁶ is deuterium. In some embodiments, Y⁷ is hydrogen. In some embodiments, Y⁷ is deuterium. In some embodiments, Y⁸ is hydrogen. In some embodiments, Y⁸ is deuterium. In some embodiments, each of Y³, Y⁴, and Y⁵ is hydrogen. In some embodiments, one of Y³, Y⁴, and Y⁵ is deuterium and the other two are hydrogen (e.g., Y³ = D and Y⁴ = Y⁵ = H; Y⁴ = D and Y³ = Y⁵ = H; or Y⁵ = D and Y³ = Y⁴ = H). In some embodiments, two of Y³, Y⁴, and Y⁵ are deuterium and the other is hydrogen (e.g., Y³ = Y⁴ = D and Y⁵ = H; Y³ = Y⁵ = D and Y⁴ = H; or Y⁴ = Y⁵ = D and Y³ = H). In some embodiments, each of Y³, Y⁴, and Y⁵ is deuterium. In some embodiments, each of Y⁶, Y⁷, and Y⁸ is hydrogen. In some embodiments, one of Y⁶, Y⁷, and Y⁸ is deuterium and the other two are hydrogen (e.g., Y⁶ = D and Y⁷ = Y⁸ = H; Y⁷ = D and Y⁶ = Y⁸= H; or Y⁸ = D and Y⁶ = Y⁷ = H). In some embodiments, two of Y⁶, Y⁷, and Y⁸ are deuterium and the other is hydrogen (e.g., Y⁶ = Y⁷ = D and Y⁸ = H; Y⁶ = Y⁸ = D and Y⁷ = H; or Y⁷ = Y⁸ = D and Y⁶ = H). In some embodiments, each of Y⁶, Y⁷, and Y⁸ is deuterium.

[62] In some embodiments, each of Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is the same. In some embodiments, each of Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is hydrogen. In some embodiments, each of Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is deuterium.

[63] In some embodiments, R³ is H. In some embodiments, R³ is C₁-C₈ alkyl. In some embodiments, R³ is C1-C8 alkyl, wherein the C1-C8 alkyl is substituted with one or more deuteriums. For example, R³ can be methyl substituted with 1-3 deuteriums (e.g., CH₂D, CHD₂, or CD₃), ethyl substituted with 1-5 deuteriums (e.g., CHDCH₃, CD₂CH₃, CD₂CH₂D, CD₂CHD₂, CD₂CD₃, etc.), propyl substituted with 1-7 deuteriums, butyl substituted with 1-9 deuteriums, pentyl substituted with 1-11 deuteriums, hexyl substituted with 1-13 deuteriums, heptyl substituted with 1-15 deuteriums, or octyl substituted with 1-17 deuteriums.

In some embodiments of Formula I, when each Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is deuterium, at least one of R¹ and R² comprises one or more hydrogens. In some embodiments of Formula I, when each Y¹and each Y² is deuterium, at least one of R¹ and R² comprises one or more hydrogens. In some embodiments, at least one of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, R¹, and R² comprises hydrogen.

[64] In some embodiments of a compound of Formula I, Y³, Y⁴, and Y⁵ are the same, Y⁶, Y⁷, and Y⁸ are the same, R³ is H and the compound is selected from any one of the compounds set forth in Table 1 (below):

Table 1: Exemplary Embodiments of Formula I

, or a pharmaceutically acceptable salt thereof.

[65] In some embodiments of Formula I, any atom not designated as deuterium is present at its natural isotopic abundance.

[66] In some embodiments, when Y¹ is deuterium, the level of deuterium incorporation at each Y¹ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[67] In some embodiments, when Y² is deuterium, the level of deuterium incorporation at each Y² is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[68] In some embodiments, when Y³ is deuterium, the level of deuterium incorporation at Y³ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[69] In some embodiments, when Y⁴ is deuterium, the level of deuterium incorporation at Y⁴ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[70] In some embodiments, when Y⁵ is deuterium, the level of deuterium incorporation at Y⁵ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[71] In some embodiments, when Y⁶ is deuterium, the level of deuterium incorporation at Y⁶ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[72] In some embodiments, when Y⁷ is deuterium, the level of deuterium incorporation at Y⁷ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[73] In some embodiments, when Y⁸ is deuterium, the level of deuterium incorporation at Y⁸ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[74] In some embodiments, when R¹ comprises deuterium, the level of deuterium incorporation at R¹ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[75] In some embodiments, when R² comprises deuterium, the level of deuterium incorporation at R² is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[76] In some embodiments, when R³ comprises deuterium, the level of deuterium incorporation at R³ is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.

[77] In some embodiments, any atom not designated as deuterium in any of the embodiments set forth herein is present at its natural isotopic abundance. [78] The synthesis of compounds of Formula I 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 and intermediates thereof are disclosed, for instance in PCT patent publications WO 2005/123731 and WO 2007/068418.

[79] 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

[80] A convenient method for synthesizing compounds of Formula I is depicted in Scheme I, below.

Scheme 1: General Synthesis of Compounds of Formula I

Reagents and conditions: (a) BnEt₃NCl, NaOH, PhSO₂Cl; (b) LDA; (c) TBAF; (d) n-BuLi, ZnCl2; (e) NaH or BEMP; (f) NaOH [81] In a manner analogous to a procedure described in WO2005123731 and by Sandham, D. et al., Bioorganic & Medicinal Chemistry, 21(21), 6582-6591; 2013, sulfonation of appropriately deuterated azaindole intermediate (1) using

phenylsulfonyl chloride affords protected and appropriately deuterated sulfonyl azaindole intermediate (2). Subsequent deprotonation of (2) with a lithium amide base such as lithium diisopropylamide (LDA), followed by alkylation with appropriately deuterated alkyl halide intermediate (3) furnishes protected and appropriately deuterated alkyl azaindole intermediate (4). Deprotection of sulfonyl group in (4) using tetrabutylammonium fluoride (TBAF) affords appropriately deuterated alkyl azaindole (5), which is subsequently deprotonated with a strong base such as butyl lithium, followed by treatment with zinc chloride affording a zinc salt, which is directly C-alkylated with appropriately deuterated alkyl bromoacetate intermediate (6) at elevated temperature to afford appropriately deuterated azaindole acetate intermediate (7). N-alkylation of (7) with appropriately deuterated aryl-methyl bromide intermediate (8) using sodium hydride or alternatively, 2-tert-butylimino-2- diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) as a base, produces appropriately deuterated N-aryl-methyl azaindole acetate compounds of Formula I, wherein R³ =C₁-C₈ alkyl. Base hydrolysis of acetate in compounds of Formula I, wherein R³ =C₁-C₈ alkyl, using a base such as sodium hydroxide furnishes appropriately deuterated compounds of Formula I, wherein R³= H.

[82] Alternatively, appropriately deuterated (5) (for example, wherein R² is CH3, CH₂D, CHD₂ or CD₃) may be directly prepared by analogy to a procedure described by Sandham, D. et al., Bioorganic & Medicinal Chemistry, 21(21), 6582-6591; 2013 using, for example, commercially available N,N-Dimethylacetamide-2,2,2-d3 (98 atom %D) for the introduction of R² moiety.

[83] Using commercially available reagents and deuterated reagents that can be readily prepared by known methods, compounds of Formula I can be prepared with greater than 90% or greater than 95% deuterium incorporation at each position designated as D (see below for details).

[84] Appropriately deuterated intermediate (1), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from

corresponding deuterated reagents exemplified in Scheme 2.

Reagents and conditions: (a) (Boc)₂O; (b) n-BuLi; (c) DMF, HCl or DMF-d₁, DCl; (d) NaOH [85] By analogy to a procedure described by Hands, D. et al., Synthesis, (7), 877- 882; 1996, appropriately deuterated pyridylamine intermediate (9) is treated with di- tert-butyl dicarbonate affording appropriately deuterated pyridylamine-carbamate intermediate (10), which is subsequently treated with butyl lithium to furnish appropriately deuterated lithiated dianion intermediate (11). Quenching of dianion (11) with N,N-Dimethylformamide (DMF) followed by treatment with HCl or N,N- Dimethylformamide-d1 (DMF-d1) (99 atom %D) followed by treatment with DCl affords appropriately deuterated aldehyde (12). Finally, treatment of (12) with HCl followed by NaOH produces appropriately deuterated 7-azaindole intermediate (1). 1H-Pyrrolo[2,3-b]pyridine-1,2,3,4,5,6-d6 (98 atom %D) (1a) is commercially available.

[86] Use of appropriately deuterated reagents allows deuterium incorporation at the Y³, Y⁴, Y⁵ positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any Y³, Y⁴ and /or Y⁵.

[87] Appropriately deuterated intermediate (9), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from

corresponding deuterated reagents exemplified in Scheme 3. Scheme 3: Preparation of Intermediate (9)

Reagents and conditions: (a) H2O2; (b) t-BuNH2, Ts2O, TFA

[88] By analogy to a procedure described in WO 2012160464, oxidation of appropriately deuterated picoline intermediate (13) using hydrogen peroxide affords appropriately deuterated picoline N-oxide intermediate (14). Subsequent amination in a manner analogous to a procedure described by Yin, J. et al., Journal of Organic Chemistry, 72(12), 4554-4557; 2007, using t-butylamine and tosylic anhydride followed by in situ deprotection with trifluoroacetic acid produces appropriately deuterated pyridylamine intermediate (9). 3-Methylpyridine-d₇ (98 atom % D) intermediate (13a) is commercially available.

[89] Use of appropriately deuterated reagents allows deuterium incorporation at the Y³, Y⁴, Y⁵ positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any Y³, Y⁴ and /or Y⁵.

[90] Certain intermediates (3), for use in the preparation of compounds of Formula I according to Scheme 1, are commercially available: Iodomethane-d3 (99 atom % D) (3a), Iodomethane-d₂ (99 atom % D) (3b), Iodomethane-d (99 atom % D) (3c).

[91] Use of appropriately deuterated reagents allows deuterium incorporation at the R² positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any R².

[92] Appropriately deuterated intermediate (6), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from

corresponding deuterated reagents exemplified in Scheme 4.

Scheme 4: Preparation of Intermediate (6)

[93] By analogy to a procedure described by Werkhoven, T. et al., European Journal of Organic Chemistry, (11), 2909-2914; 1999, esterification of appropriately deuterated bromoacetic acid intermediate (15) with alcohol intermediate (16) using oxalyl chloride or other commonly known methods in the art, produces appropriately deuterated bromoacetate intermediate (6). Bromoacetic acid-d₃ (98 atom % D) (15a) is commercially available. The following intermediates (6) are commercially available: Methyl bromoacetate-2, 2-d2 (98 atom % D) (6a) and Ethyl bromoacetate- 2, 2-d₂ (97 atom % D) (6b).

[94] Use of appropriately deuterated reagents allows deuterium incorporation at the Y² positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any or Y².

[95] Appropriately deuterated intermediate (8), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from

corresponding deuterated reagents exemplified in Scheme 5.

Scheme 5: Pre aration of Intermediate 8

Reagents and conditions: (a) heat; (b) NaBD4, or NaBH4; (c) PBr3

[96] In a manner analogous to a procedure described in WO200512373, appropriately deuterated aryl aldehyde intermediate (17) is treated with appropriately deuterated sulfinate salt intermediate (18) to furnish appropriately deuterated aryl sulfonyl aldehyde intermediate (19). Reduction of aldehyde in (19) with reductant such as sodium borohydride or sodium borodeuteride affords correspondingly and appropriately deuterated benzyl alcohol intermediate (20) which is subsequently brominated with phosphorus tribromide to produce appropriately deuterated benzyl bromide intermediate (8).

[97] Use of appropriately deuterated reagents allows deuterium incorporation at the R¹, Y¹, Y⁶, Y⁷, Y⁸ positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any R¹, Y¹, Y⁶, Y⁷ and /or Y⁸.

[98] Appropriately deuterated intermediate (17), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from

corresponding deuterated reagents exemplified in Scheme 6 (wherein Y^6a, Y^7a and Y^8a are independently selected from H and D).

Scheme 6: Preparation of Intermediate (17)

Reagents and conditions: (a) TMSCF3, AgO3SCF3, KF; (b) H2SO4, HNO3; (c) H2, Pd/C; (d) HF-pyridine, NaNO₂, heat; (e) KBrO₃, H₂SO₄; (f) Mg, I₂, DMF

[99] In a manner analogous to a procedure described by Ye, Y. et al., Organic Letters, 13(20), 5464-5467; 2011, silver-mediated trifluoromethylation of

appropriately deuterated arene intermediate (21) using trifluoromethyltrimethylsilane (TMSCF3) furnishes appropriately deuterated aryltrifluoromethyl intermediate (22), which is subsequently nitrated using nitric acid to produce appropriately deuterated nitroaryl intermediate (23), by analogy to a procedure described by Ghaffarzadeh, M. et al., Journal of Chemical Research, 38(4), 200-201; 2014. Reduction of nitro moiety in (23) using hydrogen gas in the presence of palladium on carbon affords

appropriately deuterated aniline intermediate (24), by analogy to a procedure described by Cai, C. et al., Nongyao, 41(9), 12-13; 2002. Sequential treatment of (24) with HF-pyridine and sodium nitrite followed by heating, provides appropriately deuterated aryl fluoride intermediate (25), in a manner analogous to a procedure described by Fukuhara, T. et al., Synthetic Communications, 17(6), 685-92; 1987. Subsequent bromination using potassium bromate in the presence of sulfuric acid furnishes appropriately deuterated arylbromide (26), by analogy to a procedure described in CN104311386. Finally, Grignard reaction of (26) with magnesium in the presence of iodine results in the formation of the Grignard reagent, which is formylated with DMF producing appropriately deuterated aryl aldehyde intermediate (17), by analogy to a procedure described in CN 101759597.

[100] Certain intermediate (21) are commercially available: Benzene-d6 (99.6 atom %D) (21a); Benzene-d₅ (99 atom %D) (21b); Benzene-1,2,3,5-d₄ (99 atom %D) (21c); Benzene-1,2,4-d3 (99 atom %D) (21d). Additionally, α,α,α-Trifluorotoluene-d5 (99 atom %D) (22a) and 3-(Trifluoromethyl)aniline-2,4,5,6-d4 (98 atom %D) (24a) are commercially available.

[101] Use of appropriately deuterated reagents allows deuterium incorporation at the Y⁶, Y⁷, Y⁸ positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any Y⁶, Y⁷ and /or Y⁸.

[102] Appropriately deuterated intermediate (18), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from

corresponding deuterated reagents exemplified in Scheme 7.

Scheme 7: Preparation of Intermediate (18)

[103] In a manner analogous to a procedure described by Lacour, J. et al., Helvetica Chimica Acta, 86(1), 65-81; 2003, appropriately deuterated alkyl sulfonyl chloride (27) is treated with sodium sulfite in the presence of sodium bicarbonate to furnish appropriately deuterated sodium sulfinate intermediate (18).

[104] Methane-d3-sulfonyl chloride (98 atom %D) (27a) is commercially available, or may be prepared according to a procedure described by Burlingham, B. et al., Journal of the American Chemical Society, 123(13), 2937-2945; 2001, from

Iodomethane-d3 (99 atom % D) (3a). Additionally, Methane-d2-sulfonyl chloride (27b) and Methane-d-sulfonyl chloride (27c) may be prepared using said procedure for intermediate (27a), from Iodomethane-d2 (99 atom % D) (3b) and Iodomethane-d (99 atom % D) (3c), respectively.

[105] Use of appropriately deuterated reagents allows deuterium incorporation at the R¹ positions of a compound of Formula I or any appropriate intermediate herein, e.g., 90, 95, 97, or 99% deuterium incorporation at any R¹.

[106] 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.

[107] Additional methods of synthesizing compounds of Formula I 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.

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

[109] Certain aspects of the present invention provide pharmaceutical compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), 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. [110] Pharmaceutically acceptable carriers, adjuvants, excipients, 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 (e.g., phosphate- buffered saline, etc.), 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.

[111] 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.

[112] 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^TM and PLURONIC^TM (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.

[113] 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). [114] Such preparative methods include the step of bringing into association with the compound 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.

[115] 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.

[116] 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.

[117] 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.

[118] 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. [119] 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.

[120] 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.

[121] 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.

[122] 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.

[123] 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.

[124] 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.

[125] 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.

[126] 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.

[127] 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.

[128] 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.

[129] 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.

[130] In another embodiment, a pharmaceutical 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 fevipiprant. Such agents include those indicated as being useful in combination with fevipiprant, including but not limited to, those described in PCT patent publications WO 2005/123731 and WO 2007/068418.

[131] Preferably, the second therapeutic agent is an agent useful in the treatment of a disease or condition selected from obstructive or inflammatory airways diseases, e.g., as anti-inflammatory, bronchodilatory or antihistamine drug substances. A compound of the invention may be mixed with the second therapeutic agent in a fixed

pharmaceutic composition or it may be administered separately, before,

simultaneously with or after the second therapeutic agent. Accordingly the invention includes a combination of a compound or composition of the invention as described herein with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.

[132] Anti-inflammatory drugs include steroids, in particular, glucocorticosteroids, such as budesonide, beclomethasone, dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; or steroids, described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 50, 72, 73, 90, 99and101), WO 03/035668, WO

03/048181, WO 03/062259, WO 03/064445 and WO 03/072592; non-steroidal glucocorticoid receptor agonists, such as those described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195 and WO 04/005229; LTB455 antagonists, such as those described in U.S. Pat. No.5,451, 700; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19- 8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma), PD189659 (ParkeDavis), AWD-12-281 (Asta Medica), CDC-801 (Celgene),

SelCID™ CC-10004 (Celgene), KW-4490 (Kyowa Hakka Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, WO 04/000839 and WO 04/005258 (Merck), as well as those described in WO 98/18796 and WO 03/39544; A2a agonists, such as those described in EP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO

99/67266, WO 00/23457, WO 00/77018, W000/78774, WOOl/23399, WOOl/27130, WOOl/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO 02/96462 and WO 03/086408; A2b antagonists, such as those described in WO 02/42298; and beta (~)-2-adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or solvate form) of formula (I) of WO 00/75114, which document is incorporated herein by reference, preferably compounds of the Examples thereof, and

pharmaceutically acceptable salts thereof, as well as compounds (in free or salt or solvate form) of formula (I) of WO 04/16601. Further ~-2-adrenoreceptor agonists include compounds, such as those described in WO 99/64035, WO 01/42193, WO 01/83462, WO 02/066422, WO 02/070490, WO 02/076933, WO 2004/011416 and US 2002/0055651.

[133] Bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), but also those described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/33495, WO 03/53966, EP 0424021, U.S. Pat. No.5,171,744 and U.S. Pat. No.3,714,357. [134] Co-therapeutic antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride.

[135] Combinations of compounds of the invention and steroids, β-2 agonists, PDE4 inhibitors or LTD4 antagonists may be used, e.g., in the treatment of COPD or, particularly, asthma. Combinations of compounds of the invention and

anticholinergic or antimuscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists may be used, e.g., in the treatment of asthma or, particularly, COPD.

[136] Other useful combinations of compounds of the invention with anti- inflammatory drugs are those with antagonists of chemokine receptors, e.g., CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9, CCR-10, CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5; particularly useful are CCR-3 antagonists, such as those described in WO 2002/026723, especially 4-{3-[(S)-4-(3,4- dichlorobenzyl)-morpholin-2-ylmethyl]-ureidomethyl}-benzamide and those described in WO 2003/077907, WO 2003/007939 and WO 2002/102775.

[137] Also especially useful are CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D; Takeda antagonists, such as N-[[4- [[[6, 7-dihydro-2-(4-methylphenyl )-5H-benzo-cyclohepten-8- yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770); and CCR-5 antagonists, described in U.S. Pat. No.6,166,037, WO 00/66558 and WO 00/66559.

[138] In one embodiment, the second therapeutic agent is montelukast (Singulair). Phase II clinical trials are ongoing for treatment of allergic rhinitis with a combination of fevipiprant and montelukast.

[139] 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). [140] 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.

[141] 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.

[142] In some embodiments, an effective amount of a compound of this invention can range from about 1 mg to about 5000 mg per dose, from about 50 mg to about 2000 mg per dose, from about 100 mg to about 1000 mg per dose, from about 300 mg to about 600 mg per dose, or from about 400 mg to about 500 mg per dose. In some embodiments, an effective amount of a compound of this invention can range from about 10 mg to about 2000 mg per dose, from about 20 mg to about 1000 mg per dose, from about 25 mg to about 500 mg per dose, from about 50 mg to about 300 mg per dose, or from about 75 mg to about 150 mg per dose. Effective dosage amounts may be administered as a single dose once a day, or as split doses administered two, three or four times a day, e.g., about 450 mg once per day, or about 225 mg twice per day; about 300 mg once per day, or about 150 mg twice per day; about 200 mg once per day, or about 100 mg twice per day; about 150 mg once per day, or about 75 mg twice per day.

[143] In some embodiments, an effective amount of a compound of this invention can range from about 0.15 mg to about 32 mg per kg of body weight, from about 0.5 mg to about 25 mg/kg, from about 1.5 mg to about 15 mg/kg, or from about 5 to about 10 mg/kg.

[144] 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. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for fevipiprant. [145] 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.

[146] 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

[147] In another aspect, the invention provides a method of modulating (e.g., antagonizing) the activity of the prostaglandin D2 receptor 2 (e.g., CRTH2, GPR44, or PTGDR2) in a cell, comprising contacting a cell with one or more compounds of Formula I herein, or a pharmaceutically acceptable salt thereof. Compounds of Formula I in free or salt form, are antagonists of the G-protein-coupled

chemoattractant receptor CRTh2, expressed on Th2 cells, eosinophils and basophils. Prostaglandin D₂ (PGD₂) is the natural ligand for CRTh2. Thus, antagonists which inhibit the binding of CRTh2 and PGD2 are useful in the treatment of neuropathic pain as described, for example, in WO 05/102338, and in the treatment of allergic and anti-inflammatory conditions. Treatment in accordance with the invention may be symptomatic or prophylactic. In some embodiments, the cell is contacted in vitro. In some embodiments, the cell is contacted in vivo. In some embodiments, the cell is contacted ex vivo. [148] According to another aspect, the invention provides a method of treating a disease that is beneficially treated by fevipiprant in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention. In one embodiment the subject is a patient in need of such treatment. Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: WO 2005/123731 and WO 2007/068418.

[149] Such diseases include, but are not limited to, inflammatory or obstructive airways diseases, resulting, e.g., in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g., of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early- phase asthmatics. (For convenience this particular asthmatic condition is referred to as "wheezy-infant syndrome".) Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g., of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e., therapy for or intended to restrict or abort symptomatic attack when it occurs, e.g., anti-inflammatory (e.g., corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may, in particular, be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g., between the hours of about 4-6 a.m., i.e., at a time normally substantially distant from any previously administered symptomatic asthma therapy. Other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular, other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis including, e.g., aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. Having regard to their anti-inflammatory activity, in particular, in relation to inhibition of eosinophil activation, agents of the invention are also useful in the treatment of eosinophil related disorders, e.g., eosinophilia, in particular, eosinophils-related disorders of the airways, e.g., involving morbid eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs, as well as, e.g., eosinophil-related disorders of the airways consequential or concomitant to Liiffler's syndrome; eosinophilic pneumonia;

parasitic, in particular, metazoan, infestation including tropical eosinophilia;

bronchopulmonary aspergillosis; polyarteritis nodosa including Churg-Strauss syndrome; eosinophilic granuloma; and eosinophil-related disorders affecting the airways occasioned by drug-reaction. Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, e.g., psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita and other inflammatory or allergic conditions of the skin.

[150] Compounds of the invention may also be used for the treatment of other diseases or conditions, in particular, diseases or conditions having an inflammatory component, e.g., treatment of diseases and conditions of the eye, such as

conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis; diseases affecting the nose including allergic rhinitis; and inflammatory disease, in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune hematological disorders, e.g., hemolytic anemia, aplastic anaemia, pure red cell anaemia and idiopathic

thrombocytopenia; systemic lupus erythematosus; polychondritis; sclerodoma; Wegener granulamatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Steven Johnson syndrome; idiopathic sprue; autoimmune inflammatory bowel disease, e.g., ulcerative colitis and Crohn's disease; endocrine ophthalmopathy;

Grave's disease; sarcoidosis; alveolitis; chronic hypersensitivity pneu monitis;

multiple sclerosis; primary billiary cirrhosis; uveitis (anterior and posterior);

keratoconjunctivitis sicca and vernal

keratoconjunctivitis; interstitial lung fibrosis; psoriatic arthritis; and

glomerulonephritis, with and without nephrotic syndrome, e.g., including idiopathic nephrotic syndrome or minimal change nephropathy. In one embodiment, the method of this invention is used to treat a disease or condition selected from the group consisting of atopic dermatitis, asthma, and allergic rhinitis in a subject in need thereof.

[151] 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).

[152] 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 may be made from any second therapeutic agent known to be useful for co-administration with fevipiprant. 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.

[153] In particular, the combination therapies of this invention include co- administering a compound of Formula I and montelukast as a second therapeutic agent to a subject in need thereof. In some embodiments, the invention provides a method of treating allergic rhinitis, wherein the second therapeutic agent is montelukast.

[154] 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.

[155] 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.

[156] 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.

[157] 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 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 in a subject of a disease, disorder or symptom thereof delineated herein. Example 1. Evaluation of Metabolic Stability

[158] 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.

[159] 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 µM 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 μL aliquot of the 12.5-50 µM 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 μM 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 μL aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 μL of ice-cold ACN with internal standard to stop the reactions. The plates are stored at 4 °C for 20 minutes after which 100 μL 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 µM). Testing is done in triplicate.

[160] Data analysis: The in vitro t_1/2s for test compounds are calculated from the slopes of the linear regression of % parent remaining (ln) vs incubation time relationship.

in vitro t _½ = 0.693/k

k = -[slope of linear regression of % parent remaining (ln) vs incubation time] [161] Data analysis is performed using Microsoft Excel Software.

[162] 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. Any publication or patent cited herein is hereby incorporated by reference in its entirety.

Claims

CLAIMS What is claimed is:

1. A compound of Formula I:

(I), or a pharmaceutically acceptable salt thereof, wherein: each of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, and Y⁸ is independently hydrogen or deuterium; each of R¹ and R² is independently selected from the group consisting of CH₃, CH₂D, CHD₂, and CD₃; and

R³ is H or C1-C8 alkyl;

provided that at least one of Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷, Y⁸, R¹, and R² comprises deuterium.

2. The compound of claim 1, wherein each Y¹ is the same and each Y² is the same.

3. The compound of claim 1 or 2, wherein R¹ is CH₃.

4. The compound of claim 1 or 2, wherein R¹ is CD₃.

5. The compound of any one of claims 1-4, wherein R² is CH3.

6. The compound of any one of claims 1-4, wherein R² is CD₃.

7. The compound of any one of claims 1-6, wherein each Y¹ is hydrogen.

8. The compound of any one of claims 1-6, wherein each Y¹ is deuterium.

9. The compound of any one of claims 1-8, wherein each Y² is hydrogen.

10. The compound of any one of claims 1-8, wherein each Y² is deuterium.

11. The compound of any one of claims 1-10, wherein Y³ is hydrogen.

12. The compound of any one of claims 1-10, wherein Y³ is deuterium.

13. The compound of any one of claims 1-12, wherein Y⁴ is hydrogen.

14. The compound of any one of claims 1-12, wherein Y⁴ is deuterium.

15. The compound of any one of claims 1-14, wherein Y⁵ is hydrogen.

16. The compound of any one of claims 1-14, wherein Y⁵ is deuterium.

17. The compound of any one of claims 1-16, wherein Y⁶ is hydrogen.

18. The compound of any one of claims 1-16, wherein Y⁶ is deuterium.

19. The compound of any one of claims 1-18, wherein Y⁷ is hydrogen.

20. The compound of any one of claims 1-18, wherein Y⁷ is deuterium.

21. The compound of any one of claims 1-20, wherein Y⁸ is hydrogen.

22. The compound of any one of claims 1-20, wherein Y⁸ is deuterium.

23. The compound of any one of claims 1-22, wherein each of Y³, Y⁴, and Y⁵ is hydrogen.

24. The compound of any one of claims 1-22, wherein each of Y³, Y⁴, and Y⁵ is deuterium.

25. The compound of any one of claims 1-24, wherein each of Y⁶, Y⁷, and Y⁸ is hydrogen.

26. The compound of any one of claims 1-24, wherein each of Y⁶, Y⁷, and Y⁸ is deuterium.

27. The compound of claim 1, wherein Y³, Y⁴, and Y⁵ are the same, Y⁶, Y⁷, and Y⁸ are the same, R³ is H, and the compound is selected from the group consisting of the compounds of Table 1:

, or a pharmaceutically acceptable salt thereof, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

28. The compound of any one of claims 1-26, wherein any atom not designated as deuterium is present at its natural isotopic abundance.

29. The compound of any one of claims 1-28, wherein deuterium incorporation at any atom designated as deuterium is at least 90%.

30. The compound of any one of claims 1-28, wherein deuterium incorporation at any atom designated as deuterium is at least 95%.

31. The compound of any one of claims 1-28, wherein deuterium incorporation at any atom designated as deuterium is at least 97%.

32. A pharmaceutical composition comprising a compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. A method of antagonizing the prostaglandin D2 receptor 2 in a cell, comprising contacting the cell with a compound of any one of claims 1-31 or a composition of claim 32.

34. A method of treating a disease or condition selected from the group consisting of asthma, allergic rhinitis, and atopic dermatitis, comprising the step of administering to a subject in need thereof a compound of any one of claims claims 1-31 or a composition of claim 32.

35. The method of claim 34, wherein the subject is suffering from allergic rhinitis, and further comprising co-administering montelukast to the subject in need thereof.