Deuterated p2x3 modulators

Abstract

Provided herein are deuterated P2X3 modulators and methods of utilizing deuterated P2X3 modulators in the treatment of diseases, disorders, or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

DEUTERATED P2X3 MODULATORS BACKGROUND

[0001] P2X purinoreceptors are a family of ion channels that are activated by extracellular adenosine triphosphate (ATP). Purinoreceptors have been implicated in a variety of biological functions. The P2X3 receptor subunit is a member of this family. It was originally cloned from rat dorsal root ganglia. Chen et al., Nature, vol.377, pp.428-431 (1995). The nucleotide and amino acid sequences of both rat and human P2X3 are now known. Lewis, et al., Nature, vol.377, pp. 432-435 (1995); and Garcia-Guzman, et al., Brain Res. Mol. Brain Res., vol.47, pp.59-66 (1997).

[0002] Compounds having an ability to act as P2X3 modulators are described in U.S. Patent No. 9,598,409 and U.S. Patent No.10,111,883, an example of which is the compound methyl (S)-2- ((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate (Compound A). Development of a pharmaceutical comprising such compounds for treating a disorder or disorders related to the P2X3 receptor would be beneficial to patients in need thereof who are afflicted with maladies or suffering from symptoms that may be abated or otherwise relieved by administration of a pharmaceutical comprising one or more such P2X3 modulators. BRIEF SUMMARY OF THE INVENTION

[0003] This disclosure provides, for example, compounds and compositions which are deuterated P2X3 modulators, and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compounds as at least one active ingredient. The disclosure also provides for the use of disclosed compounds as medicaments and / or in the manufacture of medicaments for P2X3 modulation in warm-blooded animals such as humans. In some embodiments, the deuterated P2X3 modulator is a P2X3 antagonist.

[0004] In one aspect is a deuterated P2X3 modulator compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I);wherein: R1, R2, R4, R5, R6, R7, R9, R10, R11, R12, R13, R15, R16, R17, and R18are independently selected from hydrogen and deuterium; each R3is independently selected from hydrogen and deuterium; each R8is independently selected from hydrogen and deuterium; and each R14is independently selected from hydrogen and deuterium; wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18is deuterium.

[0005] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):

[0006] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R4, R5, R6, and R7are hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R4, R5, R6, and R7is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R4, R5, R6, and R7are deuterium.

[0007] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10are hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10are deuterium.

[0008] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R11, R12, R13, R15, R16, R17, and R18is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, R13, R15, R16, R17, and R18are hydrogen. Insome embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, R13, R15, R16, R17, and R18are deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, and R13are hydrogen and R15, R16, R17, and R18are deuterium.

[0009] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R3is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R3is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is deuterium.

[0010] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R8is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R8is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8is deuterium.

[0011] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R14is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R14is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R14is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R14is deuterium.

[0012] In another aspect is a pharmaceutical composition comprising a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, thepharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

[0013] In another aspect is a method for treating a disorder associated with P2X3 activity in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0014] In another aspect is a method for treating pain in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0015] In another aspect is a method for treating urinary tract disorder in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the urinary tract disorder comprises neurogenic overactive bladder, non-neurogenic overactive bladder, interstitial cystitis, prostatitis, prostadynia, and benign prostatic hyperplasia.

[0016] In another aspect is a method of reducing or preventing uncontrolled loss of urine in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the uncontrolled loss of urine is associated with urge incontinence, cough incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence, post-prostatectomy incontinence, urinary urgency, nocturia, and enuresis.

[0017] In another aspect is a method for treating cough in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cough is an acute cough or a chronic cough. In some embodiments, the cough is associated with a disease, disorder, or condition selected from chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, suppurative pulmonary disease, respiratory malignancies, allergy, cystic fibrosis, pulmonary fibrosis, respiratory tract inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory tract infection, bronchoconstriction, sarcoidosis, viral or bacterial infection of the upper airways, angiotension converting enzyme (ACE) inhibitor therapy, smoker's cough,chronic non-productive cough, neoplastic cough, cough due to gastroesophageal reflux, and inhalation of irritants, smoke, smog, dust, or air pollution.

[0018] In another aspect is a method for treating pruritus in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof.

[0019] In another aspect is a method for treating endometriosis, endometriosis-associated pain, and endometriosis-associated symptoms in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method for treating endometriosis in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method for treating endometriosis-associated pain in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method for treating endometriosis-associated symptoms in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the endometriosis-associated symptoms are selected from dysmenorrhea, dyspareunia, dysuria, and dyschezia.

[0020] In some embodiments of the methods described herein, the mammal is a human.

[0021] In some embodiments of the methods described herein, the method further comprises the administration of a second therapeutic agent. In some embodiments, the second therapeutic agent is a NK-1 antagonist. In some embodiments, the NK-1 antagonist is selected from the group consisting of serlopitant, aprepitant, casopitant, dapitant, ezlopitant, fosaprepitant, lanepitant, maropitant, netupitant, nolpitant, orvepitant, rolapitant, vestipitant, vofopitant, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102, and TA-5538. In some embodiments, the second therapeutic agent is selected from a hormonal contraceptive, a non-steroidal anti-inflammatory agent (NSAID), a prostaglandin E synthase (PTGES) inhibitor, an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, a prostanoid EP4 receptor antagonist, an aldo-keto reductase 1C3 (AKR1C3) inhibitor, and a prolactin receptor (PRLR) antagonist. In some embodiments, the second therapeutic agent is selected from one or more compounds or medications for treating or alleviating the symptoms of heartburn and / or acidreflux. In some embodiments, the second therapeutic agent is selected from one or more compounds or medications for treating or alleviating the symptoms of heartburn and / or acid reflux selected from a histamine H2-receptor antagonist, proton pump inhibitor, promotility agent, and over-the-counter antacid. In some embodiments, the second therapeutic agent is selected from one or more compounds or medications for treating or alleviating cough, or the symptomology of coughing associated with a medical condition by inhibiting the cough reflex or other physiological aspects associated with cough. INCORPORATION BY REFERENCE

[0022] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0023] As described in U.S. Patent No.7,456,317 and U.S. Patent No.9,249,149, deuteration of pharmaceuticals to improve one or more aspects such as the pharmacokinetics (PK), and / or the pharmacodynamics (PD), and / or the toxicity profile of the particular pharmaceutical has been demonstrated previously with some classes of drugs, and a list of deuterated pharmaceuticals for various disorders is provided in Stemmerich et al., TIAFT Bulletin, vol.52(4), pp.24-33 (2022), Kaur and Gupta, Glob. J. Pharmaceu. Sci, vol 1(4), pp.79-90 (2017), Belete, Drug Design, Development and Therapy, vol.16, pp.3465-3472 (2022), Harbeson and Tung, Medchem News, vol.2, pp.8-22 (2014). The first FDA-approved deuterated pharmaceutical product is that of deutetrabenazibe, its approval being in 2017.

[0024] Deuterium (D or2H), the discovery of which was published by Urey et al., Phys. Rev., vol.39, pp 164-165 (1932), is a naturally-occurring, stable, non-radioactive isotope of hydrogen that differs from the more abundant, common (>99.9%) hydrogen isotope protium (1H) due to the presence in the nucleus of a deuterium atom of a neutron and a proton (as opposed to only a proton for1H (the third isotope of hydrogen, namely tritium (3H or T) has two neutrons and a proton in its atomic nucleus)). Hence, deuterium is also referred to as “heavy hydrogen”. As described in, for example, Stemmerich (2022), Harbeson and Tung (2014), and U.S. Patent Nos. 7,456,317 and 9,249,149, the mass difference between protium and deuterium is such that the physiochemical properties of a deuterated molecule may differ from that of the non-deuterated molecule. The chemical reactivity of deuterium is nearly identical to that of protium and, notwithstanding that a carbon (C)-D bond is stronger than a carbon-H bond, exchangingdeuterium for protium in a chemical synthesis reaction is possible. However, the increased bond strength exhibited by a C-D bond (versus that of a C-H bond) on a deuterated compound can lead to lower reaction rates as the C-D bond is more resistant to cleavage, in particular with respect to oxidation reactions such as those catalyzed by the cytochrome P450 (CYP450) enzymes (see Russak and Bednarczyk, Annals of Pharmacol., vol.53(2), pp.211-216 (2019), at page 212). This lower reaction rate phenomenon is referred to as the kinetic isotope effect (KIE) or more particularly, in reference to deuterium, the deuterium isotope effect (DIE). As such, the metabolism of a deuterated compound may be altered with respect to reaction rates and the compound’s metabolic profile (see Stemmerich et al. (2022) at page 25), and although in some cases the KIE (which is expressed as the ratio of the reaction rate constants of protonated to deuterated compounds kh / kd) may be quite substantial (see Haberson et al, J. Pharmacol. Exp. Ther., vol.362(2), pp.359-367 (2017)) there is no way to predict a KIE for a specific compound (see Stemmerich et al. (2022), at page 25).

[0025] As noted by Harbeson and Tung (2014), while the DIE could potentially affect the pharmacokinetics of a drug that is metabolized by pathways involving C-H bond scission, due to the complexity of the actual metabolic degradation pathway and / or the involvement of alternative clearance pathways or sites of metabolism being involved, the actual DIE of the compound may be “masked”. In some cases, an increase in KIE may be observed on the particular deuterated form of a compound. As such, as noted in U.S. Patent No.9, 249,149 (at column 3, lines 32-38) with respect to the overall substrate consumption via metabolism, on comparing a deuterated form of a compound versus a protonated form, studies measuring deuterium substitution’s effect on overall metabolic stability are variable and unpredictable, and (at column 3, lines 42-47) it is to be noted that 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. Notwithstanding rapid advances being made in the field of deuterization synthesis processes and methodologies yielding various compounds and chemical moieties (see, for example, Wood and Lin, “Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis”, ChemRxiv. (2023) preprint accessible at https: / / doi.org / 10.26434 / chemrxiv-2023- 2xfjs, and Lecomte et al., Chem. Sci., vol.12, pp.1157-1165 (2021), the unpredictability of altering a drug’s pharmacodynamics through deuterization has not changed, and as emphasized by Stemmerich et al. (2022) while “[d]euterization may alter the pharmacokinetics withoutspecifically altering the pharmacodynamics of the substance; however, these effects on the metabolic profile of a drug are not predictable and must be investigated on an individual basis” (citing Harbeson and Tung (2014)) and such remains true regardless of the class of drug that may be under consideration (see Belete (2022), an example in the context of deuterated anti-cancer candidate compounds). Definitions

[0026] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that which in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described features.

[0027] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0028] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. C1-Cxrefers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

[0029] "Amino" refers to the -NH2radical.

[0030] "Cyano" refers to the CN radical.

[0031] "Nitro" refers to the NO2radical.

[0032] "Oxa" refers to the -O- radical.

[0033] "Oxo" refers to the =O radical.

[0034] "Thioxo" refers to the =S radical.

[0035] "Imino" refers to the =N-H radical.

[0036] "Oximo" refers to the =N-OH radical.

[0037] "Alkyl" or "alkylene" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1- C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (nbutyl), 1- methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1dimethylethyl (tertbutyl), and 1pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - ORa, -SRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)- NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0038] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0039] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop1enyl (i.e., allyl), but1enyl, pent1enyl, penta1,4dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, ORa, -SRa, OC(O)Rf, N(Ra)2, C(O)Ra, C(O)ORa, C(O)N(Ra)2, N(Ra)C(O)ORf, OC(O) NRaRf, N(Ra)C(O)Rf, N(Ra)S(O)tRf(where t is 1 or 2), S(O)tORa(where t is 1 or 2), S(O)tRf(where t is 1 or 2) and S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0040] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -N(Ra)2, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-NRaRf, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0041] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(O)N(Ra)2, RbORcC(O)N(Ra)2,RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2) and RbS(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0042] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula –O-aryl, where aryl is as defined above.

[0043] "Aralkyl" refers to a radical of the formula Rcaryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0044] "Aralkyloxy" refers to a radical bonded through an oxygen atom of the formula –O- aralkyl, where aralkyl is as defined above.

[0045] "Aralkenyl" refers to a radical of the formula –Rdaryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0046] "Aralkynyl" refers to a radical of the formula Rearyl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0047] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyls are saturated, (i.e., containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.) Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C3-C8cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). A partially unsaturated cycloalkyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C( O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O) Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0048] “Deuterated” refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0049] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0050] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.

[0051] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2trifluoroethyl, 1fluoromethyl2fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical are optionally substituted as defined above for an alkyl group.

[0052] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above.

[0053] "Heterocycloalkyl" refers to a stable 3 to 18membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which include fused, spiro,or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2oxopiperazinyl, 2oxopiperidinyl, 2oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1oxothiomorpholinyl, and 1,1dioxothiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, RbORa, RbOC(O)Ra, RbOC(O)ORa, RbOC(O)N(Ra)2, RbN(Ra)2, RbC(O)Ra, RbC(O)ORa, RbC(O)N(Ra)2, RbORcC(O)N(Ra)2, RbN(Ra)C(O)ORa, RbN(Ra)C(O)Ra, RbN(Ra)S(O)tRa(where t is 1 or 2), RbS(O)tORa(where t is 1 or 2), RbS(O)tRa(where t is 1 or 2) and RbS(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0054] "Heteroaryl" refers to a radical derived from a 5 to 18membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, - Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0055] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0056] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0057] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.

[0058] "Heteroarylalkyl" refers to a radical of the formula –Rcheteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogencontaining heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0059] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- Rcheteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogencontaining heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0060] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R) or (S). Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unlessspecified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0061] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0062] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0063] “Prodrugs”, includes compounds that, after administration, are metabolized into a pharmacologically active drug (R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp.8). A prodrug may be used to improve how a compound is absorbed, distributed, metabolized, and excreted.

[0064] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0065] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0066] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0067] The term “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0068] As used herein, "treatment" or "treating " or "palliating" or "ameliorating" are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. Compounds

[0069] The compounds of Formula (I) or (Ia) described herein are P2X3 modulators. In some embodiments, the compounds of Formula (I) or (Ia) described herein are P2X3 antagonists. In some embodiments, the compounds of Formula (I) or (Ia) described herein, and compositions comprising these compounds, are useful for treating pain, a urinary tract disorder, cough, pruritus, endometriosis, endometriosis-associated pain, or endometriosis-associated symptoms.

[0070] In some embodiments is a compound of Formula (I):wherein:R1, R2, R4, R5, R6, R7, R9, R10, R11, R12, R13, R15, R16, R17, and R18are independently selected from hydrogen and deuterium; each R3is independently selected from hydrogen and deuterium; each R8is independently selected from hydrogen and deuterium; and each R14is independently selected from hydrogen and deuterium; wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18is deuterium.

[0071] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):

[0072] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein two of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein three of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or apharmaceutically acceptable salt or solvate thereof, wherein four of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein five of R1, R2, R4, R5, R6, and R7is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R4, R5, R6, and R7are hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R4, R5, R6, and R7is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R4, R5, R6, and R7are deuterium.

[0073] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10are hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R9is hydrogen and R10is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10are deuterium.

[0074] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein one of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein two of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein three of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein four of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein five of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein six of R11, R12, R13, R15, R16, R17, and R18is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, and R13are hydrogen and R15, R16, R17, and R18are deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, R13, R15, R16, R17, and R18are deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt orsolvate thereof, wherein at least one of R11, R12, R13, R15, R16, R17, and R18is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, R13, R15, R16, R17, and R18are hydrogen.

[0075] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R3is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein one R3is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein two R3is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R3is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

[0076] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R8is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein one R8is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein two R8is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R8is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R8is hydrogen.

[0077] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R14is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein one R14is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein two R14is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R14is deuterium. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R14is hydrogen. In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R14is hydrogen.

[0078] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18are deuterium. Preparation of the Compounds

[0079] The compounds used in the methods described herein are made according to procedures disclosed in U.S. Patent No.9,598,409, which is herein incorporated by reference in its entirety, or by known organic synthesis techniques, starting from commercially available chemicals and / or from compounds described in the chemical literature. Commercially available chemicals are obtained from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Cambridge Isotope Laboratories (Tewksbury, MA), CDN Isotopes (Pointe-Claire, Quebec), Chemservice Inc. (West Chester, PA), Combi-blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).

[0080] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif.1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised andEnlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527- 29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0081] Specific and analogous reactants are also identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002. Further Forms of Compounds Disclosed Herein Isomers

[0082] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methodsprovided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. Labeled compounds

[0083] In some embodiments, the compounds described herein exist in their isotopically labeled forms apart from being deuterated. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds of the invention include isotopes of hydrogen (apart from2H), carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as2H,3H,13C,14C,l5N,16O,17O,31P,32P,35S,18F, and36Cl, respectively. Compounds described herein, and the pharmaceutically acceptable salts, esters, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i. e.,3H and carbon14, i. e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeledcompounds, pharmaceutically acceptable salt, ester, solvate, hydrate or derivative thereof is prepared by any suitable method.

[0084] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts

[0085] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0086] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. Prodrugs

[0087] In some embodiments, the compounds described herein are formulated as agents which are converted in vivo to active forms in order to alter the biodistribution or the pharmacokinetics for a particular agent. For example, a carboxylic acid group can be esterified, e.g., with a methyl group or an ethyl group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate agent which subsequently decomposes to yield the active agent. The prodrug moieties may be metabolized in vivo by esterases or by other mechanisms to carboxylic acids. Alternatively, other functional groups may be modified into a prodrug form. For instance, an amine group may be converted into a carbamate or amide which would be cleavable in vivo. Solvates

[0088] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention furtherprovides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0089] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Pharmaceutical Compositions

[0090] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0091] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[0092] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof.

[0093] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[0095] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.

[0096] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0097] In some embodiments, a compound of Formula (I) or (Ia), described herein are administered to subjects in a biologically compatible form suitable for topical administration to treat or prevent dermal diseases, disorders or conditions. By “biologically compatible form suitable for topical administration” is meant a form of the compound of Formula (I) or (Ia), to be administered in which any toxic effects are outweighed by the therapeutic effects of the inhibitor. Administration of a compound of Formula (I) or (Ia), as described herein can be in any pharmacological form including a therapeutically effective amount of a compound of Formula (I) or (Ia), alone or in combination with a pharmaceutically acceptable carrier.

[0098] Topical administration of a compound of Formula (I) or (Ia), may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term “a semi-solid composition” is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.

[0099] Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer suchas DMSO to increase the absorption of the compounds. Patches can include those that control the rate of drug delivery to the skin. Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively. The reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water-resistant backing. Such a design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of skin. The monolithic design, for example, typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a water-proof backing. This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin. As the drug amount decreases in the patch to below the saturating level, the delivery rate falls.

[0100] In one embodiment, the topical composition may, for example, take the form of hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethylene glycol (PEG) as the carrier, like the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, especially a microemulsion based on water-in-oil or oil-in-water, optionally with added liposomes. Suitable permeation accelerators (entraining agents) include sulfoxide derivatives such as dimethylsulfoxide (DMSO) or decylmethylsulfoxide (decyl-MSO) and transcutol (diethyleneglycolmonoethylether) or cyclodextrin; as well as pyrrolidones, for example 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or the biodegradable N- (2-hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3-diphenylurea; terpenes, for example D-limonene, menthone, a-terpinol, carvol, limonene oxide, or 1,8-cineol.

[0101] Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals. In general, such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0102] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0103] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0104] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistenedwith an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0105] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0106] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0107] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0108] Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin,amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0109] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0110] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

[0111] The dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[0112] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0113] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Methods Pain

[0114] P2X3 is selectively expressed on nociceptive, small diameter sensory neurons (i.e., neurons that are stimulated by pain or injury), which is consistent with a role in pain sensitivity.And blocking P2X3 receptors has been reported to be analgesic in animal models of chronic inflammatory and neuropathic pain. Jarvis, et al., PNAS, 99, 17179-17184 (2002). It is, therefore, believed that a method for reducing the P2X3 level or activity would be useful for modulating pain sensation in a subject suffering from pain.

[0115] In some embodiments is a method for treating pain in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pain is inflammatory and pain. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is chronic pain. Urinary tract disorder

[0116] P2X3 is reportedly involved in afferent pathways controlling urinary bladder volume reflexes. Consequently, inhibiting P2X3 may have therapeutic potential for treating disorders of urine storage and voiding, such as overactive bladder. Cockayne, et al., Nature, vol.407, pp. 1011-1015 (2000). Results from recent studies also suggest that P2X2 / 3 is predominantly expressed (over P2X3) in bladder sensory neurons, and are likely to play a role in sensing of urinary bladder filling and nociception. Zhong, et al., Neuroscience, vol.120, pp.667-675 (2003).

[0117] In some embodiments is a method for treating urinary tract disorder in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the urinary tract disorder comprises neurogenic overactive bladder, non-neurogenic overactive bladder, interstitial cystitis, prostatitis, prostadynia, and benign prostatic hyperplasia.

[0118] In some embodiments is a method of reducing or preventing uncontrolled loss of urine in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the uncontrolled loss of urine is associated with urge incontinence, cough incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence, post-prostatectomy incontinence, urinary urgency, nocturia, and enuresis. Cough

[0119] The majority of stimuli triggering cough are affecting the upper airways (e.g. strong odor / smoke, cold air, post-nasal drips, aspiration of gastroesophageal reflux, speaking).Furthermore, the greatest concentration of cough receptors is in the larynx, carina and bifurcation of the medium to large-sized bronchi. These observations indicate that the upper airways play a major role in cough. Therefore, given that upper airways are innervated by jugular C-fibres that express primarily P2X3 channels, it suggests that P2X3 homotrimeric receptors are responsible for the increase in cough reflex sensitivity.

[0120] In some embodiments is a method for treating cough in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cough is an acute cough or a chronic cough. In some embodiments, the cough is associated with a disease, disorder, or condition selected from chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, suppurative pulmonary disease, respiratory malignancies, allergy, cystic fibrosis, pulmonary fibrosis, respiratory tract inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory tract infection, bronchoconstriction, sarcoidosis, viral or bacterial infection of the upper airways, angiotension converting enzyme (ACE) inhibitor therapy, smoker's cough, chronic non-productive cough, neoplastic cough, cough due to gastroesophageal reflux, and inhalation of irritants, smoke, smog, dust, or air pollution. Pruritus

[0121] Pruritogenic stimuli can be induced by mechanical, thermal and chemical means, which are sensed by afferent neurons innervating the skin and transmitted to the thalamus for processing and reflex initiation. Stimuli and afferent transmission acts through a wide variety of afferent neurons (pruriceptive neurons), which are a population partially overlapping in molecular phenotype with pain-sensing neurons in the skin. Pruriceptive neurons can respond to a wide variety of stimuli, but pathological itch is induced primarily by endogenous chemical agents (e.g. histamine, substance P, gastrin-release peptide, interleukins, nerve growth factors) acting at neuron terminals in the skin. These pruritogenic agents are released in the context of disorders with excessive inflammation (e.g. atopic dermatitis, psoriasis), systemic disease (e.g. chronic liver and kidney disease) neuropathic disorders (e.g. post-herpetic itch), or psychogenic conditions (e.g. obsessive compulsive disorder, substance abuse) (Yosipovitch et al., N. Engl. J. Med., 2013, 1625-1634).

[0122] Pruriceptive afferent neurons are characterized as c- or a δ-fibers of the dorsal root ganglions that innervate skin tissues and form synapses with the spinal cord. C- and aδ-fibers terminals in the skin express receptors responding to pruritogenic chemical agents to initiateaction potentials that are transmitted to the CNS. These neurons also express P2X3 cation channels that regulate neuronal sensitivity to excitation by a pruritogenic stimuli. Notably, P2X3 channels are co-expressed on the cell membrane of MgprA3+ neurons, the major pruriceptive neuron phenotype innervating the skin, and the number of these neurons is increased in mouse models of chronic itch (Han et al., Nat. Neurosci., 2013, 174-182; Zhao et al., J. Clin. Invest., 2013, 4769-4780).

[0123] P2X3 channels are neuronal excitability regulators that are activated by local release of ATP, a neurotransmitter and extracellular messenger with pro-inflammatory properties. ATP is well established as an important chemical messenger released in excess by neuronal and non- neuronal cell types in multiple pathological conditions (Burnstock, Front. Pharmacol., 2017, 661; Burnstock, Biochem. Pharmacol., 2017, doi:10.1016 / j.bcp.2017.07.016). Accordingly, the increased release of ATP can lead to hyperexcitability of afferent pruriceptive neurons and heightened sensitivity to any pruritogenic agent released pathologically in the skin. Overall, P2X3 channels acting through pathological ATP release may be potentially relevant targets to modulate the sensitivity of afferent neurons to itch sensations. Their inhibition could offer an approach to dampen peripheral hypersensitivity to itch in various diseases, with a broad mechanism independent of the pathological stimuli acting at itch receptors.

[0124] In some embodiments is a method for treating pruritus in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pruritus is associated with an inflammatory skin disease, an infectious skin disease, an autoimmune skin disease, or a pregnancy-related skin disease. In some embodiments, the pruritus is associated with an inflammatory skin disease selected from the group consisting of atopic dermatitis, allergic, irritant contact dermatitis, exsiccation dermatitis, nummular and dyshidrotic dermatitis, lichen planus, lichen sclerosus et atrophicus, polymorphous light eruption psoriasis, Grover's disease, mucinosis, mastocytosis, and urticaria. In some embodiments, the pruritus is associated with an infectious skin disease selected from the group consisting of mycoses, bacterial and viral infections, scabies, pediculosis, insect bites, and folliculitides. In some embodiments, the pruritus is associated with an autoimmune skin disease selected from the group consisting of dermatitis herpetiformis (Duhring's disease), bullous pemphigoid; genodermatoses, Darier's disease, and Hailey-Hailey disease. In some embodiments, the pruritus is associated with a pregnancy-related skin disease selected from the group consisting of polymorphic eruption of pregnancy (PEP), atopic eruption of pregnancy, pemphigoid gestationis,neoplasias, and cutaneous T-cell lymphoma. In some embodiments, the pruritus is associated with prurigo nodularis. In some embodiments, the pruritus is associated with a kidney disease or a therapeutic procedure to treat a kidney disease. In some embodiments, the pruritus is associated with a chronic kidney disease. In some embodiments, the pruritus is associated with a therapeutic procedure to treat a kidney disease, wherein the therapeutic procedure to treat the kidney disease is selected from the group consisting of hemodialysis and peritoneal dialysis. In some embodiments, the pruritus is associated with a medical procedure or treatment. In some embodiments, the pruritus is associated with a medical treatment with a drug selected from the group consisting of opioids, anti-malarial drugs, anti-cancer therapies, and epidermal growth factor receptor inhibitors. Endometriosis

[0125] The pain associated with endometriosis is attributed to functional endometriotic lesions, embedded with nerve fibers, on the outside of the uterine cavity. Afferent sensory fibers and pro- inflammatory mediators are correlated with endometriosis-associated pain. In particular, women with endometriosis have elevated levels of pro-inflammatory cytokines, such as interleukin (IL)- 1β, IL-6, prostaglandins (PGs), tumor necrosis factor (TNF)-α, and nerve growth factor (NGF) in peritoneal fluid and endometriotic lesions. Inflammatory mediators in the endometriotic peritoneal inflammatory microenvironment activate nociceptive receptors on afferent neurons by stimulating sensory nerve fibers (including C- or Aδ-fibers) innervated within endometriotic lesions, providing the sensitization of sensory neurons and ultimately triggering a pain signal cascade. In some cases, anti-inflammatory agents provide pain relief. However, these agents often provide minimal relief of pain symptoms, and recurrence and serious side-effects can occur (Ding et al., PloS one, 2017, 12(9), 1-17; Yuan et al., Int. J. Nanomed., 2017, 8171-8183).

[0126] Afferent neurons found in endometriotic lesions on the outside of the uterine cavity consist of C- or A δ-fibers of the dorsal root ganglions and form synapses with the spinal cord. C- and A δ-fiber terminals express receptors that respond to pro-inflammatory mediators to initiate action potentials that are transmitted to the CNS. Important transducers of this signaling pathway expressed by these neurons are P2X3 cation channels. Notably, P2X3 channels are co-expressed on the cell membrane of small- and medium-diameter sensory neurons, which are critical pain transducers of noxious stimuli. Additionally, P2X3 expression in endometriosis endometrium and endometriotic lesions are significantly higher than normal endometrial tissue, and both are positively linked to endometriosis-associated pain. (Han et al., Nat. Neurosci., 2013, 174-182; Vilotti et al., PloS one, 2013, 8(11):e81138; Ding et al., PloS one, 2017, 12(9), 1-17).

[0127] Under pathophysiological conditions, the increased release of ATP modulated by inflammatory mediators can lead to activation of P2X3, leading to hyperexcitability of afferent neurons located in the endometrium outside the uterine cavity and heightened sensitivity to endometriosis-associated pain. Overall, P2X3 channels acting through pathological ATP release may be potentially relevant targets to modulate the sensitivity of afferent neurons coupled to endometriosis-associated pain. Their inhibition offers an approach to alleviate pain resulting from endometriosis and endometriosis-like symptoms (Yuan et al., Int. J. Nanomed., 2017, 8171- 8183).

[0128] In some embodiments is a method for treating endometriosis, endometriosis-associated pain, and endometriosis-associated symptoms in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method for treating endometriosis in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method for treating endometriosis-associated pain in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method for treating endometriosis-associated symptoms in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the endometriosis-associated symptoms are selected from dysmenorrhea, dyspareunia, dysuria, and dyschezia. Pharmaceutical Combinations

[0129] Also contemplated herein are combination therapies, for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration ofthese therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.

[0130] Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, (e.g., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0131] In some embodiments is a method of treating a disorder associated with P2X3 activity in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments is a method of treating pain in a mammal in need thereof, the method comprising administering to the mammal a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments is a method of treating a urinary tract disorder in a mammal in need thereof, the method comprising administering to the mammal a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments is a method of treating reducing or preventing uncontrolled loss of urine in a mammal in need thereof, the method comprising administering to the mammal a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments is a method of treating cough in a mammal in need thereof, the method comprising administering to the mammal a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments is a method of treating pruritus in a mammal in need thereof, the method comprising administering to themammal a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments is a method of treating endometriosis, endometriosis-associated pain, and endometriosis-associated symptoms in a mammal in need thereof, the method comprising administering to the mammal a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional pharmaceutical agents.

[0132] In some embodiments, the additional pharmaceutical agent is a NK-1 antagonist. In some embodiments, the NK-1 antagonist is selected from the group consisting of serlopitant, aprepitant, casopitant, dapitant, ezlopitant, fosaprepitant, lanepitant, maropitant, netupitant, nolpitant, orvepitant, rolapitant, vestipitant, vofopitant, AV-818, BIIF 1149CL, CP122,721, DNK- 333, GSK-424887, L-733060, L-759274, LY-686017, M516102, and TA-5538.

[0133] In some embodiments, the one or more additional pharmaceutical agents are selected from the group consisting of selected from a hormonal contraceptive, a non-steroidal anti- inflammatory agent (NSAID), a prostaglandin E synthase (PTGES) inhibitor, an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, a prostanoid EP4 receptor antagonist, an aldo- keto reductase 1C3 (AKR1C3) inhibitor, and a prolactin receptor (PRLR) antagonist. In some embodiments, the additional pharmaceutical agent is a hormonal contraceptive. In some embodiments, the additional pharmaceutical agent is a non-steroidal anti-inflammatory agent (NSAID). In some embodiments, the additional pharmaceutical agent is a prostaglandin E synthase (PTGES) inhibitor. In some embodiments, the additional pharmaceutical agent is an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor. In some embodiments, the additional pharmaceutical agent is a prostanoid EP4 receptor antagonist. In some embodiments, the additional pharmaceutical agent is an aldo-keto reductase 1C3 (AKR1C3) inhibitor. In some embodiments, the additional pharmaceutical agent is a prolactin receptor (PRLR) antagonist.

[0134] In some embodiments, the additional pharmaceutical agent is selected from one or more compounds or medications for treating or alleviating the symptoms of heartburn and / or acid reflux (also referred to as gastroesophageal reflux disease or GERD). In some embodiments, GERD- relief or GERD-treatment compounds or medications are selected from histamine-H2 blockers (also known as histamine H2-receptor antagonists), proton pump inhibitors (PPIs), promotility agents, and over-the-counter antacids. In some embodiments, histamine-H2 blockers are selected from cimetidine (Tagamet®), famotidine (Pepcid AC®), and nizatidine (Axid AR®). In some embodiments, proton pump inhibitors are selected from dexlansoprazole (Dexilant®),esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®, and the version with sodium bicarbonate, namely, Zegerid®), pantoprazole (Protonix® and Pantoloc®), and rabeprazole (Aciphex®). In some embodiments, the promotility agent is metoclopramide (Reglan®). In some embodiments, over-the-counter (also referred to as non-prescription) medications are selected from those which contain calcium carbonate, such as Mylanta®, Rolaids®, and Tums®.

[0135] In some embodiments, compounds described herein are used in combination with one or more compounds or medications used for treating or alleviating cough, or the symptomology of coughing associated with a medical condition by inhibiting the cough reflex. In some embodiments, compounds described herein are used in combination with one or more compounds or medications used for other physiological aspects associated with cough selected from expectorants, mucolytics, antitussives, bronchodilators, anti-histamines, anti-inflammatory agents and other types of medications such as pregabalin. In some embodiments, antitussive compounds or medications are selected from benzonatate compounds, dextromethorphan compounds, gabapentin compounds, compounds comprising dextromethorphan and guaifenesin, compounds comprising a narcotic analgesic compound such as an opioid such as codeine or hydromorphone or hydrocodone, or such narcotic analgesic compounds in combination with another compound such as acetaminophen and hydrocodone, or homatropine and hydrocodone, and compounds that act on the cough center in the brain, such as those comprising chlophedian.

[0136] In some embodiments of the methods of treatment disclosed herein, the methods comprise administering methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7- methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (the non-deuterated compound of Formula (Ia)), or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need thereof, further comprising administering to the mammal one or more additional pharmaceutical agents. In some embodiments of the methods of treatment disclosed herein, methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with an additional pharmaceutical agent selected from one or more compounds or medications for treating or alleviating the symptoms of heartburn and / or acid reflux (also referred to as gastroesophageal reflux disease or GERD). In some embodiments, GERD- relief or GERD-treatment compounds or medications are selected from histamine-H2 blockers (also known as histamine H2-receptor antagonists), proton pump inhibitors (PPIs), promotility agents, and over-the-counter antacids. In some embodiments, histamine-H2 blockers are selectedfrom cimetidine (Tagamet®), famotidine (Pepcid AC®), and nizatidine (Axid AR®). In some embodiments, proton pump inhibitors are selected from dexlansoprazole (Dexilant®), esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®, and the version with sodium bicarbonate, namely, Zegerid®), pantoprazole (Protonix® and Pantoloc®), and rabeprazole (Aciphex®). In some embodiments, the promotility agent is metoclopramide (Reglan®). In some embodiments, over-the-counter (also referred to as non-prescription) medications are selected from those which contain calcium carbonate, such as Mylanta®, Rolaids®, and Tums®.

[0137] In some embodiments of the methods of treatment disclosed herein, methyl (S)-2-((2- (2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with an additional pharmaceutical agent selected from one or more compounds or medications for treating or alleviating cough, or the symptomology of coughing associated with a medical condition by inhibiting the cough reflex. In some embodiments, methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate is used in combination with one or more compounds or medications used for other physiological aspects associated with cough selected from expectorants, mucolytics, antitussives, bronchodilators, anti-histamines, anti-inflammatory agents and other types of medications such as pregabalin. In some embodiments, antitussive compounds or medications are selected from benzonatate compounds, dextromethorphan compounds, gabapentin compounds, compounds comprising dextromethorphan and guaifenesin, compounds comprising a narcotic analgesic compound such as an opioid such as codeine or hydromorphone or hydrocodone, or such narcotic analgesic compounds in combination with another compound such as acetaminophen and hydrocodone, or homatropine and hydrocodone, and compounds that act on the cough center in the brain, such as those comprising chlophedian.

[0138] Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.

[0139] The components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, that are administered either simultaneously or sequentially. EXAMPLES

[0140] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. List of abbreviations

[0141] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile Bn benzyl BOC or Boc t-butyl carbamate CDI 1,1'-carbonyldiimidazole Cy cyclohexyl D deuterium DCE dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF dimethylformamide DMA N,N-dimethylacetamide DMSO dimethylsulfoxide equiv equivalent(s) Et ethyl EtOH ethanol EA or EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphateHPLC high performance liquid chromatography LAH lithium aluminum hydride Me methyl MeOH methanol MS mass spectroscopy NMM N-methylmorpholine NMR nuclear magnetic resonance PMB para-methoxybenzyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography I. Chemical Synthesis

[0142] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm ( δ) and coupling constants (J) are reported in Hertz. For proton spectra the solvent peak was used as the reference peak. Example 1: Synthesis of methyl-d3 (S)-2-((2-(2,6-difluoro-4-((methyl- d3)carbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate (B1)

[0143] The hydroxymethyl group of A (106 kg, 487.9 mole) was oxidized to the corresponding aldehyde B at a temperature of -3oC to 1.5oC under biphasic conditions (dichloromethane-water)by reaction with sodium bromide, sodium bicarbonate, catalytic TEMPO (2,2,6,6,-tetramethyl-1- piperidinyloxy, free radical) and sodium hypochlorite (added dropwise over ~10 h while maintaining a temperature of -3oC to 1.5oC). After stirring an additional 2 h, the reaction was quenched at -5oC to 0oC using sodium thiosulfate and stirred for 30 minutes.

[0144] The biphasic system containing aldehyde B was treated in portions at 5oC to 10oC with commercially available (carbethoxymethylene)triphenylphosphorane. After stirring for 1 h at 8oC to 15oC, water was added, the mixture was stirred for 30 minutes, the layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers containing unsaturated ester C were washed with brine and concentrated to remove most of the dichloromethane. A mixture of petroleum ether / THF was added the resulting mixture was stirred for 1 h at 20oC. The mixture was then filtered to remove triphenylphosphine oxide and the filter cake was washed with additional petroleum ether / THF. The filtrate containing C was concentrated and THF was added. The mixture was concentrated again and fresh THF was added. This solution of C was used “as is” in the following step. The assay yield of C was 58.2 kg.

[0145] The solution of C in THF was treated dropwise with a solution of 3M NaOH over 2 hours at 15oC to 25oC. The mixture was then warmed to 25oC to 35oC and stirred for 8 hours. The mixture was cooled to 20oC to 25oC, MTBE was added, and the layers were separated. The organic layer was extracted with water and, while maintaining the temperature at below 15oC, the combined aqueous layers containing the sodium salt of D were acidified slowly with 3N HCl until the pH was 10-11. The aqueous mixture was then washed with dichloromethane to remove any residual triphenylphosphine oxide and then slowly acidified to pH 5 using 3N HCl while maintaining a temperature below 15oC. The resulting mixture was extracted with dichloromethane and the organic extracts containing D were concentrated. THF was then added and evaporated. The crude product D was dissolved in THF and used directly in the following step.

[0146] The solution of D in THF (43.7 kg by assay) was charged to a hydrogenation reactor. A THF slurry of Pd / C (2.90 kg) was added, and the resulting mixture was stirred under hydrogen (~145 psi) at 25oC to 49oC for 12 h. The mixture was filtered under nitrogen, the filter cake was washed with THF and the filtrate was concentrated. Dichloromethane was added and concentrated to remove THF and the operation was repeated. Fresh dichloromethane was added to the mixture and the resulting solution of E (43.5 kg based on assay) was used directly in the following step.

[0147] A solution of E in dichloromethane at 10oC to 15oC was treated with N- hydroxybenzotriazole (HOBT), N, O-dimethylhydroxylamine hydrochloride, and triethylamine. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was then added in portions. The mixture was stirred at 15oC to 25oC for 12 h. Water was added, the resulting mixture was stirred for 12 h, and the layers were separated. The aqueous layer was separated and extracted with fresh dichloromethane. The combined organic layers were washed with sodium bicarbonate solution to remove HOBT and dried. The dichloromethane was concentrated, n- heptane was added, and the mixture was concentrated to remove the dichloromethane. Fresh n- heptane was added and the mixture was stirred at 15oC for 10 h. The solid was filtered and dried to afford 38.6 kg of F.

[0148] A solution of 3,5-difluorobenzoic acid, tert-butyl ester in THF was cooled to -65oC under nitrogen and treated dropwise with 1.5 equivalents of LDA solution. The mixture was stirred at -60oto -65oC for 1 h and then treated dropwise with a solution of compound F (37 kg) in THF. The reaction was stirred between -65oC and -60oC for 6 h and then quenched at -65oC with a solution of acetic acid in THF. The temperature was raised to -33oC and the mixture was stirred for 30 minutes. Ethyl acetate was added and the mixture was diluted with brine. The layers were separated and the organic layer was washed with brine and then concentrated to generate a solution of compound G in ethyl acetate which was used directly in the next step.

[0149] HCl gas (60.4 kg) was bubbled into ethyl acetate (360 kg) between -6oC and 0oC. Compound G was added to the mixture over 2 h at a temperature of 20oC to 25oC. The reaction was then stirred for 16 h, filtered, and the product was washed with ethyl acetate and MTBE and dried under vacuum to afford H.

[0150] Methanol was charged into a reactor at 26oC, and cooled to -7oC. HCl was then bubbled into the methanol at -7oC to 0oC over 8 h. Compound H (28.8 kg) was added at 2oC and the mixture was heated to 40oC to 50oC and then stirred for 6 h. The reaction was then concentrated and the residual dichloromethane solvent was swapped initially to heptane (addition of heptane followed by concentration) and then to THF (addition of THF followed by concentration). The resulting solution of compound I was used directly in the next step.

[0151] A solution of compound I (~24.6 kg) in THF was diluted with water, the mixture was cooled to -5oC to 0oC, and the pH was adjusted to 7-8 using sodium bicarbonate solution (2.5 equiv bicarbonate). An additional 2 equivalents of sodium bicarbonate were added and methyl chloroformate (1.2 equivalents) was added dropwise over 1.5 h and the reaction was stirred at -5oC to 0oC for 1.5 h. Water, ethyl acetate, and 2N HCl were added, the layers were separated,and the organic layer was washed with brine and then concentrated. Additional ethyl acetate was added and evaporated to generate an ethyl acetate solution of J. Heptane (4 volumes) was added while stirring at 55oC, the mixture was cooled to 10oC and stirred for 6 h. The product was filtered, washed with ethyl acetate:heptane (1:4), and dried to give J (20.6 kg).

[0152] The product was further purified by dissolving J (20.6 kg) in ethyl acetate at 28oC and filtering through a pad of silica gel (25 kg). The filtrate was concentrated at 40oC to 50oC to ~50 liters and 50 kg of ethyl acetate:heptane (1:3) was added at 55oC. After stirring for 1 h, the mixture was cooled to 10oC and stirred for 6 h. The product was filtered and washed with ethyl acetate: heptane (1:3) and dried to afford J (18.5 kg).

[0153] A solution of 3,5-difluorobenzoic acid (75 kg) in tert-butanol was treated with DMAP (5.8 kg) and triethylamine (67.2 kg) and cooled to 5oC. Di-tert-butyldicarbonate (124 kg, 1.2 equivalents) was added in portions over 3 h, and the mixture was then stirred at 20oC to 25oC for 12 h. The mixture was diluted with MTBE and water, and stirred for 30 minutes. The organic layer was cooled to 0oC, acidified with 1.5M HCl (470 kg), and the mixture was stirred for 30 minutes. The organic layer was then washed with brine, concentrated to ~150 L, and then THF (90 kg) was added and the mixture was concentrated. This procedure was repeated (90 kg THF added and evaporated) and the resulting solution of 3,5-difluorobenzoic acid, tert-butyl ester in THF was used directly in Step 6 (above) to prepare compound G.

[0154] Ethyl acetate was charged into a reactor and degassed. Compound J (80 g) was added followed by CuBr2(101 g). The resulting mixture was stirred at 65oC to 75oC for 15 to 24 h and treated with additional CuBr2 if HPLC shows the reaction was incomplete. The reaction was stirred an additional 3 h to 5 h at 65oC to 75oC for an additional 3 to 5 h, cooled to 20oC to 30oC and water was added followed by sodium bicarbonate. The resulting mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic later was washed with 5% EDTA disodium salt solution to remove copper residues and then washed with 1% sodium bicarbonate solution followed by water to afford compound K which was used directly (“as is”) in the following step.

[0155] The ethyl acetate solution from above was exchanged with acetonitrile to generate a solution of K (100 g) in acetonitrile. 2-amino-4-methylpyridine (72.06 g) was charged to the solution which was then stirred under nitrogen at 75oC to 85oC for 30 h to 40 h. The mixture was concentrated below 40oC to 1-2 volumes and diluted with dichloromethane. Water was added, the mixture was cooled to 0oC to 10oC, and acidified with 2N HCl to pH 4-5. The layers were separated and the aqueous layer was extracted with additional dichloromethane. The combinedorganic layers were washed with water at 0oC to 10oC, 7% sodium bicarbonate solution at 0oto 10o, and then water. The organic layer was treated with silica gel and the mixture was concentrated to dryness below 35oC. The residue was transferred to a silica pad which was eluted with dichloromethane-ethyl acetate (1V / 9V) and the fractions containing compound L were concentrated and diluted with THF. This was repeated until the residual ethyl acetate was <1%.

[0156] The THF solution of L was cooled to 15oC to 25oC and treated with a 10% LiOH solution and the mixture was stirred for 2 h to 5 h. NaBH4(2.11 g) was then added to the mixture in portions at 15oC to 25oC and the reaction was stirred for 2 h to 4 h. Water was added dropwise at 0oC to 10oC and the mixture was diluted with MTBE. The layers were separated and the aqueous layer was washed with fresh MTBE. The aqueous layer was cooled to 0oC to 10oC, treated with dichloromethane-methanol (~6-1) and the pH was adjusted to 4-5 using 2N HCl. The mixture was filtered through celite and the aqueous layer was extracted with fresh dichloromethane-methanol (6-1). The combined organic layers were concentrated below 35oC to 1-2V and ethanol (2-3 V) was added. This solution was concentrated to 1-2 V, treated with ethyl acetate, and the resulting mixture was concentrated to 1-2 V. Additional ethanol-ethyl acetate was added and the mixture was heated to 70oC to 85oC for 10 to 30 minutes. The mixture was cooled and stirred at -15oC to 5oC for 2 to 8 h. The mixture was filtered to afford compound M which was washed with ethyl acetate. Compound M was slurried in ethyl acetate and stirred for 1 to 3 h at -15oC to 5oC. The mixture was filtered and compound M was washed with additional ethyl acetate and dried.

[0157] To a solution of compound M (1.00 g, 2.17 mmol, 1.00 eq) in DCM (10.0 mL) was added trideuteriomethanamine (460 mg, 6.52 mmol, 3.00 eq, HCl) and DIPEA (1.12 g, 8.69 mmol, 1.51 mL, 4.00 eq), was added T3P (2.77 g, 4.35 mmol, 2.59 mL, 50% purity, 2.00 eq) at 0oC, then the mixture was warmed to 25oC for 12 h. The mixture was poured into water (10.0 mL), then was added NaHCO3 to adjust pH = 7. The water phase was separated, washed with DCM (10.0 mL × 2). The combined organic phase was washed with brine (10.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product N was used into the next step without further purification.

[0158] Compound N (1.18 g, 2.48 mmol, 1.00 eq) was added to HBr / CH3COOH (2.48 mmol, 6.00 mL) at 25oC, then the mixture was stirred at 70oC for 18 hrs. The excess HBr and AcOH were removed in vacuo. To the residue was added MeOH (5.00 mL) and removed in vacuo to get a brown solid. The crude product O was used directly into next step.

[0159] To a solution of compound O (1.54 g) and Et3N (1.07 g) in DCM (10 mL) was added compound Q (541 mg). The mixture was stirred at 25oC for 12h. The mixture was poured into ice water (10.0 mL), the water phase separated and washed with DCM (15.0 mL × 2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to provide compound B1 (1.03 g, 84% yield) as a white solid. LCMS (ESI, m / z): 465.2 [M+H]+.1H NMR (400 MHz CDCl3): δ 8.18 (d, J = 7.2 Hz, 1H), 7.44-7.39 (m, 3H), 6.68 (d, J = 6.8 Hz, 2H), 3.87-3.78 (m, 3H), 3.55 (d, J = 2.4 Hz, 1H), 3.45-3.3 (m, 1H), 3.05-2.7 (m, 3H), 2.65-2.55 (m, 1H), 2.43 (s, 3H). Methyl-d3 carbonochloridate (compound Q)

[0160] To a mixture of compound P (2.96 g) in THF (10 mL) was added trideuterio (deuteriooxy)methane (1.08 g) and Et3N (3.33 g) in THF (5 mL) at 0oC under N2. The mixture was stirred at 0oC for 1 hr then at 25oC for 1 hr. The reaction mixture was filtered and washed three times with THF. The crude product was used directly into the next step without further purification. Example 2: Synthesis of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7- (methyl-d3)imidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (B2)

[0161] Compound B2 may be prepared by cyclizing Compounds R, S and T together to form the imidazopyridine core of the molecule. After swapping the Boc protecting group on the morpholine fragment for a Moc group, the corresponding methyl ester intermediate W may be further converted into the corresponding methylamide Y. The chloro functional group on intermediate Y may then be converted to the corresponding boronic acid Z (for example according to Molander et al., J. Am. Chem. Soc., 2010, pages 17701-17703), which would then be used to install the desired CD3 moiety on Compound B2 (for example according to Pretze et al., Molecules, 2011, pages 1129-1165). The preparation of compounds S and T is described WO 2014 / 117274 herein incorporated by reference.Example 3: Synthesis of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7- methylimidazo[1,2-a]pyridin-3-yl)methyl-d2)morpholine-4-carboxylate (B3)

[0162] Compound B3 may be prepared from the alcohol 3-A, which can be oxidized to the carboxylic acid 3-B. Reduction of the carboxylic acid 3-B with commercially available LiAlD4 introduces the two deuterium atoms of compound 3-C. Compound 3-C can be converted to the bromide 3-D and is held for further processing. The difluoroaromatic ester 3-E can be deprotonated with base and trapped with DMAc to produce the acetophenone 3-F. Compound 3-Fcan be brominated to afford the bromoketone 3-G. The imidazopyridine ring is generated by the combination of bromoketone 3-G and aminopyridine to produce compound 3-H. The imidazopyridine 3-H can be functionalized with the bromide 3-D under metal promoted conditions under UV light to give 3-I (for example according to Ma et al., New J. Chem., 2021, pages 9302-9314). Compound 3-I can be globally deprotected to afford the amine 3-J. The methyl carbamate can be introduced on 3-J to afford the carboxylic acid 3-K and finally compound B3 upon exposure to methylamine and a coupling reagent. Example 4: Synthesis of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7- methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate-5,5,6,6-d4 (B4)

[0163] Compound B4 could be prepared from commercially available ethanolamine-d4(B4-A). Reductive amination of compound B4-A with benzaldehyde would yield the secondary amine B4- B. Amine B4-B could react with the commercially available epoxide B4-C to afford the diol B4- D in an enantioselective manner. The morpholine 45-E could be accessed via activation of the primary alcohol of diol B4-D in the presence of MsCl and base. Global deprotection of the benzyl protecting groups of morpholine B4-E in an atmosphere of hydrogen and the presence of Pd / C would generate compound B4-F. The second amine of compound B4-F would be reprotected with Boc2O to afford the primary alcohol B5-G. Oxidation of compound B4-G to aldehyde B4-Hfollowed by alkyne formation would yield the terminal alkyne B4-I. A three component coupling of compounds B4-I, B4-J and 4-methylpyridin-2-amine in the presence of copper catalysts would generate the heterocycle B4-K. Removal of the Boc protecting group of B4-K with TFA affords the secondary amine B4-L. Compound B4-L would be functionalized with methyl chloroformate to produce compound B4. Example 5: Synthesis of methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7- methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate-2,3,3,5,5,6,6-d7 (B5)

[0164] Compound B5 may be prepared from a copper mediated coupling of compounds B5-A, B4-B, and 4-methylpyridin-2-amine to afford the imidazopyridine B5-C. Removal of the Boc protecting group of B5-C with TFA affords the secondary amine B5-D. Compound B5-D is then functionalized with methyl chloroformate to produce compound B5. Example 6: P2X3 Antagonist Assay

[0165] HEK293 are transiently or stably transfected with human ion channel cDNAs using methods known in the art. Stable transfectants are selected by co-expression with the antibiotic- resistance gene(s) incorporated into the expression plasmid(s). Selection pressure is maintained by including selection antibiotics in the culture medium. HEK293 cells can be cultured in Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (D-MEM / F-12) supplemented with10% fetal bovine serum, 100 U / mL penicillin G sodium, 100 J.Lg / mL streptomycin sulfate and appropriate selection antibiotics.

[0166] The effect of each test article to act as an antagonist is evaluated as follows. Each test article is evaluated at sixteen (16) concentrations ((0.00045, 0.009, 0.0018, 0.0037, 0.0073, 0.015.0.029, 0.059, 0.117, 0.234, 0.469, 0.9375, 1.875, 3.75, 7.5 and 15 µM, n=3) with 4 replicates for each concentration. Experiments are performed with the FLIPR calcium sensitive dye kit (Fluo-8®AM dye, AAT, Bioquest) according to the manufacturer's instructions. - Dye-loading: Growth media is removed and 20 μL of Mg++-free HBPS containing 1 x Fluo®-8AM is added to the cell culture plate for 30 min at 37 °C. - Preincubation (FLIPR step 1): Cells are pre-incubated with the test or control articles for 20 minutes at room temperature, protected from light. - Stimulation with the agonist (FLIPR step 2): After pre-incubation, cells are stimulated with α β-meATP at final concentration of 3 μM. ~ 5 minutes after stimulation with α,β-meATP, ionomycin is added at a final concentration of 5 µM in order to obtain the maximum calcium influx and fluorescence signal possible from the cells. Fluorescence is recorded continuously for 10 min starting 10 seconds prior to stimulation with α β-meATP. - Positive Control Antagonist: PPADS (1 mM)

[0167] Data acquisition can be performed via the FLIPRControl software that is supplied with the FLIPR System (MDS-AT) and data analyzed using GraphPad Prism®6 (GraphPad Software, Boston, MA, USA)). Curves are fitted from normalized fluorescence data in GraphPad Prism 6 using the better fit between a 4-parameter curve (variable slope). No constraints are set on the curve fits. Example 7: In vitro Metabolic Stability Assay: Determination of in vitro metabolic stability in microsomes (including calculation of hepatic in vivo blood clearance (CL))

[0168] The in vitro metabolic stability of test compounds is determined by incubating the compounds at 1 μM in a suspension liver microsomes in 100 mM phosphate buffer, pH 7.4 and at a protein concentration of 0.5 mg / mL at 37° C. The metabolic stability assay is started by adding a NADPH regenerating system in phosphate buffer, pH 7.4. Incubations containing no NADPH regenerating system are also performed to assess non mediated NADPH metabolism. During incubation, the microsomal suspensions are continuously stirred and aliquots are taken at 5, 10, 15, 20, 30, 45, 60 and 90 min to which 3 volumes of cold acetonitrile containing internal standard (100 ng / mL tolbutamide and 100 ng / ml labetalol ) are immediately added to stop thereaction. Samples are centrifuged at 4000 rpm for 20 min under 4℃. Supernatants are analyzed by LCMS / MS detection. Percent parent remaining is calculated using the T=0 min incubation. Half- life ( T1 / 2) and Clint(mic)is calculated using equation of first order kinetics:

Claims

CLAIMS We Claim:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein: R1, R2, R4, R5, R6, R7, R9, R10, R11, R12, R13, R15, R16, R17, and R18are independently selected from hydrogen and deuterium; each R3is independently selected from hydrogen and deuterium; each R8is independently selected from hydrogen and deuterium; and each R14is independently selected from hydrogen and deuterium; wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18is deuterium.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia):

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R4, R5, R6, and R7is hydrogen.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R4, R5, R6, and R7are hydrogen.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R1, R2, R4, R5, R6, and R7is deuterium.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R4, R5, R6, and R7are deuterium.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10are hydrogen.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10are deuterium.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R11, R12, R13, R15, R16, R17, and R18are hydrogen.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, R13, R15, R16, R17, and R18are hydrogen.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R11, R12, R13, R15, R16, R17, and R18are deuterium.

12. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, R13, R15, R16, R17, and R18are deuterium.

13. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R11, R12, and R13are hydrogen and R15, R16, R17, and R18are deuterium.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R3is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is hydrogen.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R3is deuterium.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is deuterium.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R8is hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8is hydrogen.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R8is deuterium.

21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R8is deuterium.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R14is hydrogen.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein each R14is hydrogen.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R14is deuterium.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein each R14is deuterium.

26. A compound selected from:acceptable salt or solvate thereof.

27. A pharmaceutical composition comprising a compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients.

28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration.

29. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

30. A method for treating a disorder associated with P2X3 activity in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-26.

31. A method for treating pain in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1- 26.

32. A method for treating a urinary tract disorder in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-26.

33. The method of claim 32, wherein the urinary tract disorder comprises neurogenic overactive bladder, non-neurogenic overactive bladder, interstitial cystitis, prostatitis, prostadynia, and benign prostatic hyperplasia.

34. A method of reducing or preventing uncontrolled loss of urine in a mammal in need thereof, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of any one of claims 1-26.

35. The method of claim 34, wherein the uncontrolled loss of urine is associated with urge incontinence, cough incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence, post-prostatectomy incontinence, urinary urgency, nocturia, and enuresis.

36. A method for treating cough in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-26.

37. The method of claim 36, wherein the cough is an acute cough or a chronic cough.

38. The method of claim 36 or 37, wherein the cough is associated with a disease, disorder, or condition selected from chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, suppurative pulmonary disease, respiratory malignancies, allergy, cystic fibrosis, pulmonary fibrosis, respiratory tract inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory tract infection, bronchoconstriction, sarcoidosis, viral or bacterial infection of the upper airways, angiotension converting enzyme (ACE) inhibitor therapy, smoker's cough, chronic non-productive cough, neoplastic cough, cough due to gastroesophageal reflux, and inhalation of irritants, smoke, smog, dust, or air pollution.

39. A method for treating pruritus in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-26.

40. A method of treating endometriosis, endometriosis-associated pain, and endometriosis- associated symptoms in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1-26.

41. The method of claim 40 for treating endometriosis in a mammal in need thereof.

42. The method of claim 40 for treating endometriosis-associated pain in a mammal in need thereof.

43. The method of claim 40 for treating endometriosis-associated symptoms in a mammal in need thereof.

44. The method of claim 43, wherein the endometriosis-associated symptoms are selected from dysmenorrhea, dyspareunia, dysuria, and dyschezia.

45. The method of any one of claims 30-44, wherein the mammal is a human.

46. The method of any one of claims 30-45, further comprising the administration of a second therapeutic agent.

47. The method of claim 46, wherein the second therapeutic agent is a NK-1 antagonist.

48. The method of claim 47, wherein the NK-1 antagonist is selected from the group consisting of serlopitant, aprepitant, casopitant, dapitant, ezlopitant, fosaprepitant, lanepitant, maropitant, netupitant, nolpitant, orvepitant, rolapitant, vestipitant, vofopitant, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102, and TA-5538.

49. The method of claim 46, wherein the second therapeutic agent is selected from a hormonal contraceptive, a non-steroidal anti-inflammatory agent (NSAID), a prostaglandin E synthase (PTGES) inhibitor, an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor, a prostanoid EP4 receptor antagonist, an aldo-keto reductase 1C3 (AKR1C3) inhibitor, and a prolactin receptor (PRLR) antagonist.

50. The method of claim 46, wherein the second therapeutic agent is selected from one or more compounds or medications for treating or alleviating the symptoms of heartburn and / or acid reflux.

51. The method of claim 50, wherein the second therapeutic agent is selected from a histamine H2-receptor antagonist, proton pump inhibitor, promotility agent, and over-the-counter antacid.

52. The method of claim 46, wherein the second therapeutic agent is selected from one or more compounds or medications for treating or alleviating cough, or the symptomology ofcoughing associated with a medical condition by inhibiting the cough reflex or other physiological aspects associated with cough.

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