Deuterated P2X3 modulators

Abstract

Provided herein are deuterated P2X3 modulators and methods of treating diseases, disorders, or conditions using deuterated P2X3 modulators. Also described herein are pharmaceutical compositions containing such compounds.

Description

BACKGROUND

[0001] P2X purinoreceptors are a family of ion channels activated by extracellular adenosine triphosphate (ATP). Purinoreceptors are involved 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 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] U.S. Patent No. 9,598,409 and U.S. Patent No. 10,111,883 describe compounds capable of being P2X3 modulators, one example of which is the compound (S)-2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl ester (Compound A). The development of medicaments for the treatment of one or more conditions associated with the P2X3 receptor comprising such compounds would be beneficial to patients in need thereof who suffer from a disease or have symptoms that can be alleviated or otherwise mitigated by taking a medicament comprising one or more such P2X3 modulators. SUMMARY

[0003] The present disclosure provides compounds and compositions, e.g., as deuterated P2X3 modulators, and their use as medicaments, methods of their preparation, and pharmaceutical compositions comprising the disclosed compounds as at least one active ingredient. The present disclosure also provides the disclosed compounds for use as a medicament and / or in the manufacture of a medicament for modulating P2X3 in a warm-blooded animal, e.g., a human. 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:

[0005]

[0006] Formula (I);

[0007] wherein:

[0008] R 1 , R 2 , R 4 , R 5 , R6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , R 16 , R 17 and R 18 are independently selected from hydrogen and deuterium;

[0009] each R 3 is independently selected from hydrogen and deuterium;

[0010] each R 8 is independently selected from hydrogen and deuterium; and

[0011] each R 14 is independently selected from hydrogen and deuterium;

[0012] wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is deuterium.

[0013] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (la):

[0014]

[0015] Formula (la).

[0016] In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 1 , R 2 , R 4 , R 5 , R 6 and R 7 is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 1 , R2 , R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are deuterium.

[0017] In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 9 and R 10 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 9 and R 10 are deuterium.

[0018] In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18at least one of R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 is deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 , R 12 , and R 13 are hydrogen and R 15 , R 16 , R 17 , and R 18 are deuterium.

[0019] In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 3 is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 3 is deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is deuterium.

[0020] In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 8 is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 8 is deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is deuterium.

[0021] In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 14 is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14is hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 14 is deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14 is deuterium.

[0022] In another aspect is a pharmaceutical composition comprising a compound of Formula (I) or (la), 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 ocular administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, gel, dispersion, solution, emulsion, ointment, or lotion.

[0023] 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 (la), or a pharmaceutically acceptable salt or solvate thereof.

[0024] 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 (la), or a pharmaceutically acceptable salt or solvate thereof.

[0025] In another aspect is 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 Formula (I) or (la), 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, prostatodynia, and benign prostatic hyperplasia.

[0026] In another aspect is a method for 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the uncontrolled loss of urine is associated with urge urinary incontinence, cough incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence, post-prostatectomy incontinence, urinary urgency, nocturia, and enuresis.

[0027] 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cough is acute cough or 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, pyogenic lung disease, respiratory tract malignancy, anaphylaxis, cystic fibrosis, pulmonary fibrosis, respiratory inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory infection, bronchial constriction, sarcoidosis, viral or bacterial infection of the upper respiratory tract, angiotensin-converting enzyme (ACE) inhibitor therapy, smoker's cough, chronic non-productive cough, neoplastic cough, cough due to gastroesophageal reflux, and cough due to inhalation of irritants, smoke, smog, dust, or air pollutants.

[0028] In another aspect is a method of treating pruritis 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 (la), or a pharmaceutically acceptable salt or solvate thereof.

[0029] In another aspect is a method of 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the endometriosis-associated symptoms are selected from dysmenorrhea, dyspareunia, dysuria, and dyschezia.

[0030] In some embodiments of the methods described herein, the mammal is a human.

[0031] In some embodiments of the methods described herein, the method further comprises administering a second therapeutic agent. In some embodiments, the second therapeutic agent is an NK-1 antagonist. In some embodiments, the NK-1 antagonist is selected from the group consisting of serlopitant, aprepitant, casopitant, damoterpant, ezlopitant, fosapitant, lanepitant, maropitant, netupitant, nolpitant, orvepitant, rolapitant, vestipitant, voxilapto, 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 the group consisting of 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 prostaglandin class 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 drugs used to treat or alleviate heartburn and / or symptoms of acid reflux. In some embodiments, the second therapeutic agent is selected from one or more compounds or drugs used to treat or alleviate heartburn and / or symptoms of acid reflux selected from the group consisting of a histamine H2 receptor antagonist, a proton pump inhibitor, a promotility agent, and an over-the-counter antacid. In some embodiments, the second therapeutic agent is selected from one or more compounds or drugs used to treat or alleviate cough or symptoms of cough associated with a medical condition by inhibiting the cough reflex or other physiological aspects associated with cough.

[0032] INCORPORATED BY REFERENCE

[0033] 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

[0034] As described in U.S. Patent No. 7,456,317 and U.S. Patent No. 9,249,149, it has been previously demonstrated that deuteration of drugs in some classes of drugs can improve one or more aspects such as pharmacokinetic (PK) and / or pharmacodynamic (PD) and / or toxicity profiles of the particular drug, and a list of deuterated drugs used to treat various diseases 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 drug product was deutetrabenazibe, approved in 2017.

[0035] Deuterium (D or 2 H) was discovered by Urey et al., Phys. Rev., vol. 39, pp 164-165 (1932), and is a naturally occurring, stable, non-radioactive isotope of hydrogen that is different from the more abundant, more common (>99.9%) isotope of hydrogen protium ( 1 H) because a deuterium nucleus has one neutron and one proton (whereas 1 H has only one proton (the third isotope of hydrogen, tritium ( 3H or T) has two neutrons and one proton in its nucleus. Thus, deuterium is also referred to as “heavy hydrogen.” For example, as described in 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 makes it possible for the physicochemical properties of deuterated molecules to be different from non-deuterated molecules. The chemical reactivity of deuterium is almost identical to protium, although carbon (C)-D bonds are stronger than carbon-H bonds, it is possible to exchange deuterium for protium in chemical synthesis reactions. However, the increased bond strength exhibited by C-D bonds (versus C-H bonds) in deuterated compounds can result in a decrease in reaction rate because C-D bonds are more resistant to breaking, especially in oxidative reactions, such as those catalyzed by cytochrome P450 (CYP450) enzymes (see Russak and Bednarczyk, Annals of Pharmacol., vol. 53(2), pp. 211-216 (2019), p. 212). This phenomenon of decreased reaction rate is referred to as the kinetic isotope effect (KIE), or more specifically, in the case of deuterium, the deuterium isotope effect (DIE). Thus, the metabolism of deuterated compounds can be altered in terms of reaction rates and metabolic profiles of the compounds (see Stemmerich et al. (2022), p. 25), although in some cases the KIE (expressed as the ratio of the rate constants for the reaction of the protonated compound and the deuterated compound, k h / k d ) can be quite large (see Haberson et al., J. Pharmacol. Exp. Ther., vol. 362, (2), pp. 359-367 (2017)), but it is not possible to predict the KIE for a particular compound (see Stemmerich et al. (2022), p. 25).

[0036] As noted by Harbeson and Tung (2014), while DIE can potentially affect the pharmacokinetics of drugs that are metabolized through pathways involving C-H bond cleavage, the actual DIE of a compound can be “masked” due to the complexity of the actual metabolic degradation pathway and / or the involvement of alternative clearance pathways or metabolic sites involved. In some cases, an increase in KIE can be observed on a particular deuterated form of a compound. Thus, as noted in U.S. Patent No. 9,249,149 (col. 3, lines 32-38) with respect to total substrate consumption by metabolism, the results of studies measuring the effect of deuterium substitution on overall metabolic stability vary and are difficult to predict when comparing deuterated and protiated forms of a compound, and (col. 3, lines 42-47), it is noted that the effect of deuterium modification on drug metabolic characteristics cannot be predicted even when deuterium atoms are introduced at known metabolic sites. Only by actually making and testing deuterated drugs can it be determined whether and how their metabolic rates differ from those of their non-deuterated counterparts. Despite rapid advances in the field of deuterated synthetic processes and methods for producing various compounds and chemical moieties (see, e.g., Wood and Lin, “Deuterodehalogenation Under Net Reductive or Redox-Neutral Conditions Enabled by Paired Electrolysis,” ChemRxiv. (2023) Preprint available 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 drug pharmacokinetics through deuteration has not changed, and as emphasized by Stemmerich et al. (2022), “deuteration can change pharmacokinetics without specifically changing the pharmacodynamics of a substance; however, these effects on drug metabolic characteristics are unpredictable and must be investigated on a case-by-case basis” (quoting Harbeson and Tung (2014)), and this principle is true regardless of the class of drug being considered (see Belete (2022), an example in the context of deuterated anticancer candidate compounds).

[0037] Definitions

[0038] As used herein and in the appended claims, the singular forms “a(a)”, “an”, and “the” include plural indicators unless the context clearly indicates otherwise. Thus, for example, reference to “an agent” includes multiple such agents, and reference to “the cell” includes reference to one or more cells (or a large number of cells) and their equivalents. When the scope used herein refers to physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), it is intended to include all combinations and sub-combinations of the scope and specific embodiments thereof. When referring to a number or numerical range, the term “about” means that the referenced number or numerical range is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range varies between 1% and 15% of the described quantity or numerical range. The term “comprising” (and related terms such as “comprising” or “having” or “including”) is not intended to exclude those embodiments of other certain embodiments, such as compositions, compositions, methods, or processes of any substance described herein, which may “consist of” or “substantially consist of” the described features.

[0039] As used in the specification and appended claims, unless otherwise stated, the following terms have the meanings indicated below.

[0040] As used in this article, C1-C x Including C1-C2, C1-C3... C1-C x C1-C x It refers to the number of carbon atoms that make up its specified part (excluding optional substituents).

[0041] "Amino" refers to the -NH2 group.

[0042] "Cyano" refers to the CN group.

[0043] "Nitro" refers to the NO2 group.

[0044] "O-" refers to the -O- group.

[0045] "Oxo" refers to the =O group.

[0046] "Thio" refers to the =S group.

[0047] "Imine" refers to the =NH group.

[0048] "Oxime group" refers to the =N-OH group.

[0049] "alkyl" or "alkylene" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, and having one to fifteen carbon atoms (e.g., C1-C1). 15Alkyl groups. In some embodiments, the alkyl group comprises 1 to 13 carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises 1 to 6 carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)-NR a R f -N(R) a )C(O)R f -N(R) a S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t Rf (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0050] “Alkoxy” refers to a radical of the formula -O-alkyl, wherein alkyl is an alkyl chain as defined above.

[0051] “Alkenyl” refers to a straight or branched hydrocarbon chain radical consisting entirely 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. Examples of alkenyl include ethylene (i.e., vinyl), prop-1 -enyl (i.e., allyl), but-1 -enyl, pent-1 -enyl, pent-1,4-dienyl, and the like. Unless stated otherwise specifically 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, OR a , -SR a , OC(O)R f , N(R a )2, C(O)R a , C(O)OR a , C(O)N(R a )2, N(R a )C(O)OR f , OC(O)NR a R f , N(R a )C(O)R f , N(R a )S(O) t R f (where t is 1 or 2), S(O) t OR a (where t is 1 or 2), S(O) t R f (where t is 1 or 2) and S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R findependently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0052] "Alkynyl" refers to straight-chain or branched-chain hydrocarbon groups having two to twelve carbon atoms, which consists solely of carbon and hydrogen atoms, contains at least one carbon-carbon triple bond, and is attached to the rest of the molecule by a single bond. In certain embodiments, an alkynyl group contains two to eight carbon atoms. In other embodiments, an alkynyl group has two to four carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specified, the alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-NR a R f , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2), where each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0053] "Aryl" means a radical derived from a monocyclic or polycyclic hydrocarbon ring system that is aromatic. The monocyclic or polycyclic hydrocarbon ring system contains only carbon and hydrogen atoms, with from six to eighteen carbon atoms, wherein at least one ring is completely unsaturated, i.e., it contains a cyclic, delocalized (4n+2) pi-electron system, according to Hückel theory. The ring system from which the aryl group is derived includes, but is not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") is meant to include aryl groups that are optionally substituted by one or more substituents selected, independently, from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, R b OR a , R b OC(O)R a , R b OC(O)OR a , R b OC(O)N(R a )2, R b N(R a )2, R b C(O)R a , R b C(O)OR a , R b C(O)N(R a )2, R b OR c C(O)N(R a )2, R b N(R a )C(O)OR a , R b N(R a )C(O)R a , R b N(R a )S(O) t R a (where t is 1 or 2), R b S(O) t OR a (where t is 1 or 2), R b S(O) t R a (where t is 1 or 2), and R b S(O) t N(R a )2 (where t is 1 or 2), where each R aindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, R b each independently is a direct bond or a straight-chained or branched alkylene or alkenylene chain, and R c is a straight-chained or branched alkylene or alkenylene chain.

[0054] "Aryloxy" means a group bound through an oxygen atom of the formula -O-aryl, wherein aryl is as defined above.

[0055] "Aryloxy" means a group bound through an oxygen atom of the formula -O-aryl, wherein aryl is as defined above. c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of an aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of an aralkyl group is optionally substituted as described above for aryl groups. c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of an aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of an aralkyl group is optionally substituted as described above for aryl groups.

[0056] "Aryloxy" means a group bound through an oxygen atom of the formula -O-aryl, wherein aryl is as defined above.

[0057] "Aryloxy" means a group bound through an oxygen atom of the formula -O-aryl, wherein aryl is as defined above. d is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of an aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of an aralkyl group is optionally substituted as described above for aryl groups. d is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of an aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of an aralkyl group is optionally substituted as described above for aryl groups.

[0058] "Aryloxy" means a group bound through an oxygen atom of the formula -O-aryl, wherein aryl is as defined above. e is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of an aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of an aralkyl group is optionally substituted as described above for aryl groups. e is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of an aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of an aralkyl group is optionally substituted as described above for aryl groups.

[0059] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, including a fused or bridged ring system having three to fifteen carbon atoms. In certain embodiments, a cycloalkyl group comprises three to ten carbon atoms. In other embodiments, a cycloalkyl group comprises five to seven carbon atoms. A cycloalkyl group is connected to the remainder of the molecule via a single bond. A cycloalkyl group is either saturated (i.e., contains only single C-C bonds) or partially unsaturated (i.e., contains one or more double or triple bonds). Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl group comprises three to eight carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, a cycloalkyl group comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl group comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl group comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl group comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). A partially unsaturated cycloalkyl group is also referred to as a "cycloalkenyl" group. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Unless stated otherwise specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl groups optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a)C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2), wherein each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain.

[0060] “Deuterated” means that one or more hydrogen atoms are replaced with a corresponding number of deuterium atoms.

[0061] “Halo” or “halogen” means a bromo, chloro, fluoro or iodo substituent.

[0062] “Haloalkyl” means an alkyl group as defined above substituted with one or more halo groups as defined above.

[0063] “Fluoroalkyl” means an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl portion of a fluoroalkyl group is optionally substituted as defined above for alkyl groups.

[0064] “Haloalkoxy” means an alkoxy group as defined above substituted with one or more halo groups as defined above.

[0065] "Heterocyclic alkyl" refers to a stable 3- to 18-membered non-aromatic cyclic group comprising 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, heterocyclic alkyl groups are monocyclic, bicyclic, tricyclic, or tetracyclic systems, including fused-ring, spirocyclic, or bridged-ring systems. The heteroatoms in the heterocyclic alkyl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heterocyclic alkyl group is partially or fully saturated. In some embodiments, the heterocyclic alkyl group is attached to the remainder of the molecule by any atom of the ring. Examples of such heterocyclic alkyl groups include, but are not limited to, dioxolanecycloyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the term "heterocyclic alkyl" is intended to include heterocyclic alkyl groups as defined above, optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, halogen, fluoroalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocyclic alkyl, heteroaryl, heteroarylalkyl, R b OR a R b OC(O)R a R b OC(O)OR a R b OC(O)N(R a )2、R b N(R a )2、R b C(O)R a R b C(O)OR a R b C(O)N(R a )2、R b OR c C(O)N(R a )2、R b N(R a )C(O)OR a R b N(R a )C(O)R a R b N(R a)S(O) t R a (wherein t is 1 or 2), R b S(O) t OR a (wherein t is 1 or 2), R b S(O) t R a (wherein t is 1 or 2) and R b S(O) t N(R a )2 (wherein t is 1 or 2), wherein R a each independently is hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, R b each independently is a direct bond or a straight-chained or branched alkylene or alkenylene chain, and R c is a straight-chained or branched alkylene or alkenylene chain.

[0066] "Heteroaryl" means a radical derived from a 5- to 18-membered aromatic ring radical containing from 1 to 17 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring is completely unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system according to Hückel theory. Heteroaryl groups include fused or bridged ring systems. The heteroatoms in a heteroaryl group are optionally oxidized. If present, one or more nitrogen atoms are optionally quaternized. The heteroaryl radical is attached to the rest of the molecule by any atom of the ring. Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl groups optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b-O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2), wherein each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, each R b is independently a direct bond or a straight-chained or branched alkylene or alkenylene chain, and R c is a straight-chained or branched alkylene or alkenylene chain.

[0067] "N-heteroaryl" means a heteroaryl group as defined above containing at least one nitrogen, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom in the heteroaryl group. An N-heteroaryl group is optionally substituted as described above for heteroaryl groups.

[0068] "C-heteroaryl" means a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. A C-heteroaryl group is optionally substituted as described above for heteroaryl groups.

[0069] "Heteroaryloxy" means a group bound through an oxygen atom of the formula -O-heteroaryl, wherein heteroaryl is as defined above.

[0070] "Heteroarylalkyl" means a group of the formula -R c -heteroaryl, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to the alkyl group at a nitrogen atom. The alkylene chain of a heteroarylalkyl group is optionally substituted as defined above for alkylene chains. The heteroaryl portion of a heteroarylalkyl group is optionally substituted as defined above for heteroaryl groups.

[0071] “Heteroaryloxy” refers to a radical of the formula -O-R wherein R is heteroaryl as defined above. c “Heteroarylalkoxy” refers to a radical of the formula -O-R wherein R is heteroarylalkyl as defined above. c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for alkylene chains. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for heteroaryl.

[0072] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which are defined in terms of absolute stereochemistry. All stereoisomeric forms of the compounds disclosed herein are intended to be within the scope of the present disclosure unless it is otherwise indicated. When the compounds described herein contain olefinic double bonds, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric, isomers (e.g., cis or trans). Likewise, all possible enantiomeric, racemic, and optically pure forms are intended to be included. The term “geometric isomer” refers to the E or Z geometric isomer (e.g., cis or trans) of an olefinic double bond. The term “positional isomer” refers to structural isomers around a central ring, e.g., ortho, meta, and para isomers around a benzene ring.

[0073] “Tautomer” refers to a molecule in which a proton can move from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds provided herein exist as tautomers. In cases where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomerization equilibria include:

[0074]

[0075] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, “optionally substituted aryl” means that the aryl group can or can not be substituted and that the description includes substituted aryl groups and aryl groups with no substituents.

[0076] “Prodrug” includes compounds that are metabolized into a pharmacologically active drug after administration (R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chp. 8). Prodrugs can be used to improve how a compound is absorbed, distributed, metabolized, and excreted.

[0077] “Pharmaceutically acceptable salt” includes both acid and base salt forms. Pharmaceutically acceptable salts of any compound described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are the pharmaceutically acceptable acid addition salts and the pharmaceutically acceptable base addition salts.

[0078] “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 di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and

[0079] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared from inorganic or organic bases. 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 salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins, such as 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-methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like. See Berge et al., supra.

[0080] The term "mammal" refers to a human, non-human primate, dog, cat, cow, sheep, pig, mouse, or other veterinary or laboratory mammal. One of skill in the art recognizes that a therapy that reduces the severity of a pathology in one mammal is predictive of the effect of the therapy on another mammal.

[0081] As used herein, "treatment" or "treating," or "palliating" or "ameliorating," are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or 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 the patient experiences an improvement in the quality of life without wiping out the disorder entirely. 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 yet been made.

[0082] Compound

[0083] The compounds of Formula (I) or (la) described herein are P2X3 modulators. In some embodiments, the compounds of Formula (I) or (la) described herein are P2X3 antagonists. In some embodiments, the compounds of Formula (I) or (la) described herein, and compositions comprising these compounds, are useful for treating pain, urinary tract disorders, cough, pruritis, endometriosis, endometriosis-related pain, or endometriosis-related symptoms.

[0084] In some embodiments are compounds of Formula (I):

[0085]

[0086] Formula (I);

[0087] wherein:

[0088] R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , R 16 , R 17 and R 18 are independently selected from hydrogen and deuterium;

[0089] each R 3 is independently selected from hydrogen and deuterium;

[0090] each R 8 is independently selected from hydrogen and deuterium; and

[0091] each R 14 is independently selected from hydrogen and deuterium;

[0092] wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R18 At least one of them is deuterium.

[0093] In some embodiments, the compound is of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia):

[0094]

[0095] Formula (Ia).

[0096] In some embodiments, the compound is of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 R 2 R 4 R 5 R 6 and R 7 At least one of them is hydrogen. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 R 2 R 4 R 5 R 6 and R 7 One of them is hydrogen. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 R 2 R 4 R 5 R 6 and R 7 Two of them are hydrogen atoms. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 R 2 R 4 R 5 R 6 and R 7 Three of them are hydrogen atoms. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 R 2 R 4 R 5 R 6 and R 7 Four of them are hydrogen atoms. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 R 2 R 4 R 5 R 6 and R7 In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are deuterium.

[0097] In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 9 and R 10 are hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 9 is hydrogen and R 10 is deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 9 and R 10 are deuterium.

[0098] In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18One of them is deuterium. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 R 12 R 13 R 15 R 16 R 17 and R 18 Two of them are deuterium. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 R 12 R 13 R 15 R 16 R 17 and R 18 Three of them are deuterium. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 R 12 R 13 R 15 R 16 R 17 and R 18 Four of them are deuterium. In some embodiments, they are compounds of formula (I) or (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 R 12 R 13 R 15 R 16 R 17 and R 18 Five of them are deuterium. In some embodiments, they are compounds of formula (I) or (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 R 12 R 13 R 15 R 16 R 17 and R 18 Six of them are deuterium. In some embodiments, they are compounds of formula (I) or (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 11 R 12 and R 13 It is hydrogen and R 15 R 16 R 17 and R 18 It is deuterium. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 R 12 R 13, R 15 , R 16 , R 17 , and R 18 are deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein at least one of R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 is hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein each of R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 is hydrogen.

[0099] In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein at least one R 3 is deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein one R 3 is deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein two R 3 are deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 is deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein at least one R 3 is hydrogen. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein each R 3 is hydrogen.

[0100] In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein at least one R 8 is deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein one R 8 is deuterium. In some embodiments are compounds of Formula (I) or (la), or pharmaceutically acceptable salts or solvates thereof, wherein two R 8deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 8 hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 hydrogen.

[0101] deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 14 deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein one R 14 deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein two R 14 deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14 deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 14 hydrogen. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14 hydrogen.

[0102] deuterium. In some embodiments is a compound of Formula (I) or (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 deuterium.

[0103] Preparation of compounds

[0104] Compounds used in the methods described herein are prepared according to the methods disclosed in U.S. Patent No. 9,598,409, which is incorporated by reference herein 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).

[0105] Suitable reference books and treatises detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing such preparations 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. Other suitable reference books and treatises detailing the synthesis of reactants useful in the preparation of the compounds described herein or providing references to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged 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, 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[0106] Specific and analogous reactants can also be identified through the use of the Index of Known Chemical Substances produced by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and through on-line databases (for further details, contact the American Chemical Society, Washington, D.C.). Chemicals that are known but not commercially available in the catalogs are optionally prepared by custom chemical synthesis companies, many of which are offered as a service by standard chemical supply companies (e.g., those listed above). A reference for the preparation and selection of pharmaceutically acceptable salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

[0107] Additional forms of the compounds disclosed herein

[0108] isomers

[0109] Further, in some embodiments, the compounds described herein exist in geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis (syn / entgegen (E)) and trans (anti / zusammen (Z)) isomers, and mixtures thereof. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers of the formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, and mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion can be used in 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 pair of diastereoisomeric compounds, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes (e.g., crystalline diastereomeric salts) are preferred. In some embodiments, the diastereoisomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are separated by exploiting these differences. In some embodiments, the diastereoisomers are separated by chiral chromatography, or, preferably, by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered by any practical method which does not cause racemization of the compound and the resolving agent.

[0110] labeled compounds

[0111] In some embodiments, the compounds described herein exist in their isotopically-labeled forms, in addition to deuterium. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds as a pharmaceutical composition. Accordingly, 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 2 H), carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C,l5 N, 16 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes of compounds described herein and their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labelled compounds, for example those into which radioactive isotopes (e.g., 3 H and 14 C) are incorporated, can be used in the preparation of pharmaceuticals and / or in assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labelled compounds, their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives are prepared by any suitable method.

[0112] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0113] pharmaceutically acceptable salts

[0114] In some embodiments, the compounds described herein exist in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0115] In some embodiments, the compounds described herein have an acidic or basic group 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 application, or by separately reacting the purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0116] prodrugs

[0117] In some embodiments, the compounds described herein are formulated as agents that are converted in vivo to active forms to alter the biodistribution or pharmacokinetics of a particular agent. For example, carboxylic acid groups can be esterified, for example, with methyl or ethyl groups, to produce esters. When the ester is administered to a subject, the ester is enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically cleaved to expose an anionic group. Anionic groups can be esterified with moieties (e.g., acyloxymethyl esters) that are cleaved to expose an intermediate agent that subsequently decomposes to produce the active agent. Prodrug moieties can be metabolized in vivo to carboxylic acids by esterases or other mechanisms. Alternatively, other functional groups can be modified into prodrug forms. For example, amine groups can be converted to carbamates or amides that are cleavable in vivo.

[0118] solvates

[0119] In some embodiments, the compounds described herein exist as solvates. The present application provides methods of treating diseases by administering such solvates. The present application also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0120] Solvates comprise either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process with a pharmaceutically acceptable solvent, such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from a water / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein exist in both 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.

[0121] Pharmaceutical compositions

[0122] In certain embodiments, the compounds described herein are administered as pure chemicals. In additional embodiments, the compounds described herein are combined with a pharmaceutically suitable carrier 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), which is selected on the basis of the selected route of administration and standard pharmaceutical practice as described in, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)).

[0123] Accordingly, provided herein are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt described herein, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0124] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof.

[0125] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I) or (la), or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments, a 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 small organic molecules, e.g., contaminating intermediates or byproducts produced, for example, in one or more steps of a synthetic process.

[0127] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0128] Exemplary pharmaceutical compositions are in the form of a pharmaceutical formulation, e.g., in solid, semi-solid, or liquid form, which includes one or more of the disclosed compounds as an active ingredient combined with a suitable organic or inorganic carrier or excipient and, if desired, other active ingredients. In some embodiments, the active ingredient is mixed with one or more non-toxic pharmaceutically acceptable carriers such as

[0129] In some embodiments, a compound of Formula (I) or (la) described herein is administered to a subject in a biologically compatible form suitable for local administration to treat or prevent a skin disease, disorder, or condition. By "a biologically compatible form suitable for local administration" is meant a form of the compound of Formula (I) or (la) to be administered in which the therapeutic effects of the inhibitor outweigh any toxic effects. Administration of a compound of Formula (I) or (la) as described herein can be in any pharmacological form that is suitable for local administration, including a therapeutically effective amount of a compound of Formula (I) or (la), alone or in combination with a pharmaceutically acceptable carrier.

[0130] Topical application of a compound of Formula (I) or (la) can be in the form of an aerosol, a semisolid pharmaceutical composition, a powder, or a solution. The term "semisolid composition" means an ointment, cream, salve, gel, or other pharmaceutical composition of essentially similar consistency suitable for application to the skin. Examples of semisolid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lea and Febiger (1970) by Lachman, Lieberman and Kanig and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) by Mack Publishing Company.

[0131] Dermal or transdermal patches are another method of transdermal delivery of the therapeutic or pharmaceutical compositions described herein. The patch can provide an absorption enhancer, such as DMSO, to increase absorption of the compound. The patch can include those that control the rate of drug delivery to the skin. The patch can provide a variety of drug delivery systems, including a reservoir system or a monolithic system, respectively. For example, a reservoir design can have four layers: an adhesive layer that contacts the skin directly, a control membrane that controls diffusion of the drug molecules, a reservoir of the drug molecules, and a water-resistant backing. Such a design delivers a uniform amount of drug over a specified period of time, and the rate of delivery must be less than the saturation limit for different types of skin. For example, a monolithic design typically has only three layers: an adhesive layer, a polymer matrix containing the complex, and a water-resistant backing. This design brings the saturation amount of drug to the skin. Thus, the delivery is controlled by the skin. When the amount of drug in the patch decreases below the saturation level, the rate of delivery decreases.

[0132] In one embodiment, the topical composition can for example take the form of a polyacrylic acid or polyacrylamide based hydrogel; as an ointment, for example with polyethylene glycol (PEG) as a carrier, like the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, in particular a water-in-oil or oil-in-water microemulsion, optionally with the addition of liposomes. Suitable penetration enhancers (carriers) include sulfoxide derivatives, such as dimethyl sulfoxide (DMSO) or decylmethylsulfoxide (decyl-MSO) and carbitol (diethylene glycol monoethyl ether) or cyclodextrins; and pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and its fatty acid esters; urea derivatives, such as dodecylurea, 1,3-bis-dodecylurea and 1,3-diphenylurea; terpenes, such as D-limonene, menthone, a-terpineol, carvol, limonene oxide or 1,8-eucalyptol.

[0133] Ointments, pastes, creams and gels can also contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid and talc, or mixtures thereof. Powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate 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 methods conventionally used for the preparation of aerosol medicaments. Typically, such methods include pressurization or provision of means for pressurizing the solution container, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can also contain commonly used propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0134] In some embodiments of 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 nontoxic 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 can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0135] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the compositions of the present application are 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, hydroxypropylmethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as, for example, crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetostearyl alcohol, and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as 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 also comprise buffering agents. In some embodiments, similar types of solid compositions are also used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0136] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, the compositions are compressed, molded, or compressed molded with a binder (e.g., gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the composition of the present application moistened with an inert liquid diluent. In some embodiments, the 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.

[0137] 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, the liquid dosage forms can comprise 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- butyleneglycol, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, baby oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0138] In some embodiments, suspensions comprise, in addition to the subject composition, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0139] In some embodiments, powders and sprays comprise, in addition to the subject composition, excipients such as, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can in some embodiments further comprise customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0140] The compositions and compounds disclosed herein can alternatively be administered by aerosol. This is achieved by the preparation of aqueous aerosols, liposome preparations or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In some embodiments, sonic nebulizers are used as they minimize the degree of exposure of the agent to shearing that causes degradation of the compounds contained in the subject compositions. Generally, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, pluronics or polyethylene glycols), innocuous proteins such as serum albumul, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are typically made from isotonic solutions.

[0141] Pharmaceutical compositions adapted for parenteral administration include one or more compounds of the present application in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use, which can contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0142] Examples of suitable aqueous and nonaqueous carriers for 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 can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0143] The dosage of the composition comprising at least one compound described herein varies depending on the condition of the patient (e.g., human), i.e., the stage of the disease, the general health status, the age, and other factors.

[0144] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). Appropriate dosages and suitable durations and frequencies of administration will be determined by factors such 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. Generally, appropriate dosages and treatment regimens provide amounts of the composition sufficient to provide therapeutic and / or prophylactic benefit (e.g., improved clinical outcomes, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival times, or lessening of symptom severity). Optimal dosages are generally determined using experimental models and / or clinical trials. In some embodiments, optimal dosages depend on the body mass, weight, or blood volume of the patient.

[0145] Oral dosages are generally in the range of about 1.0 mg to about 1000 mg, one to four or more times per day.

[0146] Methods

[0147] pain

[0148] P2X3 is selectively expressed on nociceptive, small diameter sensory neurons (i.e., neurons stimulated by pain or injury), which is consistent with a role in pain sensitivity. And it has been reported that blockade of P2X3 receptors has analgesic effects in animal models of chronic inflammatory and neuropathic pain. Jarvis et al., PNAS, 99, 17179-17184 (2002). Thus, methods that reduce P2X3 levels or activity are believed to be useful in modulating pain perception in subjects afflicted with pain.

[0149] 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 (la), 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.

[0150] urinary tract disorders

[0151] P2X3 has been reported to be involved in the control of the afferent pathway of the bladder capacity reflex. Thus, inhibition of P2X3 can have therapeutic potential for the treatment of urinary storage and voiding disorders such as overactive bladder. Cockayne et al., Nature, vol. 407, pp. 1011-1015 (2000). Recent studies have also suggested that P2X2 / 3 is predominantly expressed in bladder sensory neurons (over P2X3) and can play a role in the perception of bladder filling and nociception. Zhong et al., Neuroscience, vol. 120, pp. 667-675 (2003).

[0152] In some embodiments is 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 Formula (I) or (la), 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, prostatodynia, and benign prostatic hyperplasia.

[0153] In some embodiments is a method for 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 (la), 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.

[0154] cough

[0155] Most of the stimuli that initiate cough affect the upper airways (e.g., strong odors / smoke, cold air, postnasal drip, aspiration of gastroesophageal reflux, talking). In addition, the maximum concentration of cough receptors is at the larynx, carina, and bifurcation of the medium to large bronchi. These observations suggest that the upper airways play a major role in cough. Thus, given that the upper airways are innervated by jugular C-fibers that express P2X3 channels predominantly, this suggests that P2X3 homotrimeric receptors are responsible for the increased sensitivity of the cough reflex.

[0156] In some embodiments are methods 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cough is acute cough or chronic cough. In some embodiments, the cough is associated with a disease, disorder, or condition selected from the group consisting of chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, pyogenic lung disease, respiratory tract malignancy, anaphylaxis, cystic fibrosis, pulmonary fibrosis, respiratory inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory infection, bronchoconstriction, sarcoidosis, viral or bacterial infection of the upper respiratory tract, angiotensin-converting enzyme (ACE) inhibitor therapy, smoker's cough, chronic nonproductive cough, neoplastic cough, cough due to gastroesophageal reflux, and inhalation of irritants, smoke, smog, dust, or air pollutants.

[0157] pruritis

[0158] Itch-producing stimuli can be induced by mechanical, thermal, and chemical means, which are sensed by afferent neurons that innervate the skin and transmitted to the thalamus for processing and reflex initiation. The stimuli and afferent transmission are mediated by a variety of afferent neurons (pruriceptive neurons), which are a population that partially overlaps in molecular phenotype with pain-sensing neurons in the skin. Pruriceptive neurons can respond to a variety of stimuli, but pathological itch is primarily induced by endogenous chemical agents that act on the terminals of neurons in the skin (e.g., histamine, substance P, gastrin-releasing peptide, interleukins, nerve growth factor). These itch-producing agents are released in conditions with excessive inflammation (e.g., atopic dermatitis, psoriasis), systemic diseases (e.g., chronic liver and kidney disease), neuropathic disorders (e.g., post-herpetic itch), or psychiatric conditions (e.g., obsessive-compulsive disorder, substance abuse) (Yosipovitch et al., N. Engl. J. Med., 2013, 1625-1634).

[0159] Itch-sensing afferent neurons are characterized by c- or a5-fibers of dorsal root ganglia that innervate skin tissue and form synapses with the spinal cord. The c- and a5-fibers in the skin express receptors at their terminal ends that respond to chemical agents that produce itch to initiate action potentials transmitted to the CNS. These neurons also express P2X3 cation channels that modulate the sensitivity of the neurons to excitatory stimuli that produce itch. Notably, P2X3 channels are co-expressed on the cell membrane of MgprA3+ neurons, which are the predominant itch-sensing neuronal phenotype that innervate 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).

[0160] P2X3 channels are modulators of neuronal excitability that are activated by local release of ATP, neurotransmitters, and extracellular messengers with proinflammatory properties. ATP, as an important chemical messenger, is over-released by neuronal and non-neuronal cell types under a variety of pathological conditions (Burnstock, Front. Pharmacol., 2017, 661; Burnstock, Biochem. Pharmacol., 2017, doi:10.1016 / j.bcp.2017.07.016). Thus, an increase in ATP release can lead to hyperexcitability of afferent itch-sensing neurons and increased sensitivity to any itch-producing agents pathologically released in the skin. In sum, P2X3 channels acting through pathological ATP release can be a relevant target for modulating the sensitivity of afferent neurons to the sensation of itch. Their inhibition can provide a means to suppress the peripheral hypersensitivity to itch in a variety of diseases with a broad mechanism independent of acting on the pathological stimuli of itch receptors.

[0161] In some embodiments are methods 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 (la), 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, xerotic dermatitis, nummular and dyshidrotic dermatitis, lichen planus, sclerosing atrophic lichen planus, 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 fungal, bacterial and viral infections, scabies, pediculosis, insect bites, and folliculitis. 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; inherited skin diseases, 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 prurigo eruption of pregnancy (PEP), atopic eruption of pregnancy, pemphigoid gestationis, neoplasia, and cutaneous T-cell lymphoma. In some embodiments, the pruritus is associated with nodular prurigo. In some embodiments, the pruritus is associated with kidney disease or a therapeutic procedure to treat kidney disease. In some embodiments, the pruritus is associated with chronic kidney disease. In some embodiments, the pruritus is associated with a therapeutic procedure to treat kidney disease, wherein the therapeutic procedure to treat 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 drug treatment with a drug selected from the group consisting of opioid drugs, anti-malarial drugs, anti-cancer therapies, and epidermal growth factor receptor inhibitors.

[0162] endometriosis

[0163] Pain associated with endometriosis is attributed to functional endometriotic lesions that are embedded with nerve fibers outside the uterine cavity. Afferent sensory fibers and proinflammatory mediators are associated with endometriosis-associated pain. In particular, women with endometriosis have elevated levels of proinflammatory cytokines, such as interleukin (IL)-1 beta, IL-6, prostaglandins (PGs), tumor necrosis factor (TNF)-alpha, and nerve growth factor (NGF) in peritoneal fluid and endometriotic lesions. Inflammatory mediators in the peritoneal inflammatory milieu of endometriosis activate nociceptive receptors on afferent neurons by stimulating innervated sensory nerve fibers, including C- or A delta- fibers, within endometriotic lesions, providing sensitization of sensory neurons and ultimately triggering a pain signaling cascade. In some cases, anti-inflammatory agents provide pain relief. However, these agents often have little effect on the relief of pain symptoms, and relapse 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).

[0164] Afferent neurons found in endometriotic lesions outside the uterine cavity consist of C- or A delta- fibers of the dorsal root ganglion and form synapses with the spinal cord. C- or A delta- fiber terminals express receptors that respond to proinflammatory mediators to initiate action potentials transmitted to the CNS. An important transducer of this signaling pathway expressed by these neurons is the P2X3 cation channel. Notably, P2X3 channels are co-expressed on the cell membranes of small-diameter and medium-diameter sensory neurons, which are key pain sensors of noxious stimuli. Furthermore, P2X3 expression in endometriotic endometrium and endometriotic lesions is significantly higher than in normal endometrial tissue, and both are positively correlated with 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).

[0165] Under pathophysiological conditions, an increase in ATP release modulated by inflammatory mediators can lead to activation of P2X3, resulting in hyperexcitability of afferent neurons in the endometrium located outside the uterine cavity and increased sensitivity to endometriosis-associated pain. In summary, P2X3 channels acting through pathologic ATP release can be a potential relevant target to modulate the sensitivity of afferent neurons coupled to endometriosis-associated pain. Their inhibition provides a method to reduce pain caused by endometriosis and endometriosis-like symptoms (Yuan et al., Int. J. Nanomed., 2017, 8171-8183).

[0166] In some embodiments are methods of 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments are methods 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments are methods 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments are methods 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 (la), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the endometriosis-associated symptoms are selected from dysmenorrhea, dyspareunia, dysuria, and dyschezia.

[0167] Pharmaceutical combinations

[0168] Combination therapy is also contemplated herein, e.g., co-administration of a disclosed compound and another active agent, as part of a specific treatment regimen intended to provide a 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 of the therapeutic agents resulting from their combination. Co-administration of these therapeutic agents is typically carried out within a specified period of time (usually weeks, months, or years, depending on the combination selected). Combination therapy is intended to include administration of multiple therapeutic agents in a sequential manner, i.e., wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0169] Substantial simultaneous administration is achieved, for example, by administering a single formulation or composition (e.g., tablets or capsules of each therapeutic agent in a fixed proportion, or multiple, single formulations of each therapeutic agent (e.g., capsules)) to a subject. The sequential or substantially simultaneous administration of each therapeutic agent is achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents are administered via the same or different routes. For example, the first therapeutic agent in a selected combination is administered intravenously, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered intravenously.

[0170] In some embodiments, a method for treating a condition related to P2X3 activity in mammals of need includes administering to the mammal a therapeutically effective amount of a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents. In some embodiments, a method for treating pain in mammals of need includes administering to the mammal a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents. In some embodiments, a method for treating a urinary tract condition in mammals of need includes administering to the mammal a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents. In some embodiments, a method for treating to reduce or prevent uncontrolled urinary loss in mammals of need includes administering to the mammal a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents. In some embodiments, a method for treating cough in mammals in need includes administering to the mammal a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents. In some embodiments, a method for treating pruritus in mammals in need includes administering to the mammal a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents. In some embodiments, a method for treating endometriosis, endometriosis-related pain, and endometriosis-related symptoms in mammals in need includes administering to the mammal a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, and further includes administering to the mammal one or more additional agents.

[0171] In some embodiments, the additional agent is an NK-1 antagonist. In some embodiments, the NK-1 antagonist is selected from serlopitant, aprepitant, casopitant, damotopitant, ezlopitant, fosapitant, lanepitant, maropitant, netupitant, nolpitant, orvepitant, rolapitant, vestipitant, volinixtat, AV-818, BIIF 1149CL, CP122,721, DNK-333, GSK-424887, L-733060, L-759274, LY-686017, M516102, and TA-5538.

[0172] In some embodiments, the one or more additional agents 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 prostaglandin EP4 receptor antagonist, an aldo-keto reductase 1C3 (AKR1C3) inhibitor, and a prolactin receptor (PRLR) antagonist. In some embodiments, the additional agent is a hormonal contraceptive. In some embodiments, the additional agent is a non-steroidal anti-inflammatory agent (NSAID). In some embodiments, the additional agent is a prostaglandin E synthase (PTGES) inhibitor. In some embodiments, the additional agent is an interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor. In some embodiments, the additional agent is a prostaglandin EP4 receptor antagonist. In some embodiments, the additional agent is an aldo-keto reductase 1C3 (AKR1C3) inhibitor. In some embodiments, the additional agent is a prolactin receptor (PRLR) antagonist.

[0173] In some embodiments, the additional agent is selected from one or more compounds or drugs used to treat or alleviate heartburn and / or symptoms of acid reflux from the stomach (also known as gastroesophageal reflux disease or GERD). In some embodiments, the GERD-alleviating or GERD-treating compound or drug is selected from histamine-H2 blockers (also known as histamine H2 receptor antagonists), proton pump inhibitors (PPIs), prokinetic agents, and over-the-counter antacids. In some embodiments, the histamine-H2 blocker is selected from cimetidine (Tagamet®), famotidine (Pepcid AC®), and nizatidine (Axid AR®). In some embodiments, the proton pump inhibitor is selected from dexlansoprazole (Dexilant®), esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®, as well as the version containing sodium bicarbonate, Zegerid®), pantoprazole (Protonix® and Pantoloc®), and rabeprazole (Aciphex®). In some embodiments, the prokinetic agent is metoclopramide (Reglan®). In some embodiments, the over-the-counter (also known as non-prescription) drug is selected from drugs containing calcium carbonate, such as Mylanta®, Rolaids®, and Tums®.

[0174] In some embodiments, the compounds described herein are used in combination with one or more compounds or drugs used to treat or alleviate cough or symptoms of cough associated with a medical condition by inhibiting the cough reflex. In some embodiments, the compounds described herein are used in combination with one or more compounds or drugs used for other physiological aspects associated with cough, selected from expectorants, mucolytics, antitussives, bronchodilators, antihistamines, anti-inflammatories, and other types of drugs, such as pregabalin. In some embodiments, the antitussive compound or drug is selected from a benzonatate compound, a dextromethorphan compound, a gabapentin compound, a compound comprising dextromethorphan and guaifenesin, a compound comprising a narcotic analgesic compound (e.g., an opioid, such as codeine or a hydro morphinone or hydrocodone), or a combination of such narcotic analgesic compound with another compound (e.g., acetaminophen and hydrocodone, or pholcodine and hydrocodone), and a compound that acts on the brain cough center, such as those comprising chlophedian.

[0175] In some embodiments of the treatment methods disclosed herein, the method comprises administering to a mammal in need thereof (S)-methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate, a non-deuterated compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the mammal one or more additional agents. In some embodiments of the treatment methods disclosed herein, (S)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination with an additional agent selected from one or more compounds or drugs used to treat or relieve symptoms of heartburn and / or acid regurgitation (also known as gastroesophageal reflux disease or GERD). In some embodiments, the compound or drug that relieves or treats GERD is selected from a histamine-H2 blocker (also known as a histamine H2 receptor antagonist), a proton pump inhibitor (PPI), a prokinetic agent, and an over-the-counter antacid. In some embodiments, the histamine-H2 blocker is selected from cimetidine (Tagamet®), famotidine (Pepcid AC®), and nizatidine (Axid AR®). In some embodiments, the proton pump inhibitor is selected from dexlansoprazole (Dexilant®), esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®, as well as the version containing sodium bicarbonate, Zegerid®), pantoprazole (Protonix® and Pantoloc®), and rabeprazole (Aciphex®). In some embodiments, the prokinetic agent is metoclopramide (Reglan®). In some embodiments, the over-the-counter (also known as non-prescription) drug is selected from a drug containing calcium carbonate, such as Mylanta®, Rolaids®, and Tums®.

[0176] In some embodiments of the treatment methods disclosed herein, (S)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate, or a pharmaceutically acceptable salt or solvate thereof, is used in combination with an additional agent selected from one or more compounds or drugs used to treat or alleviate cough or cough symptoms associated with a medical condition by suppressing the cough reflex. In some embodiments, (S)-methyl 2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3- yl)methyl)morpholine-4-carboxylate is used in combination with one or more compounds or drugs used for other physiological aspects associated with cough selected from expectorants, mucolytics, antitussives, bronchodilators, antihistamines, anti-inflammatory drugs, and other types of drugs, such as pregabalin. In some embodiments, the antitussive compound or drug is selected from a benzonatate compound, a dextromethorphan compound, a gabapentin compound, a compound comprising dextromethorphan and guaifenesin, a compound comprising a narcotic analgesic compound (e.g., an opioid, such as codeine or hydrocodone), or a combination of such narcotic analgesic compound with another compound (e.g., acetaminophen and hydrocodone, or pholcodine and hydrocodone), and a compound that acts on the brain cough center, such as those comprising chlophedianol.

[0177] Combination therapy also includes further administration of the therapeutic agents described above in 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 performed at any suitable time, so long as the beneficial effects of the combination of the therapeutic agents and the non-drug treatment are realized. For example, where appropriate, the beneficial effects can still be realized when the non-drug treatment is temporarily removed from the administration of the therapeutic agents, perhaps for days or even weeks.

[0178] The components of the combination are administered to the patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and thus are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, for example, conventional oral dosage forms that are administered simultaneously or sequentially. Examples

[0179] These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0180] List of Abbreviations

[0181] As used above and throughout the description of the application, the following abbreviations shall have the following meanings unless indicated otherwise:

[0182] ACN or MeCN acetonitrile

[0183] Bn benzyl

[0184] BOC or Boc tert-buty\ carbamate

[0185] CDI 1,1'-carbonyldiimidazole

[0186] Cy cyclohexyl

[0187] D deuterium

[0188] DCE dichloroethane (ClCH2CH2Cl)

[0189] DCM dichloromethane (CH2Cl2)

[0190] DIPEA or DIEA diisopropylethylamine

[0191] DMAP 4-(N,N-dimethylamino)pyridine

[0192] DMF dimethylformamide

[0193] DMAN, N-dimethylacetamide

[0194] DMSO dimethyl sulfoxide

[0195] equiv equivalent

[0196] Et ethyl

[0197] EtOH ethanol

[0198] EA or EtOAc ethyl acetate

[0199] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0200] HPLC high performance liquid chromatography

[0201] LAH lithium aluminum hydride

[0202] Me methyl

[0203] MeOH methanol

[0204] MS mass spectrometry

[0205] NMM N-methylmorpholine

[0206] NMR nuclear magnetic resonance

[0207] PMB p-methoxybenzyl

[0208] TEA triethylamine

[0209] TFA trifluoroacetic acid

[0210] THF tetrahydrofuran

[0211] TLC thin layer chromatography

[0212] I. Chemical synthesis

[0213] Reagents and solvents were used as received from commercial suppliers unless otherwise stated. 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 not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise stated. Spectra are expressed in ppm (δ) and coupling constants (J) in hertz. For proton spectra, the solvent peak was used as the reference peak.

[0214] Example 1: Synthesis of (S)-2-((2-(2,6-difluoro-4-((methyl-d3)carbamoyl)phenyl)-7- methylimidazo[l,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylic acid methyl-d3 ester (B1)

[0215]

[0216]

[0217] The hydroxymethyl group of A (106 kg, 487.9 mol) was oxidized to the corresponding aldehyde B at -3 °C to 1.5 °C by reaction with sodium bromide, sodium bicarbonate, catalyst TEMPO (2,2,6,6,-tetramethyl-l-piperidinyloxy, radical) and sodium hypochlorite (added dropwise while maintaining a temperature of -3 °C to 1.5 °C over approximately 10 hours) under biphasic conditions (dichloromethane-water). After stirring for a further 2 hours, the reaction was quenched with sodium thiosulfate at -5 °C to 0 °C and stirred for 30 minutes.

[0218] The biphasic system containing aldehyde B was treated with commercially available (ethoxycarbonylmethylidene)triphenylphosphonium at 5 °C to 10 °C in portions. After stirring for 1 hour at 8 °C to 15 °C, water was added, the mixture was stirred for 30 minutes, partitioned, 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 petroleum ether / THF mixture was added and the resulting mixture was stirred at 20 °C for 1 hour. 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" for the next step. The measured yield of C was 58.2 kg.

[0219] The THF solution of C is treated dropwise with 3M NaOH solution over 2 hours at 15°C to 25°C. The mixture is then warmed to 25°C to 35°C and stirred for 8 hours. The mixture is cooled to 20°C to 25°C, MTBE is added, and the layers are separated. The organic layer is extracted with water, and the combined aqueous layer containing the sodium salt of D is slowly acidified with 3N HC1 while maintaining the temperature below 15°C until the pH is 10-11. The aqueous mixture is then washed with dichloromethane to remove any residual triphenylphosphine oxide, and then slowly acidified with 3N HC1 while maintaining the temperature below 15°C until the pH is 5. The resulting mixture is extracted with dichloromethane, and the organic extract containing D is concentrated. THF is then added and evaporated. The crude product D is dissolved in THF and used directly in the next step.

[0220] The THF solution of D (assay 43.7 kg) is charged to a hydrogenation reactor. A THF slurry of Pd / C (2.90 kg) is added, and the resulting mixture is stirred under hydrogen (about 145 psi) at 25 o C to 49 o C is stirred for 12 hours. The mixture is filtered under nitrogen, the filter cake is washed with THF, and the filtrate is concentrated. Dichloromethane is added and concentrated to remove THF, which is repeated. Fresh dichloromethane is added to the mixture, and the resulting solution of E (assay 43.5 kg) is used directly in the next step.

[0221] The dichloromethane solution of E is stirred at 10 o C to 15 o C is treated with N-hydroxybenzotriazole (HOBT), N,O-dimethylhydroxylamine hydrochloride, and triethylamine. Then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) is added in portions. The mixture is stirred at 15°C to 25°C for 12 hours. Water is added, the resulting mixture is stirred for 12 hours, and then the layers are separated. The aqueous layer is separated and extracted with fresh dichloromethane. The combined organic layers are washed with sodium bicarbonate solution to remove HOBT and dried. The dichloromethane is concentrated, n-heptane is added, and the mixture is concentrated to remove the dichloromethane. Fresh n-heptane is added, and the mixture is stirred at 15°C for 10 hours. The solids are filtered and dried to give 38.6 kg of F.

[0222] A solution of tert-butyl 3,5-difluorobenzoate in THF was cooled to -65 °C under nitrogen and treated dropwise with 1.5 equivalents of LDA solution. The mixture was stirred at -60 to -65 °C for 1 hour, then treated dropwise with a solution of Compound F (37 kg) in THF. The reaction was stirred between -65 and -60 °C for 6 hours, then quenched at -65 °C with a solution of acetic acid in THF. The temperature was raised to -33 °C and the mixture was stirred for 30 minutes. Ethyl acetate was added and the mixture was diluted with brine. The layers were separated, the organic layer was washed with brine, then concentrated to give a solution of Compound G in ethyl acetate which was used directly in the next step.

[0223] HCl gas (60.4 kg) was passed into ethyl acetate (360 kg) at 6 to 0 °C. Compound G was added to the mixture over 2 hours at a temperature of 20 to 25 °C. The reaction was then stirred for 16 hours, filtered, the product was washed with ethyl acetate and MTBE, and dried under vacuum to give H.

[0224] Methanol was charged to a reactor at 26 °C and cooled to -7 °C. HCl was then passed into the methanol at -7 to 0 °C over 8 hours. Compound H (28.8 kg) was added at 2 °C and the mixture was heated to 40 to 50 °C and stirred for 6 hours. The reaction was then concentrated and the residual dichloromethane solvent was exchanged first to heptane (concentrated after addition of heptane) and then to THF (concentrated after addition of THF). The resulting solution of Compound I was used directly in the next step.

[0225] A solution of Compound I (~24.6 kg) in THF was diluted with water, the mixture was cooled to -5 to 0 °C and the pH was adjusted to 7-8 with a solution of sodium bicarbonate (2.5 equivalents of bicarbonate). A further 2 equivalents of sodium bicarbonate were added and methyl chloroformate (1.2 equivalents) was added dropwise over 1.5 hours and the reaction was stirred at -5 to 0 °C for 1.5 hours. Water, ethyl acetate and 2N HCl were added, the layers were separated and the organic layer was washed with brine, then concentrated. Ethyl acetate was added and evaporated to give a solution of J in ethyl acetate. Heptane (4 volumes) was added while stirring at 55 °C, the mixture was cooled to 10 °C and stirred for 6 hours. The product was filtered, washed with ethyl acetate:heptane (1:4) and dried to give J (20.6 kg).

[0226] The product was further purified by dissolving J (20.6 kg) in ethyl acetate at 28 °C and filtering through a pad of silica gel (25 kg). The filtrate was concentrated to about 50 L at 40 °C to 50 °C and 50 kg of ethyl acetate:heptane (1 :3) was added at 55 °C. After stirring for 1 hour, the mixture was cooled to 10 °C and stirring was continued for 6 hours. The product was filtered, washed with ethyl acetate:heptane (1 :3) and dried to give J (18.5 kg).

[0227] 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 5 °C. Di-tert-butyl dicarbonate (124 kg, 1.2 equivalents) was added portionwise over 3 hours and the mixture was stirred at 20 °C to 25 °C for 12 hours. The mixture was diluted with methyl tert-butyl ether (MTBE) and water and stirred for 30 minutes. The organic layer was cooled to 0 °C, acidified with 1.5 M HC1 (470 kg) and the mixture was stirred for 30 minutes. The organic layer was then washed with brine, concentrated to about 150 L, then THF (90 kg) was added and the mixture was concentrated. This procedure was repeated (90 kg THF was added and evaporated) and the resulting THF solution of tert-butyl 3,5-difluorobenzoate was used directly in Step 6 (above) to prepare compound G.

[0228] Ethyl acetate was added to the reactor and degassed. Compound J (80 g) was added, followed by CuBr2(101 g). The resulting mixture was stirred at 65 o C to 75 o C for 15 to 24 hours, and if the reaction was not complete as shown by HPLC, treated with additional CuBr2. The reaction was stirred at 65 o C to 75 o C for an additional 3 to 5 hours, cooled to 20 o C to 30 o C, then 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 layer was washed with 5% EDTA disodium salt solution to remove copper residues, then with 1% sodium bicarbonate solution, then with water to give compound K which was used directly ("as is") in the next step.

[0229] The ethyl acetate solution described above was exchanged with acetonitrile to give a solution of K (100 g) in acetonitrile. 2-Amino-4-methylpyridine (72.06 g) was added to the solution, which was then stirred at 75 °C to 85 °C under nitrogen for 30 to 40 hours. The mixture was concentrated to 1-2 volumes at less than 40 °C and diluted with dichloromethane. Water was added, the mixture was cooled to 0 °C to 10 °C, and acidified to pH 4-5 with 2N HCl. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were washed with water (0 °C to 10 °C), 7% sodium bicarbonate solution (0 °C to 10 °C), and water. The organic layer was treated with silica gel, and the mixture was concentrated to dryness at less than 35 °C. The residue was transferred to a silica gel pad, which was eluted with dichloromethane-ethyl acetate (1V / 9V), and fractions containing compound L were concentrated and diluted with THF. This was repeated until the residual amount of ethyl acetate was less than 0.5% by GC. < 1%.

[0230] The THF solution of L was cooled to 15 °C to 25 °C and treated with 10% LiOH solution, and the mixture was stirred for 2 hours to 5 hours. NaBH4 (2.11 g) was then added to the mixture in portions at 15 °C to 25 °C, and the reaction was stirred for 2 hours to 4 hours. Water was added dropwise at 0 °C to 10 °C, 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 0 °C to 10 °C, treated with dichloromethane-methanol (~6-1), and the pH was adjusted to 4-5 with 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 to 1-2V at less than 35 °C, and ethanol (2-3V) 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 70 °C to 85 °C for 10 to 30 minutes. The mixture was cooled, and stirred at -15 °C to 5 °C for 2 to 8 hours. The mixture was filtered to give compound M, which was washed with ethyl acetate. Compound M was slurried in ethyl acetate and stirred at -15 °C to 5 °C for 1 to 3 hours. The mixture was filtered, and compound M was washed with additional ethyl acetate and dried.

[0231] Trideuterated methylamine (460 mg, 6.52 mmol, 3.00 equivalent, HCl) and DIPEA (1.12 g, 8.69 mmol, 1.51 mL, 4.00 equivalent) were added to a DCM (10.0 mL) solution of compound M (1.00 g, 2.17 mmol, 1.00 equivalent). T3P (2.77 g, 4.35 mmol, 2.59 mL, 50% purity, 2.00 equivalent) was added at 0 °C, and the mixture was then heated to 25 °C and maintained for 12 hours. The mixture was poured into water (10.0 mL), and the pH was adjusted to 7 with NaHCO3. The aqueous phase was separated and washed with DCM (10.0 mL × 2). The combined organic phases were washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product N was used in the next step without further purification.

[0232] Compound N (1.18 g, 2.48 mmol, 1.00 equivalent) was heated at 25°C. o C was added to HBr / CH3COOH (2.48 mmol, 6.00 mL), and then at 70 °C... o The mixture was stirred for 18 hours. Excess HBr and AcOH were removed under vacuum. MeOH (5.00 mL) was added to the residue and removed under vacuum to obtain a brown solid. The crude product O was used directly for the next step.

[0233] Compound Q (541 mg) was added to a solution of compound O (1.54 g) and Et3N (1.07 g) in DCM (10 mL). The mixture was heated to 25 °C. o Stirred at C for 12 h. Pour the mixture into ice water (10.0 mL), separate the aqueous phase, and wash with DCM (15.0 mL × 2). Dry the combined organic phases with Na₂SO₄, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue by prep-HPLC to provide compound B1 (1.03 g, 84% yield) as a white solid. LCMS (ESI, m / z): 465.2 [M+H] + . 1 H 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).

[0234] methyl-d3 chloroformate (compound q)

[0235] at 0 o C To a mixture of compound P (2.96 g) in THF (10 mL) was added a solution of trideuterated (deuteratedoxy)methane (1.08 g) and Et3N (3.33 g) in THF (5 mL) under N2. The mixture was stirred at 0 o C for 1 hr, then at 25 o C for 1 hr. The reaction mixture was filtered and washed with THF three times. The crude product was used directly for the next step without further purification.

[0236] Example 2: Synthesis of (S)-methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-7-(methyl-d3)imidazo[l,2-a]pyridin-3- yl)methyl)dihydropyrrol- 1 -yl)methyl)carbamic acid methyl ester (B2)

[0237]

[0238] Compound B2 can be prepared by cyclizing compounds R, S and T together to form the imidazopyridine core of the molecule. After replacing the Boc protecting group on the morpholine fragment with a Moc group, the corresponding methyl ester intermediate W can be further converted to the corresponding carboxamide Y. Then, the chloro function on intermediate Y can be converted to the corresponding boronic acid Z (for example, according to Molander et al., J. Am. Chem. Soc, 2010, pp. 17701-17703), which is then used to install the desired CD3 moiety on compound B2 (for example, according to Pretze et al., Molecules, 2011, pp. 1129-1165). The preparation of compounds S and T is described in WO 2014 / 117274, which is incorporated herein by reference.

[0239] Example 3: Synthesis of (S)-methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3- yl)methyl-d2)dihydropyrrol- 1 -yl)methyl)carbamic acid methyl ester (B3)

[0240]

[0241] Compound B3 can be prepared from alcohol 3-A, which can be oxidized to carboxylic acid 3-B. Reduction of carboxylic acid 3-B with commercially available LiAlD4 introduces two deuterium atoms of compound 3-C. Compound 3-C can be converted to bromide 3-D and left for further processing. Difluoro aryl ester 3-E can be deprotonated with base and trapped with DMAc to generate acetophenone 3-F. Compound 3-F can be brominated to give bromoketone 3-G. The combination of bromoketone 3-G with aminopyridine generates the imidazopyridine ring to give compound 3-H. Under metal-promoted conditions, imidazopyridine 3-H can be functionalized with bromide 3-D under UV light to give 3-I (e.g., according to Ma et al., New J. Chem., 2021, pp. 9302-9314). Compound 3-I can be subjected to global deprotection to give amine 3-J. A methyl carbamate can be introduced on 3-J to give carboxylic acid 3-K, and finally upon exposure to methylamine and a coupling agent to give compound B3.

[0242] Example 4: Synthesis of (S)-methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate-5,5,6,6-d4 (B4)

[0243]

[0244] Compound B4 can be prepared from commercially available ethanolamine-d4 (B4-A). Compound B4-A undergoes a reductive amination reaction with benzaldehyde to generate secondary amine B4-B. Amine B4-B can react with commercially available epoxide B4-C in an enantioselective manner to generate diol B4-D. Morpholine 45-E can be obtained by activating the primary alcohol of diol B4-D in the presence of MsCl and a base. Global deprotection of the benzyl protecting group of morpholine B4-E is performed in the presence of hydrogen atmosphere and Pd / C to generate compound B4-F. The secondary amine of compound B4-F is reproteced with Boc2O to generate primary alcohol B5-G. Compound B4-G is oxidized to aldehyde B4-H, which is then formed into an alkyne to generate terminal alkyne B4-I. A three-component coupling of compound B4-I, B4-J, and 4-methylpyridin-2-amine is performed in the presence of a copper catalyst to generate heterocyclic compound B4-K. Removal of the Boc protecting group of B4-K with TFA gives secondary amine B4-L. Compound B4-L is functionalized with methyl chloroformate to give compound B4.

[0245] Example 5: Synthesis of methyl 2-((2-(2,6-difluoro-4- (methylcarbamoyl)phenyl)-7-methylimidazo[l,2-a]pyridin-3-yl)methyl)morpholine-4- carboxylate-2,3,3,5,5,6,6-d7 (B5)

[0246]

[0247] Compound B5 can be prepared by copper-mediated coupling of compound B5-A, B4-B and 4-methylpyridin-2-amine to give imidazopyridine B5-C. Removal of the Boc protecting group of B5-C with TFA gives secondary amine B5-D. Compound B5-D is then functionalized with methyl chloroformate to give compound B5.

[0248] Example 6: P2X3 antagonist testing

[0249] HEK293 cells can be cultured in Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (D-MEM / F-12) supplemented with 10% fetal bovine serum, 100 U / mL penicillin G sodium, 100 J.Lg / mL streptomycin sulfate, and the appropriate selective antibiotic.

[0250] Each test article was evaluated for its effect as an antagonist as follows. Each test article was 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 per concentration. The experiment used the FLIPR Calcium Ratiometric Assay Kit (Fluo-8 AM dye, AAT, Bioquest) according to the manufacturer's instructions. ®

[0251] - Dye loading: Remove growth media and add 20 μL of 1 x Fluo®-8 AM dye in Mg ++ HBPS was added to the cell culture plate for 30 minutes at 37 °C.

[0252] - Pre-incubation (FLIPR Step 1): Cells were pre-incubated with test or control samples for 20 minutes at room temperature in the dark.

[0253] - Agonist stimulation (FLIPR Step 2): After pre-incubation, cells were stimulated with a final concentration of 3 μM a,b-meATP. After approximately 5 minutes of a,b-meATP stimulation, ionomycin was added to a final concentration of 5 μM to obtain the maximum possible calcium influx and fluorescent signal in the cells. Fluorescence was recorded continuously for 10 minutes starting 10 seconds before a,b-meATP stimulation.​

[0254] - Positive control antagonist: PPADS (1 mM)

[0255] Data acquisition was performed by the FLIPR Control software provided by the FLIPR system (MDS-AT) and data were analyzed using GraphPad Prism 6 (GraphPad Software, Boston, MA, USA). In GraphPad Prism 6, curves were fitted from the normalized fluorescence data using the better fit in a 4-parameter curve (variable slope). No constraints were set for the curve fitting. ® 6 (GraphPad Software, Boston, MA, USA). In GraphPad Prism 6, curves were fitted from the normalized fluorescence data using the better fit in a 4-parameter curve (variable slope). No constraints were set for the curve fitting.

[0256] Example 7: In vitro metabolic stability assay: determination of the in vitro metabolic stability of microparticles (including calculation of the in vivo blood clearance from the liver (CL))

[0257] The in vitro metabolic stability assay of the test compound was performed as follows: 1 mM of the compound was incubated in suspended liver microsomes in 100 mM phosphate buffer at pH 7.4 and at a protein concentration of 0.5 mg / mL at 37°C. The metabolic stability assay was initiated by the addition of an NADPH regenerating system in the phosphate buffer at pH 7.4. Incubations without the NADPH regenerating system were also performed to assess non-mediated NADPH metabolism.

[0258] During the incubation, the microsomal suspension was constantly stirred and aliquots were taken at 5, 10, 15, 20, 30, 45, 60 and 90 minutes, to which 3 volumes of cold acetonitrile containing internal standards (100 ng / mL tolbutamide and 100 ng / mL labetalol) were immediately added to stop the reaction. The samples were centrifuged at 4000 rpm for 20 minutes at 4°C. The supernatants were analyzed by LCMS / MS detection. The percentage of remaining parent was calculated using the T=0 minute incubation. The half-life (T 1 / 2 ) and Cl int(mic) :

[0259]

Claims

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof: ###0001### Formula (I); wherein: R1 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R2 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R3 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R4 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R5 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R6 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R7 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R8 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R9 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R10 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R11 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R12 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R13 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R14 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R15 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R16 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R17 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R18 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R19 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R20 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R21 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R22 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R23 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R24 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R25 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R26 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R27 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R28 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R29 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R30 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R31 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R32 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R33 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R34 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R35 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R36 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R37 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R38 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R39 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R40 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R41 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R42 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R43 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R44 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R45 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R46 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R47 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R48 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R49 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R50 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R51 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R52 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R53 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R54 is H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroalkyl; R55 is H, alkyl, haloalkyl, cycloalkyl, heter ​ ​ R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , R 15 , R 16 , R 17 and R 18 are independently selected from hydrogen and deuterium; Each R 3 Independently selected from hydrogen and deuterium; Each R 8 Independently selected from hydrogen and deuterium; and Each R 14 Independently selected from hydrogen and deuterium; wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 are at least one deuterium. ​ ​ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 is hydrogen.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are hydrogen.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 is deuterium.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 are deuterium.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 and R 10 are hydrogen.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9 and R 10 are deuterium.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 is hydrogen.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are hydrogen.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one of R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 is deuterium.

12. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , and R 18 are deuterium.

13. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 11 , R 12 , and R 13 are hydrogen and R 15 , R 16 , R 17 , and R 18 are deuterium.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 3 is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is hydrogen.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 3 is deuterium.

17. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is deuterium.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 8 is hydrogen.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is hydrogen.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 8 is deuterium.

21. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 8 is deuterium.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 14 is hydrogen.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14 is hydrogen.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R 14 is deuterium.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14 is deuterium. ​ ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , ， ， ， ， ， , , and ; or a pharmaceutically acceptable salt or solvate thereof. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 38. The method of claim 36 or 37, wherein the cough is associated with a disease, disorder, or condition selected from the group consisting of chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, pyogenic lung disease, respiratory tract malignancy, anaphylaxis, cystic fibrosis, pulmonary fibrosis, respiratory tract inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory tract infection, bronchial constriction, sarcoidosis, viral or bacterial infection of the upper respiratory tract, angiotensin-converting enzyme (ACE) inhibitor therapy, smoker’s cough, chronic nonproductive cough, neoplastic cough, cough due to gastroesophageal reflux, and cough due to inhalation of irritants, smoke, smog, dust, or air pollutants.

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 for 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 the group consisting of 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 administering a second therapeutic agent.

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

48. The method of claim 47, wherein the NK-1 antagonist is selected from the group consisting of serlopitant, aprepitant, casopitant, damoterpant, ezlopitant, fosapitant, lanepitant, maropitant, netupitant, nolpitant, orvepitant, rolapitant, vetibixant, voxilaptoant, 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 the group consisting of 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 prostaglandin class 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 drugs used to treat or alleviate heartburn and / or symptoms of acid reflux.

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

52. The method of claim 46, wherein the second therapeutic agent is selected from one or more compounds or drugs used to treat or alleviate a cough or symptoms of a cough associated with a medical condition by inhibiting a cough reflex or other physiological aspect associated with a cough.

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