Compositions and methods for treating chronic cough

Abstract

Provided herein are compounds, including ifenprodil, and pharmaceutical compositions for use in treating refractory chronic cough. The compounds and pharmaceutical compositions may also be suitable for treating refractory chronic cough in subjects also diagnosed with idiopathic pulmonary fibrosis.

Description

WSGR Docket No. 68117-704.601 COMPOSITIONS AND METHODS FOR TREATING CHRONIC COUGH CROSS-REFRENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 657,222, filedJune 7, 2024, U.S. Provisional Application No. 63 / 671,991, filed July 16, 2024, and U.S. Provisional Application No. 63 / 708,699, filed October 17, 2024, each of which is incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION

[0002] Refractory chronic cough (RCC) impacts 4-6 million individuals per year in the UnitedStates. Several drug candidates, including non-selective N-methyl-D-aspartate (NMDA) antagonists (e.g., memantine), have been evaluated in preclinical models and clinical trials, but have been dose-limited by adverse effects. Further, chronic cough in certain patient populations, such as those with idiopathic pulmonary fibrosis (IPF), are particularly resistant to treatment. New therapies for treatment of RCC, such as RCC in subjects with idiopathic pulmonary fibrosis (IPF), that are efficacious and avoid adverse effects are needed. SUMMARY OF THE INVENTION

[0003] RCC may include a cough that lasts eight weeks or longer in adults, or four weeks or longerin children, and in some instances is resistant to current treatments for cough or underlying conditions. RCC has the ability to interrupt sleep, cause exhaustion, and in severe cases can cause vomiting, light-headedness, and rib fractures. Provided herein are compounds and pharmaceutical compositions for use in treating RCC in subjects in need thereof. In some embodiments, the compound includes ifenprodil, which is a highly selective GluN2B inhibitor. GluN2B is a subunit of the N-methyl-D-aspartate (NMDA) receptor. The high selectivity of the compounds provided herein for GluN2B may provide enhanced therapeutic effect in absence of side effects of other non-selective clinical / pre-clinical treatments which result in off-target-associated adverse effects or adverse events resulting from generally blocking the NMDA receptor. In some instances, provided herein are methods of treating RCC in subjects with an underlying diagnosis of idiopathic pulmonary fibrosis, for which the RCC is known in the art to be difficult to treat. The compounds and pharmaceutical compositions provided herein may be effective in treating such RCC. As such, the compounds provided herein may be effective in decreasing frequency of cough and increasing quality of life in subjects with RCC (and IPF). -1-WSGR Docket No. 68117-704.601

[0004] Provided herein, in some embodiments, is a method of treating refractory chronic cough ina subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising a selective N-methyl D-aspartate (NMDA) receptor inhibitor.

[0005] In some embodiments, the selective NMDA receptor inhibitor is specific for a GluN2Bsubunit.

[0006] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitor is acompound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X1is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cyclyl, or substituted or unsubstituted heterocyclyl; Y1is a substituted or unsubstituted straight chain or branched alkyl; Z1is CR’R’’, NR’, or OR’; each R1is independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; R' and R’’ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; n is an integer from 0 to 3; and m is an integer from 0 to 6.

[0007] In some embodiments, X1 is substituted or unsubstituted aryl.

[0008] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitor is acompound of Formula (II): -2-WSGR Docket No. 68117-704.601Formula (II) or a pharmaceutically acceptable salt thereof, wherein, each R2is independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; or two R2are taken together with the atoms from which they are attached to form substituted or unsubstituted aryl, substituted or unsubstituted cyclyl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl; and p is an integer from 0 to 5.

[0009] In some embodiments, Y1 is substituted or unsubstituted alkyl.

[0010] In some embodiments, R’ and R’’, when present, are each independently selected fromhydrogen or alkyl substituted with substituted or unsubstituted aryl.

[0011] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitor is acompound of Formula (III):Formula (III) wherein, R3is hydrogen, halogen, or substituted or unsubstituted alkyl; R4is hydroxyl or hydrogen; R5is hydrogen; or R4and R5are taken together to form oxo; and R6is hydrogen or substituted or unsubstituted alkyl.

[0012] In some embodiments, R4 and R5 are taken together to form oxo.

[0013] In some embodiments, R6 is alkyl.-3-WSGR Docket No. 68117-704.601

[0014] In some embodiments, Z1 is CR’R’’ or NR’.

[0015] In some embodiments, each R2, when present, is independently selected from the groupconsisting of hydrogen, halo, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl.

[0016] In some embodiments, R6 is unsubstituted alkyl.

[0017] In some embodiments, p is an integer from 0 to 3.

[0018] In some embodiments, n is 1 or 2.

[0019] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitor isselected from the compounds in Table 1.

[0020] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitor isselected from the group consisting of: ifenprodil, radiprodil, and pharmaceutically acceptable salts thereof.

[0021] In specific embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitor isifenprodil or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the ifenprodil or a pharmaceutically acceptable salt thereof isifenprodil hemitartrate, ifenprodil oleate, ifenprodil nicotinate, ifenprodil pamoate, ifenprodil fumarate, ifenprodil benzoate, or any combination thereof.

[0023] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitorselectively reduces high frequency neuronal firing as measured by blockade of the NMDA pathway.

[0024] In some embodiments, the selective N-methyl D-aspartate (NMDA) receptor inhibitorselectively reduces sustained neuronal firing (e.g., as measured by blockade of the NMDA pathway).

[0025] In some embodiments, the subject has been diagnosed with a disease associated with cough,has been treated for the disease associated with cough, or both.

[0026] In some embodiments, the subject is resistant to a treatment that the subject has receivedfor the disease.

[0027] In some embodiments, the disease comprises idiopathic pulmonary fibrosis, asthma,chronic obstructive pulmonary disease, sarcoidosis, bronchiectasis, non-asthmatic eosinophilic bronchitis, gastroesophageal reflux disease (GERD), laryngeal dysfunction, or pneumonia.

[0028] In some embodiments, the disease comprises an interstitial lung disease.

[0029] In some embodiments, the disease comprises idiopathic pulmonary fibrosis.-4-WSGR Docket No. 68117-704.601

[0030] In some embodiments, the treatment comprises inhalable corticosteroids, proton pumpinhibitors, GABAB agonists, antihistamines, decongestants, antibiotics, opiates, gabapentinoids, tricyclic antidepressants, or any combination thereof.

[0031] In some embodiments, the treatment comprises dextromethorphan, codeine, morphine,hydrocodone, codeine, benzonatate, guaifenesin, hydromorphone, promethazine, chlorpheniramine, diphenhydramine, or any combination thereof.

[0032] In some embodiments, the subject is an adult human subject, and wherein the refractorychronic cough in the subject has lasted eight weeks or longer.

[0033] In some embodiments, the subject is a child human subject, and wherein the refractorychronic cough in the subject has lasted four weeks or longer.

[0034] In some embodiments, administration of the pharmaceutical composition reduces meancough count in the subject over a given time period by at least about 30%, at least about 35%, at least about 38%, or at least about 40%.

[0035] In some embodiments, administration of the pharmaceutical composition reduces meancough count in the subject over a given time period by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

[0036] In some embodiments, the given time period is 5 minutes, 15 minutes, 30 minutes, 1 hour,2 hours, 3 hours, 4 hours, 6 hours, 12 hours, 24 hours, or 72 hours. In some embodiments, the given time period is 24 hours.

[0037] In some embodiments, administration of the pharmaceutical composition increases averagetime to cough onset in the subject by at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%. In some embodiments, administration of the pharmaceutical composition increases average time to cough onset in the subject by at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0038] In some embodiments, administration of the pharmaceutical composition improves averagevisual analog score (VAS) by at least about 25%, at least about 30%, at least about 32%, at least about 35%, at least about 37%, at least about 38%, or at least about 40% as measured in a group of human subjects that suffer from refractory chronic cough. In some embodiments, administration of the pharmaceutical composition improves average visual analog score (VAS) by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99% as measured in a group of human subjects that suffer from refractory chronic cough.

[0039] In some embodiments, the treating comprises an improvement in Global Rating of ChangeScale for at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of subjects after 12 weeks of administration with the pharmaceutical composition. -5-WSGR Docket No. 68117-704.601

[0040] In some embodiments, the treating comprises improvements in Leicester CoughQuestionnaire (LCQ) of at least 1 point, at least 1.25 points, or at least 1.5 points after 12 weeks of administration with the pharmaceutical composition. In some embodiments, the treating comprises improvements in Leicester Cough Questionnaire (LCQ) of at least 2 points, at least 5 points, at least 10 points, or at least 15 points.

[0041] In some embodiments, administration of the pharmaceutical composition reduces ageometric mean awake cough count by at least about 30%.

[0042] In some embodiments, administration of the pharmaceutical composition reduces afrequency of 2-second cough bouts by at least about 30%. In some embodiments, administration of the pharmaceutical composition reduces a frequency of 3-second cough bouts by at least about 30%. In some embodiments, administration of the pharmaceutical composition reduces a frequency of single breath clusters by at least about 35%.

[0043] In some embodiments, the pharmaceutical composition comprises 20 mg to about 960 mgof the selective NMDA receptor inhibitor. In some embodiments, the pharmaceutical composition comprises 20 mg or 40 mg of the selective NMDA receptor inhibitor.

[0044] In some embodiments, the selective NMDA receptor inhibitor is administered to the subjectin an amount of at least 20 mg, at least 40 mg, at least 60 mg, or at least 100 mg. In some embodiments, the selective NMDA receptor inhibitor is administered to the subject in an amount of about 20 mg, about 40 mg, about 60 mg, or about 100 mg.

[0045] In some embodiments, the selective NMDA receptor inhibitor is administered in an amountof at least 0.3 mg / kg, at least 0.7 mg / kg, at least 1 mg / kg, or at least 1.2 mg / kg. In some embodiments, the selective NMDA receptor inhibitor is administered in an amount of about 0.3 mg / kg, about 0.7 mg / kg, about 1 mg / kg, or about 1.2 mg / kg.

[0046] In some embodiments, a total daily dose of the selective NMDA receptor inhibitor is atleast 60 mg, at least 120 mg, at least 180 mg, at least 200 mg, or at least 400 mg. In some embodiments, a total daily dose of the selective NMDA receptor inhibitor is about 60 mg, about 120 mg, about 180 mg, about 200 mg, or about 400 mg.

[0047] In some embodiments, a total daily dose of the selective NMDA receptor inhibitor is atleast 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 3.3 mg / kg, or at least 6.6 mg / kg. In some embodiments, a total daily dose of the selective NMDA receptor inhibitor is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 3.3 mg / kg, or about 6.6 mg / kg.

[0048] In some embodiments, the method further comprises administering to the subject one ormore additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is a P2X3 receptor antagonist. In some embodiments, the one or more additional therapeutic -6-WSGR Docket No. 68117-704.601 agents are selected from camlipixant, Haduvio (nalbuphine ER), taplucainium, AX-8, and gefapixant.

[0049] In some embodiments, the method comprises administering the pharmaceuticalcomposition to the subject daily. In some embodiments, the method comprises administering the pharmaceutical composition to the subject once, twice, three times, four times, or five times daily. In some embodiments, the method comprises administering the pharmaceutical composition to the subject three times daily.

[0050] In some embodiments, the pharmaceutical composition is administered to the subjectorally, intravenously, intranasally, intrathecally, intradermally, subcutaneously, intracerebroventricularly, intraperitoneally, intramuscularly, intravitreally, intracranially, intrabuccally, rectally, or sublingually.

[0051] In some embodiments, the pharmaceutical composition is administered to the subjectorally. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The novel features of the invention are set forth with particularity in the appended claims.A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0053] FIG. 1 shows mean cough count in guinea pigs exposed to 1M citric acid after oraladministration of a compound provided herein, a placebo, and gefapixant.

[0054] FIG. 2 shows time to cough onset in guinea pigs exposed to 1M citric acid after oraladministration of a compound provided herein, a placebo, and gefapixant.

[0055] FIG. 3 shows geometric mean cough count reduction in subjects administered a compoundprovided herein.

[0056] FIG. 4A shows an integrated responder analysis showing reductions in 24 hr coughfrequency after administration of a compound provided herein, as compared to a historical placebo control groups.

[0057] FIG. 4B shows an integrated responder analysis showing reductions in 24 hr coughfrequency after administration of a compound provided herein, as compared to various historical placebo control groups.

[0058] FIG. 5 shows cough visual analog scores (VAS) at baseline and week 12 of treatment witha compound provided herein. -7-WSGR Docket No. 68117-704.601

[0059] FIG. 6A shows Global Rating of Change scale for subjects administered a compoundprovided herein (p-value for proportion of subjects with “better” outcomes (z-test)).

[0060] FIG. 6B shows Patient Global Impression of Change of cough severity in subjectsadministered with a compound provided herein (p-value for proportion of subjects with “better” outcomes (z-test)).

[0061] FIG. 7 shows quality of life comparisons at baseline and week 12 of administration with acompound provided herein using the Leicester Cough Questionnaire.

[0062] FIG. 8A shows cumulative coughs in guinea pigs administered placebo, and 10 or 30mg / kg of a compound intraperitoneally provided herein.

[0063] FIG. 8B shows cumulative coughs in guinea pigs administered placebo, and 1, 3, 10, or 30mg / kg of a compound intraperitoneally provided herein.

[0064] FIG. 8C shows cough bouts in guinea pigs administered placebo, and 1, 3, 10, or 30 mg / kgof a compound intraperitoneally provided herein.

[0065] FIG. 8D shows estimated effect of dose escalation on cough count reduction in guinea pigs(based on daily exposure).

[0066] FIG. 8E shows estimated effect of dose escalation on cough count reduction in guinea pigs(single dose comparison).

[0067] FIG. 9 shows respiratory rate (breaths per minute) in guinea pigs after administration of aplacebo or 1, 3, 10, or 30 mg / kg of a compound intraperitoneally provided herein.

[0068] FIG. 10A shows assessment of a population of subjects who may have refractory chroniccough.

[0069] FIG. 10B shows possible exclusion criteria for assessment of subjects with refractorychronic cough.

[0070] FIG. 11A shows 24 hour cough count in subjects administered with a compound providedherein (p-value and percent reduction based on geometric mean ratio vs. baseline (log transform ANOVA model), box plot is median, IQR, minimum, and maximum).

[0071] FIG. 11B shows 24 hour cough count (LN transformed) in subjects administered with acompound provided herein (p-value and percent reduction based on geometric mean ratio vs. baseline (log transform ANOVA model), box plot is median, IQR, minimum, and maximum).

[0072] FIG. 11C shows 24 hour cough count in subjects administered with a compound providedherein at baseline, week 4, and week 12 of administration with the compound.

[0073] FIG. 11D shows 24 hour cough change vs Patient Global Impression of Change (PGIC)cough frequency (worse, no change, better). -8-WSGR Docket No. 68117-704.601

[0074] FIG. 11E shows 24 hour cough change vs Patient Global Impression of Change (PGIC)cough severity (worse, no change, better).

[0075] FIG. 12A shows awake hour cough count in subjects administered with a compoundprovided herein (p-value and percent reduction based on geometric mean ratio vs. baseline (log transform ANOVA model), box plot is median, IQR, minimum, and maximum).

[0076] FIG. 12B shows awake hour cough count (LN transformed) in subjects administered witha compound provided herein (p-value and percent reduction based on geometric mean ratio vs. baseline (log transform ANOVA model), box plot is median, IQR, minimum, and maximum).

[0077] FIG. 12C shows awake cough count in subjects administered with a compound providedherein at baseline, week 4, and week 12 of administration with the compound.

[0078] FIG. 12D shows 24 hour cough change vs Patient Global Impression of Change (PGIC)cough frequency (worse, no change, better).

[0079] FIG. 12E shows 24 hour cough change vs Patient Global Impression of Change (PGIC)cough severity (worse, no change, better).

[0080] FIG. 13A shows cough count in subjects administered a compound provided herein atbaseline, after 4 weeks of administration with the compound, and after 12 weeks of administration with the compound.

[0081] FIG. 13B shows 2 second cough bout count in subjects administered a compound providedherein at baseline, after 4 weeks of administration with the compound, and after 12 weeks of administration with the compound.

[0082] FIG. 13C shows 3 second cough bout count in subjects administered a compound providedherein at baseline, after 4 weeks of administration with the compound, and after 12 weeks of administration with the compound.

[0083] FIG. 13D shows single breath cluster cough count (e.g., series of coughs (2+) within asingle inspiratory period) in subjects administered a compound provided herein at baseline, after 4 weeks of administration with the compound, and after 12 weeks of administration with the compound.

[0084] FIG. 13E shows percentage change in cough count, 2-second cough bouts, and 3-secondcough bouts after administration with a compound provided herein, compared to placebo.

[0085] FIG.14 shows a responder analysis for subjects administered a compound provided herein.DETAILED DESCRIPTION OF THE INVENTION Certain Definitions -9-WSGR Docket No. 68117-704.601

[0086] As used herein and in the appended claims, the singular forms "a," "and," and "the" includeplural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or "consist essentially of" the described features.

[0087] The terms “treat,” “treating,” or “treatment” as used herein, include reducing, alleviating,abating, ameliorating, managing, relieving, or lessening the symptoms associated with a disease, disease state, condition, or indication (e.g., provided herein) in either a chronic or acute therapeutic scenario. Also, treatment of a disease or disease state described herein includes the disclosure of use of such compound or composition for the treatment of such disease, disease state, disorder, or indication.

[0088] “Amino” refers to the –NH2 radical.

[0089] “Cyano” refers to the -CN radical.

[0090] “Nitro” refers to the -NO2 radical.

[0091] “Oxo” refers to the =O radical.

[0092] “Hydroxyl” refers to the -OH radical.

[0093] “Alkyl” generally refers to an acyclic (e.g., straight or branched) or cyclic hydrocarbon(e.g., chain) radical consisting solely of carbon and hydrogen atoms, such as having from one to fifteen carbon atoms (e.g., C1-C15alkyl). Unless otherwise state, alkyl is saturated or unsaturated (e.g., an alkenyl, which comprises at least one carbon-carbon double bond). Disclosures provided herein of an “alkyl” are intended to include independent recitations of a saturated “alkyl,” unless otherwise stated. Alkyl groups described herein are generally monovalent, but may also be divalent (which may also be described herein as “alkylene” or “alkylenyl” groups). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl -10-WSGR Docket No. 68117-704.601 comprises one to five carbon atoms (e.g., C1-C5alkyl). In specific embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. In general, alkyl groups are each independently substituted or unsubstituted. Each recitation of “alkyl” provided herein, unless otherwise stated, includes a specific and explicit recitation of an unsaturated “alkyl” group. Similarly, unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, - C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0094] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula –O-alkyl,where alkyl is an alkyl chain as defined above.

[0095] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solelyof 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 -11-WSGR Docket No. 68117-704.601 carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is optionally substituted as described for “alkyl” groups.

[0096] “Alkylene” or “alkylene chain” generally refers to a straight or branched divalent alkylgroup linking the rest of the molecule to a radical group, such as having from one to twelve carbonatoms, for example, methylene, ethylene, propylene, i-propylene, n-butylene, and the like. Unlessstated otherwise specifically in the specification, an alkylene chain is optionally substituted as described for alkyl groups herein.

[0097] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbonring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) –electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(RaRa)2, -Rb-N(Ra)C(O)ORa, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or -12-WSGR Docket No. 68117-704.601 alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0098] “Aralkyl” or “aryl-alkyl” refers to a radical of the formula -Rc-aryl where Rc is an alkylenechain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0099] “Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl or cycloalkyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). Examples of saturated cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “carbocyclyl” is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb- OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, - Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl -13-WSGR Docket No. 68117-704.601 (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0100] “Carbocyclylalkyl” refers to a radical of the formula –Rc-carbocyclyl where Rc is analkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0101] “Carbocyclylalkenyl” refers to a radical of the formula –Rc-carbocyclyl where Rc is analkenylene chain as defined above. The alkenylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0102] “Carbocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0103] “Halo" or “halogen” refers to fluoro, bromo, chloro, or iodo substituents.

[0104] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or morehalogen radicals, as defined above, for example, trihalomethyl, dihalomethyl, halomethyl, and thelike. In some embodiments, the haloalkyl is a fluoroalkyl, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0105] The term “heteroalkyl” refers to an alkyl group as defined above in which one or moreskeletal carbon atoms of the alkyl are substituted with a heteroatom (with the appropriate number of substituents or valencies – for example, -CH2- may be replaced with -NH- or -O-). For example, each substituted carbon atom is independently substituted with a heteroatom, such as wherein the carbon is substituted with a nitrogen, oxygen, sulfur, or other suitable heteroatom. In some instances, each substituted carbon atom is independently substituted for an oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, or -N(aryl)- or having another substituent contemplated herein), or sulfur (e.g. - S-, -S(=O)-, or -S(=O)2-). In some embodiments, a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In some embodiments, a heteroalkyl is attached to the rest of the molecule at a heteroatom of the heteroalkyl. In some embodiments, a heteroalkyl is a C1-C18heteroalkyl. In some embodiments, a heteroalkyl is a C1-C12heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, a heteroalkyl is a C1-C4-14-WSGR Docket No. 68117-704.601 heteroalkyl. In some embodiments, heteroalkyl includes alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, heterocyclyl, and heterocycloalkylalkyl, as defined herein. Unless stated otherwise specifically in the specification, heteroalkyl does not include alkoxy as defined herein. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted as defined above for an alkyl group.

[0106] “Heteroalkylene” refers to a divalent heteroalkyl group defined above which links one partof the molecule to another part of the molecule. Unless stated specifically otherwise, a heteroalkylene is optionally substituted, as defined above for an alkyl group.

[0107] “Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ring radical thatcomprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl radical is saturated (i.e., containing single C-C bonds only) or unsaturated (e.g., containing one or more double bonds or triple bonds in the ring system). In some instances, the heterocyclyl radical is saturated. In some instances, the heterocyclyl radical is saturated and substituted. In some instances, the heterocyclyl radical is unsaturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, -15-WSGR Docket No. 68117-704.601 alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0108] “N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as definedabove containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N- heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl,1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0109] “C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as definedabove containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0110] “Heterocyclylalkyl” refers to a radical of the formula –Rc-heterocyclyl where Rc is analkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0111] “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as -16-WSGR Docket No. 68117-704.601 defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0112] “Heteroaryl” refers to a radical derived from a 3- to 18-membered aromatic ring radicalthat comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) –electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant -17-WSGR Docket No. 68117-704.601 to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb- ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0113] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least onenitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0114] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point ofattachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0115] “Heteroarylalkyl” refers to a radical of the formula –Rc-heteroaryl, where Rc is an alkylenechain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The -18-WSGR Docket No. 68117-704.601 heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0116] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula –O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0117] The compounds disclosed herein, in some embodiments, contain one or more asymmetriccenters and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pureforms, and all tautomeric forms are also intended to be included. The term “geometric isomer”refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positionalisomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0118] In general, optionally substituted groups are each independently substituted orunsubstituted. Each recitation of an optionally substituted group provided herein, unless otherwise stated, includes an independent and explicit recitation of both an unsubstituted group and a substituted group (e.g., substituted in certain embodiments, and unsubstituted in certain other embodiments). Unless otherwise stated, a substituted group provided herein (e.g., substituted alkyl) is substituted by one or more substituent, each substituent being independently selected from the group consisting of halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, - N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (e.g., -19-WSGR Docket No. 68117-704.601 optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (e.g., optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0119] “Pharmaceutically acceptable salt” includes both acid and base addition salts. Apharmaceutically acceptable salt of any one of the pharmacological agents described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0120] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain thebiological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al.,Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0121] “Pharmaceutically acceptable base addition salt” refers to those salts that retain thebiological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with -20-WSGR Docket No. 68117-704.601 metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0122] The term "therapeutically effective amount" used herein refers to the amount of an activeingredient sufficient to confer a desired prophylactic or therapeutic effect in a treated subject. In some embodiments, the effective amount is determined, for example, based on the administration route and frequency, body weight and species of the subject receiving the pharmacologic compound. Compounds and Pharmaceutical Compositions for RCC

[0123] Provided herein, in some embodiments, are selective GluN2B inhibitors, which may beeffective in treating refractory chronic cough (RCC). In some instances, the compound provided herein is particularly effective in treating RCC in subjects with idiopathic pulmonary fibrosis (IPF). The GluN2B subtype of NMDA receptors may be the “master switch” for the cough reflex in the brain. As such, selective inhibitors of GluN2B may be effective in treating various etiologies of cough. The compound provided herein may be more effective than comparative treatments, such as non-specific NMDA antagonists, which have shown benefit but are limited by dose-related adverse effects. Identification of GluN2B as the NMDA pathway therapeutic target for treatment of cough, and targeting GluN2B may allow for avoidance of known NR2A-related and general NMDA-related side effects.

[0124] In some instances, the compound provided herein is highly selective for GluN2B over otherNMDA receptor subtypes (e.g., GluN1, GluN2A, GluN2C, GluN2D, GluN3A, and GluN3B) and AMPA-type glutamate receptors. In some embodiments, the compound provided herein is at least 50x (e.g., 60x, 70x, 80x, 90x, 100x, 120x, 140x, 150x, 160x, 180x, 200x, 220x, or 250x) selective for GluN2B over other NMDA receptor subtypes (e.g., GluN1, GluN2A, GluN2C, GluN2D, GluN3A, and GluN3B) and AMPA-type glutamate receptors. In specific embodiments, the -21-WSGR Docket No. 68117-704.601 compound provided herein is approximately or greater than 200x selective for GluN2B over other NMDA receptor subtypes (e.g., GluN1, GluN2A, GluN2C, GluN2D, GluN3A, and GluN3B) and AMPA-type glutamate receptors.

[0125] Provided herein are compounds of Formula (I):Formula (I).

[0126] In some embodiments, compounds of Formula (I) provided herein are a selective NMDAreceptor inhibitor, e.g., GluN2B selective inhibitor.

[0127] In some embodiments, the compound of Formula (I) is a pharmaceutically acceptable salt.

[0128] In some embodiments, X1 is substituted or unsubstituted aryl, heteroaryl, cyclyl, orheterocyclyl. In some embodiments, X1is substituted or unsubstituted aryl. In some embodiments, X1is substituted or unsubstituted heteroaryl. In some embodiments, X1is substituted or unsubstituted cyclyl. In some embodiments, X1is substituted or unsubstituted heterocyclyl.

[0129] In some embodiments, X1 is substituted aryl (e.g., substituted phenyl).

[0130] In some embodiments, X1 is unsubstituted aryl (e.g., unsubstituted phenyl). In someembodiments, X1is aryl substituted with one or more of optionally substituted (e.g., C1-C6) alkyl, (e.g., C1-C6) alkoxy (e.g., methoxy), aryloxy (e.g., -O-Ph), (e.g., C1-C6) haloalkyl (e.g., CF3), hydroxyl, halogen (e.g., F, Cl, Br), amide, or ester. In specific embodiments, the halogen is fluoro (F).

[0131] In some embodiments, X1 is aryl substituted with C1-C6 alkyl. In some embodiments, X1 isaryl substituted with C1alkyl (methyl). In some embodiments, X1is C2alkyl (ethyl).

[0132] In some embodiments, X1 is aryl substituted with C1-C6 alkoxy. In some embodiments, X1is aryl substituted with C1alkoxy (methoxy).

[0133] In some embodiments, X1 is aryl substituted with aryloxy. In some embodiments, X1 is arylsubstituted with -O-Ph.

[0134] In some embodiments, X1 is C1-C6 haloalkyl, such as C1-C6 fluoroalkyl. In someembodiments, X1is aryl substituted with CF3.

[0135] In some embodiments, X1 is aryl substituted with hydroxyl.

[0136] In some embodiments, X1 is aryl substituted with halogen. In some embodiments, thehalogen is fluoro. In some embodiments, X1is aryl substituted with one or more fluoro. In some embodiments, X1is aryl substituted with one or more chloro. In some embodiments, X1is aryl substituted with one or more bromo. -22-WSGR Docket No. 68117-704.601

[0137] In some embodiments, X1 is aryl substituted with amide (e.g., -C(O)NH2).

[0138] In some embodiments, X1 is aryl substituted with ester (e.g., -C(O)O-alkyl).

[0139] In some embodiments, Y1 is a substituted or unsubstituted straight chain or branched alkyl.In some embodiments, Y1is substituted straight chain alkyl. In some embodiments, Y1is unsubstituted straight chain alkyl. In some embodiments, Y1is substituted branched chain alkyl. In some embodiments, Y1is unsubstituted branched chain alkyl. In some embodiments, Y1is substituted or unsubstituted alkyl.

[0140] In some embodiments, Y1 is C1-C6 alkyl substituted with one or more of C1-C6 alkyl,hydroxyl, or oxo.

[0141] In some embodiments, Y1 is C1-C6 alkyl substituted with C1-C2 alkyl and hydroxyl. In someembodiments, Y1is C1-C6alkyl substituted with C1-C2alkyl. In some embodiments, Y1is C1-C6alkyl substituted with hydroxyl. In some embodiments, Y1is C1-C6alkyl substituted with one or more of oxo and alkyl. In some embodiments, Y1is C1-C6alkyl substituted with oxo.

[0142] In specific embodiments, Y1 is or . In some embodiments, Y1 is

[0143] In some embodiments, Z1 is CR’R’’, NR’, or OR’. In some embodiments, Z1 is CR’R’’orNR’. In some embodiments, Z1is CR’R’’. In some embodiments, Z1is NR’. In some embodiments, Z1is OR’.

[0144] In some embodiments, each R1 is independently selected from the group consisting ofhydrogen, halo, hydroxyl, sulfhydryl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl. In some embodiments, at least one R1is hydrogen. In some embodiments, all R1are hydrogen. In some embodiments, at least one R1is halo. In some embodiments, the halo is fluoro. In some embodiments, at least one R1is hydroxyl. In some embodiments, at least one R1is sulfhydryl. In some embodiments, at least one R1is amino. In some embodiments, at least one R1is cyano. In some embodiments, at least one R1is substituted or unsubstituted alkyl. In some embodiments, at least one R1is substituted or unsubstituted alkenyl. In some embodiments, at least one R1is substituted or unsubstituted alkynyl. In some embodiments, at least one R1is substituted or unsubstituted heteroalkyl. In some embodiments, at least one R1is substituted or unsubstituted aryl. In some embodiments, at least one R1is substituted -23-WSGR Docket No. 68117-704.601 or unsubstituted heteroaryl. In some embodiments, at least one R1is substituted or unsubstituted heterocyclyl.

[0145] In some embodiments, R' and R’’ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

[0146] In some embodiments, R’ is selected from the group consisting of hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

[0147] In some embodiments, R’ is hydrogen. In some embodiments, R’ is substituted orunsubstituted alkyl. In some embodiments, R’ is substituted alkyl. In some embodiments, R’ is unsubstituted alkyl. In some embodiments, R’ is substituted or unsubstituted alkenyl. In some embodiments, R’ is substituted alkenyl. In some embodiments, R’ is unsubstituted alkenyl. In some embodiments, R’ is substituted or unsubstituted alkynyl. In some embodiments, R’ is substituted alkynyl. In some embodiments, R’ is unsubstituted alkynyl. In some embodiments, R’ is substituted or unsubstituted aryl. In some embodiments, R’ is substituted aryl. In some embodiments, R’ is unsubstituted aryl. In some embodiments, R’ is substituted or unsubstituted heteroaryl. In some embodiments, R’ is substituted heteroaryl. In some embodiments, R’ is unsubstituted heteroaryl. In some embodiments, R’ is substituted or unsubstituted heterocyclyl. In some embodiments, R’ is substituted heterocyclyl. In some embodiments, R’ is unsubstituted heterocyclyl.

[0148] In some embodiments, R’’ is selected from the group consisting of hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

[0149] In some embodiments, R’’ is hydrogen. In some embodiments, R’’ is substituted orunsubstituted alkyl. In some embodiments, R’’ is substituted alkyl. In some embodiments, R’’ is unsubstituted alkyl. In some embodiments, R’’ is substituted or unsubstituted alkenyl. In some embodiments, R’’ is substituted alkenyl. In some embodiments, R’’ is unsubstituted alkenyl. In some embodiments, R’’ is substituted or unsubstituted alkynyl. In some embodiments, R’’ is substituted alkynyl. In some embodiments, R’’ is unsubstituted alkynyl. In some embodiments, R’’ is substituted or unsubstituted aryl. In some embodiments, R’’ is substituted aryl. In some embodiments, R’’ is unsubstituted aryl. In some embodiments, R’’ is substituted or unsubstituted heteroaryl. In some embodiments, R’’ is substituted heteroaryl. In some embodiments, R’’ is -24-WSGR Docket No. 68117-704.601 unsubstituted heteroaryl. In some embodiments, R’’ is substituted or unsubstituted heterocyclyl. In some embodiments, R’’ is substituted heterocyclyl. In some embodiments, R’’ is unsubstituted heterocyclyl.

[0150] In specific embodiments, R’ is substituted or unsubstituted aryl. In specific embodiments,R’’ is hydrogen.

[0151] In specific embodiments, R’ is alkyl substituted with substituted or unsubstituted aryl. Inspecific embodiments, R’’ is hydrogen.

[0152] In some embodiments, R’ is alkyl(ene) (e.g., C1 alkylene) substituted with aryl which isoptionally substituted with one or more C1-C16alkyl (e.g., C1-C6alkyl, such as methyl), C1-C6alkoxy (e.g., methoxy), halogen (e.g., F, Cl, or Br), or C1-C6haloalkyl (e.g., CF3). In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with C1-C16alkyl. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with C1-C6alkyl. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with methyl. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with C1-C6alkoxy. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with methoxy. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with halogen. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with fluoro. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with chloro. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with bromo. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with C1-C6haloalkyl. In some embodiments, R’ is alkyl substituted with aryl which is optionally substituted with CF3.

[0153] In some embodiments, n is an integer from 0 to 3. In some embodiments, n is an integerfrom 1 to 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0154] In some embodiments, m is an integer from 0 to 6. In some embodiments, m is an integerfrom 0 to 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6.

[0155] In some embodiments, the compound (e.g., selective NMDA receptor inhibitor) is acompound of Formula (II):-25-WSGR Docket No. 68117-704.601 Formula (II).

[0156] In some embodiments, compounds of Formula (II) provided herein are a selective NMDAreceptor inhibitor, e.g., GluN2B selective inhibitor.

[0157] In some embodiments, the compound of Formula (II) is a pharmaceutically acceptable salt.

[0158] In some embodiments, R2 is independently selected from the group consisting of hydrogen,halo, hydroxyl, sulfhydryl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.

[0159] In some embodiments, R2 is hydrogen. In some embodiments, R2 is halo. In someembodiments, the halo is fluoro. In some embodiments, R2is hydroxyl. In some embodiments, R2is sulfhydryl. In some embodiments, R2is amino. In some embodiments, R2is cyano. In some embodiments, R2is substituted or unsubstituted alkyl. In some embodiments, R2is substituted alkyl. In some embodiments, R2is unsubstituted alkyl. In some embodiments, R2is substituted or unsubstituted alkenyl. In some embodiments, R2is substituted alkenyl. In some embodiments, R2is unsubstituted alkenyl. In some embodiments, R2is substituted or unsubstituted alkylyne. In some embodiments, R2is substituted or unsubstituted alkoxy. In some embodiments, R2is unsubstituted alkoxy. In some embodiments, R2is substituted or unsubstituted heteroalkyl. In some embodiments, R2is unsubstituted heteroalkyl. In some embodiments, R2is substituted heteroalkyl. In some embodiments, R2is substituted or unsubstituted aryl. In some embodiments, R2is unsubstituted aryl. In some embodiments, R2is substituted aryl. In some embodiments, R2is substituted heteroaryl. In some embodiments, R2is unsubstituted heteroaryl. In some embodiments, R2is substituted or unsubstituted heterocyclyl. In some embodiments, R2is unsubstituted heterocyclyl.

[0160] In some embodiments, two R2 are taken together with the atoms from which they areattached to form substituted or unsubstituted aryl, substituted or unsubstituted cyclyl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl. In some embodiments, two R2are taken together with the atoms from which they are attached to form substituted or unsubstituted aryl. In some embodiments, two R2are taken together with the atoms from which they are attached to form substituted or unsubstituted cyclyl. In some embodiments, two R2are taken together with the atoms from which they are attached to form substituted or unsubstituted heterocycle. In some embodiments, two R2are taken together with the atoms from which they are attached to form substituted or unsubstituted heteroaryl. -26-WSGR Docket No. 68117-704.601

[0161] In some embodiments, p is an integer from 0 to 5. In some embodiments, p is an integerfrom 0 to 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0162] Provided herein in some embodiments a compound (e.g., selective NMDA receptorinhibitor) of Formula (III):Formula (III).

[0163] In some embodiments, compounds of Formula (III) provided herein are a selective NMDAreceptor inhibitor, e.g., GluN2B selective inhibitor.

[0164] In some embodiments, R3 is hydrogen, halogen, or substituted or unsubstituted alkyl. Insome embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, the halogen is fluoro. In some embodiments, R3is fluoro. In some embodiments, R3is chloro. In some embodiments, R3is bromo. In some embodiments, R3is substituted or unsubstituted alkyl. In some embodiments, R3is unsubstituted (e.g., C1-C6alkyl). In some embodiments, R3is methyl. In some embodiments, R3is substituted (e.g., C1-C6alkyl). R3is (e.g., C1-C6) alkoxy.

[0165] In some embodiments, R4 is hydroxyl or hydrogen. In some embodiments, R4 is hydroxyl.In some embodiments, R4is hydrogen.

[0166] In some embodiments, R5 is hydrogen.

[0167] In other embodiments, R4 and R5 are taken together to form oxo.

[0168] In some embodiments, R6 is hydrogen or substituted or unsubstituted alkyl. In someembodiments, R6is hydrogen. In some embodiments, R6is substituted or unsubstituted alkyl. In some embodiments, R6is unsubstituted alkyl. In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is methyl.

[0169] In any of the embodiments provided herein, the compound may be fluorinated. Fluorinationof the compounds provided herein may provide for enhanced metabolic stability, improved lipophilicity, increased binding affinity, and increased selectivity.

[0170] As used herein “substituted or unsubstituted” refers interchangeably to “optionallysubstituted”.

[0171] In some embodiments, the compound (e.g., selective NMDA receptor inhibitor, e.g.,GluN2B selective inhibitor) is selected from Table 1. Table 1-27-WSGR Docket No. 68117-704.601-28-WSGR Docket No. 68117-704.601-29-WSGR Docket No. 68117-704.601WSGR Docket No. 68117-704.601-31-WSGR Docket No. 68117-704.601-32-WSGR Docket No. 68117-704.601-33-WSGR Docket No. 68117-704.601-34-WSGR Docket No. 68117-704.601WSGR Docket No. 68117-704.601-36-WSGR Docket No. 68117-704.601

[0172] In some embodiments, the compound (e.g., selective NMDA receptor inhibitor) is selectedfrom Table 2. -37-WSGR Docket No. 68117-704.601 Table 2

[0173] In some embodiments, the compound is ifenprodil, radiprodil, or a pharmaceuticallyacceptable salt thereof.

[0174] In some embodiments, the compound is ifenprodil. In some embodiments, the compoundis ifenprodil, or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the compound is a stereochemically pure (e.g., substantially pure,e.g., at least 95%, 96%, 97%, 98%, or 99% pure) ifenprodil, such as comprising:substantially pure (e.g., at least 95%, 96%, 97%, 98%, or 99% pure).

[0176] In some embodiments, the pharmaceutical composition comprises a pharmaceuticallyacceptable salt of any of the compounds provided herein. In some embodiments, the pharmaceutically acceptable salt is any suitable salt according to one of skill in the art. In some -38-WSGR Docket No. 68117-704.601 embodiments, the pharmaceutically acceptable salt is a hydrochloride salt, sulfate salt, nitrate salt, acetate salt, citrate salt, phosphate salt, tartrate salt, oxalate salt, maleate salt, fumarate salt (e.g., hemifumarate), succinate salt, besylate salt, mesylate salt, tosylate salt, or gluconate salt.

[0177] In some embodiments, the pharmaceutical composition provided herein comprises apharmaceutically acceptable salt of ifenprodil. In some embodiments, the pharmaceutically acceptable salt of ifenprodil is a hydrochloride salt, sulfate salt, nitrate salt, acetate salt, citrate salt, phosphate salt, tartrate salt, oxalate salt, maleate salt, fumarate salt (e.g., hemifumarate), succinate salt, besylate salt, mesylate salt, tosylate salt, or gluconate salt.

[0178] In some embodiments, the pharmaceutically acceptable salt of ifenprodil is ifenprodilhemitartrate, ifenprodil oleate, ifenprodil nicotinate, ifenprodil pamoate, ifenprodil fumarate, ifenprodil benzoate, or any combination thereof. In some embodiments, the pharmaceutically acceptable salt is ifenprodil hemitartrate. In some embodiments, the pharmaceutically acceptable salt is ifenprodil oleate. In some embodiments, the pharmaceutically acceptable salt is ifenprodil nicotinate. In some embodiments, the pharmaceutically acceptable salt is ifenprodil pamoate. In some embodiments, the pharmaceutically acceptable salt is ifenprodil fumarate. In some embodiments, the pharmaceutically acceptable salt is ifenprodil benzoate.

[0179] In some embodiments, the pharmaceutically acceptable salt is ifenprodil hemitartrate:.

[0180] In some instances, the compound provided herein is formulated as pharmaceuticallyacceptable salts, including hemitartrate salts, oleate salts, nicotinate salts, pamoate salts, fumarate salts, or benzoate salts.

[0181] In some embodiments, the compound is radiprodil.

[0182] In some embodiments, the compound is Compound 1 of Table 1.

[0183] In some embodiments, the compound is Compound 2 of Table 1.

[0184] In some embodiments, the compound is Compound 3 of Table 1.

[0185] In some embodiments, the compound is Compound 4 of Table 1.

[0186] In some embodiments, the compound is Compound 5 of Table 1.

[0187] In some embodiments, the compound is Compound 6 of Table 1.

[0188] In some embodiments, the compound is Compound 7 of Table 1.

[0189] In some embodiments, the compound is Compound 8 of Table 1.-39-WSGR Docket No. 68117-704.601

[0190] In some embodiments, the compound is Compound 9 of Table 1.

[0191] In some embodiments, the compound is Compound 10 of Table 1.

[0192] In some embodiments, the compound is Compound 11 of Table 1.

[0193] In some embodiments, the compound is Compound 12 of Table 1.

[0194] In some embodiments, the compound is Compound 13 of Table 1.

[0195] In some embodiments, the compound is Compound 14 of Table 1.

[0196] In some embodiments, the compound is Compound 15 of Table 1.

[0197] In some embodiments, the compound is Compound 16 of Table 1.

[0198] In some embodiments, the compound is Compound 17 of Table 1.

[0199] In some embodiments, the compound is Compound 18 of Table 1.

[0200] In some embodiments, the compound is Compound 19 of Table 1.

[0201] In some embodiments, the compound is Compound 20 of Table 1.

[0202] In some embodiments, the compound is Compound 21 of Table 1.

[0203] In some embodiments, the compound is Compound 22 of Table 1.

[0204] In some embodiments, the compound is Compound 23 of Table 1.

[0205] In some embodiments, the compound is Compound 24 of Table 1.

[0206] In some embodiments, the compound is Compound 25 of Table 1.

[0207] In some embodiments, the compound is Compound 26 of Table 1.

[0208] In some embodiments, the compound is Compound 27 of Table 1.

[0209] In some embodiments, the compound is Compound 28 of Table 1.

[0210] In some embodiments, the compound is Compound 29 of Table 1.

[0211] In some embodiments, the compound is Compound 30 of Table 1.

[0212] In some embodiments, the compound is Compound 31 of Table 1.

[0213] In some embodiments, the compound is Compound 32 of Table 1.

[0214] In some embodiments, the compound is Compound 33 of Table 1.

[0215] In some embodiments, the compound is Compound 34 of Table 1.

[0216] In some embodiments, the compound is Compound 35 of Table 1.

[0217] In some embodiments, the compound is Compound 36 of Table 1.

[0218] In some embodiments, the compound is Compound 37 of Table 1.

[0219] In some embodiments, the compound is Compound 38 of Table 1.

[0220] In some embodiments, the compound is Compound 39 of Table 1.

[0221] In some embodiments, the compound is Compound 40 of Table 1.

[0222] In some embodiments, the compound is Compound 41 of Table 1.

[0223] In some embodiments, the compound is Compound 42 of Table 1.-40-WSGR Docket No. 68117-704.601

[0224] In some embodiments, the compound is Compound 43 of Table 1.

[0225] In some embodiments, the compound is Compound 44 of Table 1.

[0226] In some embodiments, the compound is Compound 45 of Table 1.

[0227] In some embodiments, the compound is Compound 46 of Table 1.

[0228] In some embodiments, the compound is Compound 47 of Table 1.

[0229] In some embodiments, the compound is Compound 48 of Table 1.

[0230] In some embodiments, the compound is Compound 49 of Table 1.

[0231] In some embodiments, the compound is Compound 50 of Table 1.

[0232] In some embodiments, the compound is Compound 51 of Table 1.

[0233] In some embodiments, the compound is Compound 52 of Table 1.

[0234] In some embodiments, the compound is Compound 53 of Table 1.

[0235] In some embodiments, the compound is Compound 54 of Table 1.

[0236] In some embodiments, the compound is Compound 55 of Table 1.

[0237] In some embodiments, the compound is Compound 56 of Table 1.

[0238] In some embodiments, the compound is Compound 57 of Table 1.

[0239] In some embodiments, the compound is Compound 58 of Table 1.

[0240] In some embodiments, the compound is Compound 59 of Table 1.

[0241] In some embodiments, the compound is Compound 60 of Table 1.

[0242] In some embodiments, the compound is Compound 61 of Table 1.

[0243] In some embodiments, the compound is Compound 62 of Table 1.

[0244] In some embodiments, the compound is Compound 63 of Table 1.

[0245] In some embodiments, the compound is Compound 64 of Table 1.

[0246] In some embodiments, the compound is Compound 65 of Table 1.

[0247] In some embodiments, the compound is Compound 66 of Table 1.

[0248] In some embodiments, the compound is Compound 67 of Table 1.

[0249] In some embodiments, the compound is Compound 68 of Table 1.

[0250] In some embodiments, the compound is Compound 69 of Table 1.

[0251] In some embodiments, the compound is Compound 70 of Table 1.

[0252] In some embodiments, the compound is Compound 71 of Table 1.

[0253] In some embodiments, the compound is Compound 72 of Table 1.

[0254] In some embodiments, the compound is Compound 73 of Table 1.

[0255] In some embodiments, the compound is Compound 74 of Table 1.

[0256] In some embodiments, the compound is Compound 75 of Table 1.

[0257] In some embodiments, the compound is Compound 76 of Table 1.-41-WSGR Docket No. 68117-704.601

[0258] In some embodiments, the compound is Compound 77 of Table 1.

[0259] In some embodiments, the compound is Compound 78 of Table 1.

[0260] In some embodiments, the compound is Compound 79 of Table 1.

[0261] In some embodiments, the compound is Compound 80 of Table 1.

[0262] In some embodiments, the compound is Compound 81 of Table 1.

[0263] In some embodiments, the compound is Compound 82 of Table 1.

[0264] In some embodiments, the compound is Compound 83 of Table 1.

[0265] In some embodiments, the compound is Compound 84 of Table 1.

[0266] In some embodiments, the compound is Compound 85 of Table 1.

[0267] In some embodiments, the compound is Compound 86 of Table 1.

[0268] In some embodiments, the compound is Compound 87 of Table 1.

[0269] In some embodiments, the compound is Compound 88 of Table 1.

[0270] In some embodiments, the compound is Compound 89 of Table 1.

[0271] In some embodiments, the compound is Compound 90 of Table 1.

[0272] In some embodiments, the compound is Compound 91 of Table 1.

[0273] In some embodiments, the compound is Compound 92 of Table 1.

[0274] In some embodiments, the compound is Compound 93 of Table 1.

[0275] In some embodiments, the compound is Compound 94 of Table 1.

[0276] In some embodiments, the compound is Compound 95 of Table 1.

[0277] In some embodiments, the compound provided herein is ifenprodil or a pharmaceuticallyacceptable salt thereof. Ifenprodil, 4-[2-(4-benzylpiperidin-l-ium-l-yl)-l-hydroxypropyl] phenol; 2,3,4-trihydroxy-4-oxobutanoate, is known in the art as a selective NMDA receptor glutamate receptor antagonist specifically targeting the NMDA-type subunit 2B (Glu2NB). Ifenprodil also exhibits agonist activity for the Sigma-1 receptor, a chaperone protein up-regulated during endoplasmic reticulum stress. Ifenprodil was originally (in the early 1970's) developed as a vasodilator. Ifenprodil is currently being studied for treatment of adolescent PTSD.

[0278] In some instances, the methods for preparing the compounds provided herein are describedin US Patent No. 4,690,931 or Zampieri et al., Molecules, 2023, 28, 3431.

[0279] In some embodiments, provided herein are pharmaceutical compositions comprising anyone of the compounds provided herein.

[0280] In some embodiments, provided herein are pharmaceutical compositions comprising aselective NMDA receptor inhibitor. In some embodiments, provided herein are pharmaceutical compositions comprising a NMDA receptor inhibitor specific for a GluN2B subunit. -42-WSGR Docket No. 68117-704.601

[0281] In some embodiments, the pharmaceutical compositions provided herein comprise any ofthe compounds provided herein or pharmaceutically acceptable salts thereof. In some embodiments, provided herein is a pharmaceutical composition comprising ifenprodil or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments the pharmaceutical compositions comprise a pharmaceuticallyacceptable excipient. Treatment of RCC

[0283] Provided herein in some embodiments, is a method of treating cough in a subject in needthereof. In some embodiments, the cough is refractory chronic cough (RCC).

[0284] Provided herein are methods of treating RCC in a subject in need thereof. Refractorychronic cough may be defined as a clinical condition in which the cause of the cough remains unclear after comprehensive examination and treatment, or the cause is clear but the symptomatic treatment is ineffective. Refractory chronic cough may be defined as a clinical condition in which the chronic cough is unexplainable by underlying pathologies, or a clinical condition in which the chronic cough (e.g., cough lasting longer than 8 weeks in adults or 4 weeks in children) is refractory to treatment.

[0285] In some embodiments, refractory chronic cough is a clinical condition in which chroniccough is unresponsive to other treatment than treatment with the pharmaceutical composition or method of treatment provided herein. In some embodiments, the other treatment comprises treatment with inhaled corticosteroids, proton pump inhibitors, GABABagonists (e.g., baclofen), antihistamines, decongestants, antibiotics, opiates (e.g., codeine and / or morphine), gabapentinoids, or tricyclic antidepressants (e.g., amitriptyline). In some embodiments, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to dextromethorphan, codeine, morphine, hydrocodone, benzonatate, guaifenesin (with or without codeine or dextromethorphan), hydromorphone, promethazine (with or without codeine), chlorpheniramine (with or without hydrocodone), or diphenhydramine. In some embodiments, the other treatment does not include treatment with morphine. In some embodiments, the other treatment comprises morphine. In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more inhaled corticosteroids. In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more proton pump inhibitors. In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to GABABagonists (e.g., baclofen). In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more antihistamines. In some cases, refractory chronic -43-WSGR Docket No. 68117-704.601 cough is a clinical condition in which chronic cough is unresponsive to one or more decongestants. In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more antibiotics In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more opiates (e.g., codeine and / or morphine). In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more gabapentinoids. In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to one or more tricyclic antidepressants (e.g., amitriptyline). In some embodiments, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to dextromethorphan, codeine, morphine, hydrocodone, benzonatate, guaifenesin (with or without codeine or dextromethorphan), hydromorphone, promethazine (with or without codeine), chlorpheniramine (with or without hydrocodone), and / or diphenhydramine. In some cases, refractory chronic cough is a clinical condition in which chronic cough is unresponsive to any combination of inhaled corticosteroids, proton pump inhibitors, GABABagonists (e.g., baclofen), antihistamines, decongestants, antibiotics, opiates (e.g., codeine and / or morphine), gabapentinoids, or tricyclic antidepressants (e.g., amitriptyline), dextromethorphan, codeine, morphine, hydrocodone, benzonatate, guaifenesin (with or without codeine or dextromethorphan), hydromorphone, promethazine, chlorpheniramine, or diphenhydramine.

[0286] In some embodiments, the methods provided herein comprise administering to the subjecta selective NMDA receptor inhibitor. In some embodiments, the selective NMDA receptor inhibitor is a NMDA receptor inhibitor selective for a GluN2B subunit.

[0287] In some embodiments, the methods provided herein comprise administering to the subject(e.g., a therapeutically effective amount of) ifenprodil or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the selective NMDA receptor inhibitors (e.g., a compound providedherein, such as a compound of any one of Formula (I)-(III) or provided in Table 1 or Table 2) selectively reduces high frequency neuronal firing. In some embodiments, the high frequency neuronal firing is measured by blockade of the NMDA pathway.

[0289] In some embodiments, the methods provided here comprise administering to the subject acompound provided herein (e.g., a compound of any one of Formula (I)-(III) or provided in Table 1 or Table 2) in combination with one or more additional therapeutic agents. In some embodiments, the methods provided herein comprise administering to the subject a compound provided herein, such as ifenprodil, in combination with one or more additional therapeutic agents. The additional therapeutic agents may be administered sequentially or simultaneously, in separate dosage forms -44-WSGR Docket No. 68117-704.601 or combined in a single dosage form. In some embodiments, provided herein are pharmaceutical compositions comprising an amount of (a) a first agent comprising a compound provided herein (e.g., a compound of any one of Formula (I)-(III) or provided in Table 1 or Table 2), such as ifenprodil; (b) a second therapeutic agent; (c) optionally a third therapeutic agent, and (d) a pharmaceutically acceptable carrier, vehicle, or diluent.

[0290] In some embodiments, the one or more additional therapeutic agents is a P2X3 receptorantagonist, targets P2X3, or any other peripheral cough receptor. In some embodiments, the one or more additional therapeutic agents is a P2X3 receptor antagonist. In some embodiments, the additional therapeutic agent is camlipixant, Haduvio (nalbuphine ER), taplucainium, AX-8, or Gefapixant. In some embodiments, the additional therapeutic agent is camlipixant. In some embodiments, the additional therapeutic agent is Haduvio (nalbuphine ER). In some embodiments, the additional therapeutic agent is taplucainium. In some embodiments, the additional therapeutic agent is AX-8. In some embodiments, the additional therapeutic agent is Gefapixant.

[0291] In some embodiments, the subjects provided herein have been diagnosed with a diseaseassociated with cough. In some embodiments, the subjects provided herein have been (e.g., previously) treated for a disease associated with cough. In some embodiments, the subjects provided herein have been diagnosed with, and treated for, a disease associated with cough, such as before treatment with a compound or pharmaceutical composition provided herein. In some embodiments, the subjects provided herein are being treated for a disease associated with cough. In some embodiments, the subject is resistant to the treatment that the subject has received for the disease associated with cough.

[0292] Provided herein in some embodiments are methods of treating RCC in a subject diagnosedwith idiopathic pulmonary fibrosis. As described hereinabove, current pre-clinical and clinical treatments are ineffective at treating cough associated with idiopathic pulmonary fibrosis. As such, improved treatments are desirable.

[0293] The disease associated with cough may comprise idiopathic pulmonary fibrosis, asthma,chronic obstructive pulmonary disease (COPD), sarcoidosis, bronchiectasis, non-asthmatic eosinophilic bronchitis, gastroesophageal reflux disease (GERD), laryngeal dysfunction, or pneumonia. In some embodiments, the disease associated with cough is IPF. In some embodiments, the disease associated with cough is asthma. In some embodiments, the disease associated with cough is sarcoidosis.

[0294] In some embodiments, the disease associated with cough is an interstitial lung disease.Interstitial lung diseases associated with cough include, as described hereinabove, IPF or sarcoidosis. In other embodiments, interstitial lung disease associated with cough are -45-WSGR Docket No. 68117-704.601 hypersensitivity pneumonitis, occupational lung disease (e.g., asbestosis, silicosis, and black lung disease), or cryptogenic organizing pneumonia.

[0295] In some instances, the subject also has been diagnosed with urinary incontinence. In someinstances, about 62% of women who are diagnosed with RCC also have urinary incontinence.

[0296] In some instances, the methods provided herein comprise improving depression and / oranxiety in a subject with RCC (e.g., and IPF). Over 50% of subjects who have RCC also are concurrently treated for depression and anxiety. The methods provided herein may be effective in improving the symptoms of anxiety and depression associated with RCC.

[0297] In some embodiments, the subjects herein are human subjects. In some embodiments, thesubjects are adult human subjects. In some embodiments, the subjects are child human subjects.

[0298] In some embodiments, the subject is taking contraception. In some embodiments, thesubject is not pregnant.

[0299] In some embodiments, the subject has been identified as having refractory chronic cough(or unexplained chronic cough) for at least one year prior to the first administration of the compound or pharmaceutical composition provided herein. In some embodiments, the subject is not a current smoker (including vaping). In some embodiments, the subject is not a smoker who has quit within 6 months of the first administration of a compound or pharmaceutical composition provided herein. In some embodiments, the subject does not have a diagnosis of COPD. In some embodiments, the subject does not have a diagnosis of bronchiectasis. In some embodiments, the subject does not have a diagnosis of uncontrolled asthma. In some embodiments, the subject has not had a respiratory tract infection within 4 weeks before the first administration of the compound or pharmaceutical composition. In some embodiments, the subject does not have SARS-CoV-2 at the time of the first administration of the compound or pharmaceutical composition. In some embodiments, the subject does not have a history of alcohol or drug abuse. In some embodiments, the subject is not diagnosed with HIV. In some embodiments, the subject is not diagnosed with hepatitis B. In some embodiments, the subject is not diagnosed with hepatitis C. In some embodiments, the patient does not have a diagnosis of tuberculosis. In some embodiments, the patient does not have a diagnosis of chronic pulmonary disease(s). In some embodiments, the patient does not have a diagnosis of rib fracture(s). In some embodiments, the patient does not have a diagnosis of pneumothorax. In some embodiments, the patient does not have a diagnosis of heart failure. In some embodiments, the patient does not have a diagnosis of lung cancer. In some embodiments, the patient does not have a diagnosis of GERD. In some embodiments, the patient does not have a diagnosis of pneumonitis. In some embodiments, the patient does not have a diagnosis of cystic fibrosis. In some embodiments, the patient does not have a diagnosis of -46-WSGR Docket No. 68117-704.601 congenital lung disease. In some embodiments, the patient does not have a diagnosis of neuromuscular disease. In some embodiments, the patient does not have a diagnosis of sarcoid. In some embodiments, the patient does not have a diagnosis of connective tissue disease.

[0300] In some embodiments, the subject comprises a baseline awake cough frequency of >10coughs per hour. In some embodiments, the subject comprises a baseline awake cough frequency of 5-10 coughs per hour. In some embodiments, the subject comprises a baseline awake cough frequency of <5 coughs per hour.

[0301] In some embodiments, in adult human subjects, the refractory chronic cough has lasted atleast 4 weeks. In some embodiments, in adult human subjects, the refractory chronic cough has lasted at least 8 weeks (e.g., at least 9 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, or 20 weeks). In other embodiments, in adult human subjects, the refractory chronic cough has lasted at least 6 months (e.g., at least 1 year, 2 years, 3 years, 5 years, 10 years, or more). In some embodiments, the subject has had refractory chronic cough for at least 1 year.

[0302] In some embodiments, in child human subjects, the refractory chronic cough has lasted atleast 2 weeks. In some embodiments, in child human subjects, the refractory chronic cough has lasted at least 4 weeks (e.g., at least 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or 12 weeks). In other embodiments, in child human subjects, the refractory chronic cough has lasted at least 4 months (e.g., at least 6 months, 1 year, 2 years, 3 years, 5 years, 10 years, or more).

[0303] The compound or pharmaceutical composition provided herein may reduce (e.g.,geometric) mean cough count in a subject. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by at least 10% (e.g., at least 15%, 20%, 25%, 30%, 32%, 35%, 40%, 45%, or at least 50%) over a given period of time. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by at least 50% (e.g., at least 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, or 99%, or 100%). In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by from about 10% to about 60% over a given period of time. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by from about 20% to about 50% over a given period of time. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by from about 30% to about 40% over a given period of time, such as after 4 weeks of treatment. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by from about 35% to about 45% over a given period of time, such as after 12 weeks of treatment. In some embodiments, administration of a compound or pharmaceutical composition provided herein -47-WSGR Docket No. 68117-704.601 reduces mean cough count by about 15%, 18%, 20%, 22%, 25%, 28%, 30%, 32%, 35%, 37%, 40%, 42%, 45%, or 50%. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, 99%, or 100%. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by about 32% over a given period of time, such as shown in FIG. 3. In some embodiments, administration of a compound or pharmaceutical composition provided herein reduces mean cough count by about 40% over a given period of time, such as shown in FIG. 3.

[0304] In some embodiments, the given period of time is any period of time after administrationof the compound or pharmaceutical composition. In some embodiments, the given period of time is about 0.25 hrs, about 0.5 hrs, about 0.75 hrs, about 1 hr, about 1.5 hrs, about 2 hrs, about 3 hrs, about 4 hrs, about 5 hrs, about 6 hrs, about 7 hrs, about 8 hrs, about 9 hrs, about 10 hrs, about 11 hrs, about 12 hrs, about 14 hrs, about 16 hrs, about 18 hrs, about 20 hrs, about 24 hrs, about 36 hrs, about 48 hrs, or about 72 hours. In some embodiments, the given period of time is about 24 hrs. In some embodiments, the given period of time is about 30 minutes (e.g., therapeutic efficacy may be achieved after about 30 minutes).

[0305] The compound or pharmaceutical composition provided herein may reduce (e.g.,geometric) awake cough count in a subject. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 10% (e.g., at least 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, or 30%). In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 20%. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 30%. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 40% (e.g., after week 4 of administration in subjects with baseline awake cough counts of >20 / hr as shown in Table 4). In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by no more than 90% (e.g., no more than 80%, 70%, 60%, or 50%). In some embodiments, the compound or pharmaceutical composition provided herein awake cough count by from about 10% to about 60%, from about 10% to about 50%, from about 20% to about 50%, or from about 20% to about 40%. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by about 29%, such as after 4 weeks of administration (e.g., as shown in Table 4). In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by about 36%, such as after 12 weeks of administration (e.g., as shown in Table 4). -48-WSGR Docket No. 68117-704.601

[0306] The compound or pharmaceutical composition provided herein may reduce (e.g.,geometric) awake cough count in a subject. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 20% (e.g., at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%). In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 30%. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 50%. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by at least 75%. In some embodiments, the compound or pharmaceutical composition provided herein reduces awake cough count by no more than 95% (e.g., no more than 90%, 85%, 80%, 75%, or 70%). In some embodiments, the compound or pharmaceutical composition provided herein awake cough count by from about 20% to about 90%, from about 20% to about 80%, from about 30% to about 75%, or from about 40% to about 95%. The compound or pharmaceutical composition provided herein may reduce (e.g., geometric) the frequency cough bouts. “Cough bouts” may refer to series of coughs (2+) separated by a maximum pre-defined time period between coughs. The time period may be 2 seconds or greater or 3 seconds or greater.

[0307] The compound or pharmaceutical composition provided herein may reduce a frequency of2-second cough bouts in a subject, such as after 4 weeks or 12 weeks of administration with the compound or pharmaceutical composition. The compound or pharmaceutical composition provided herein may reduce a frequency of 2-second cough bouts by at least 10% (e.g., at least 15%, 17%, 20%, 22%, 25%, 27%, or 30%). In some embodiments, the compound or pharmaceutical composition provided herein may reduce the frequency of 2-second cough bouts by at most 80% (e.g., at most 70%, 60%, 50%, 40%, or 30%). In some embodiments, the compound or pharmaceutical composition provided herein reduces a frequency of 2-second cough bouts by at least 30%, such as shown in FIG.13B. In some embodiments, the compound or pharmaceutical composition provided herein reduces 2-second cough bouts by from about 10% to about 50%, from about 10% to about 40%, from about 20% to about 40%, or from about 30% to about 40%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of 2-second cough bouts by about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or about 40%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of 2-second cough bouts by about 35% after 4 weeks of administration, such as shown in FIG.13B. In some embodiments, the compound or pharmaceutical composition provided herein reduces frequency of 2-second cough bouts by about 36% after 12 weeks of administration, such as shown in FIG. 13B. -49-WSGR Docket No. 68117-704.601

[0308] The compound or pharmaceutical composition provided herein may reduce a frequency of2-second cough bouts in a subject. The compound or pharmaceutical composition provided herein may reduce a frequency of 2-second cough bouts by at least 20% (e.g., at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%). In some embodiments, the compound or pharmaceutical composition provided herein may reduce the frequency of 2-second cough bouts by at most 95% (e.g., at most 90%, 85%, 80%, 75%, 70%, or 65%). In some embodiments, the compound or pharmaceutical composition provided herein reduces a frequency of 2-second cough bouts by at least 60%. In some embodiments, the compound or pharmaceutical composition provided herein reduces 2-second cough bouts by from about 20% to about 90%, from about 25% to about 80%, from about 30% to about 75%, or from about 35% to about 95%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of 2-second cough bouts by about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or about 90%.The compound or pharmaceutical composition provided herein may reduce a frequency of 3-second cough bouts in a subject, such as after 4 weeks or 12 weeks of administration with the compound or pharmaceutical composition. The compound or pharmaceutical composition provided herein may reduce a frequency of 3-second cough bouts by at least 10% (e.g., at least 15%, 17%, 20%, 22%, 25%, 27%, or 30%). In some embodiments, the compound or pharmaceutical composition provided herein may reduce the frequency of 3-second cough bouts by at most 80% (e.g., at most 70%, 60%, 50%, 40%, or 30%). In some embodiments, the compound or pharmaceutical composition provided herein reduces a frequency of 3-second cough bouts by at least 30%, such as shown in FIG.13C. In some embodiments, the compound or pharmaceutical composition provided herein reduces 3-second cough bouts by from about 10% to about 50%, from about 10% to about 40%, from about 20% to about 40%, or from about 30% to about 40%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of 3-second cough bouts by about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or about 40%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of 3-second cough bouts by about 34% after 4 weeks of administration, such as shown in FIG.13C. In some embodiments, the compound or pharmaceutical composition provided herein reduces frequency of 3-second cough bouts by about 35% after 12 weeks of administration, such as shown in FIG. 13C.

[0309] The compound or pharmaceutical composition provided herein may reduce a frequency of3-second cough bouts in a subject. The compound or pharmaceutical composition provided herein may reduce a frequency of 3-second cough bouts by at least 20% (e.g., at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%). In some embodiments, the -50-WSGR Docket No. 68117-704.601 compound or pharmaceutical composition provided herein may reduce the frequency of 3-second cough bouts by at most 95% (e.g., at most 90%, 85%, 80%, 75%, 70%, or 65%). In some embodiments, the compound or pharmaceutical composition provided herein reduces a frequency of 3-second cough bouts by at least 60%. In some embodiments, the compound or pharmaceutical composition provided herein reduces 3-second cough bouts by from about 20% to about 90%, from about 25% to about 80%, from about 30% to about 75%, or from about 35% to about 95%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of 3-second cough bouts by about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or about 90%.

[0310] The compound or pharmaceutical composition provided herein may reduce a frequency ofsingle breath clusters in a subject, such as after 4 weeks or 12 weeks of administration with the compound or pharmaceutical composition. The compound or pharmaceutical composition provided herein may reduce a frequency of single breath clusters by at least 10% (e.g., at least 15%, 17%, 20%, 22%, 25%, 27%, 30%, 33%, or at least 35%). In some embodiments, the compound or pharmaceutical composition provided herein may reduce the frequency of single breath clusters by at most 80% (e.g., at most 70%, 60%, 50%, 40%, or 30%). In some embodiments, the compound or pharmaceutical composition provided herein reduces a frequency of single breath clusters by at least 30%, such as shown in FIG. 13D. In some embodiments, the compound or pharmaceutical composition provided herein reduces single breath clusters by from about 10% to about 50%, from about 20% to about 50%, or from about 30% to about 50%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of single breath clusters by about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, or 45%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of single breath clusters by about 44% after 4 weeks of administration, such as shown in FIG. 13D. In some embodiments, the compound or pharmaceutical composition provided herein reduces frequency of single breath clusters by about 37% after 12 weeks of administration, such as shown in FIG. 13D.

[0311] The compound or pharmaceutical composition provided herein may reduce a frequency ofsingle breath clusters in a subject. The compound or pharmaceutical composition provided herein may reduce a frequency of single breath clusters by at least 20% (e.g., at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%). In some embodiments, the compound or pharmaceutical composition provided herein may reduce the frequency of single breath clusters by at most 95% (e.g., at most 90%, 85%, 80%, 75%, 70%, or 65%). In some embodiments, the compound or pharmaceutical composition provided herein reduces a frequency -51-WSGR Docket No. 68117-704.601 of single breath clusters by at least 60%. In some embodiments, the compound or pharmaceutical composition provided herein reduces single breath clusters by from about 20% to about 90%, from about 25% to about 80%, from about 30% to about 75%, or from about 35% to about 95%. In some embodiments, the compound or pharmaceutical composition provided herein reduces the frequency of single breath clusters by about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or about 90%.

[0312] In some embodiments, administration of a compound or pharmaceutical compositionprovided herein increases the average time to cough onset in a subject. In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by at least 30% (e.g., at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%). In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by at most 99% (e.g., at most 95%, at most 90%, at most 85%, at most 80%, at most 75%, at most 70%, at most 65%, or at most 60%). In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by about 40% to about 99%. In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by about 40% to about 80%. In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by about 50% to about 80% (e.g., about 60% to about 80%, about 65% to about 80%, or about 70% to about 80%). In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by about 30%, 35%, 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%. In some embodiments, administration of a compound or pharmaceutical composition provided herein increases the average time to cough onset in a subject by about 74%, such as shown in FIG. 2. Increase in average time to cough onset may be an increased as compared to a placebo treatment.

[0313] In some embodiments, administration of a compound or pharmaceutical compositionprovided herein improves the average visual analog score (VAS score) in a subject. VAS score is a patient reported measure of cough severity. VAS may be measured as described in Martin Nguyen A et al. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211049743, which is incorporated herein by reference in its entirety. In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a -52-WSGR Docket No. 68117-704.601 subject by at least 20% (e.g., at least 25%, at least 30%, at least 32%, at least 35%, at least 37%, at least 38%, or at least 40%). In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by at least 50% (e.g., at least 60%, 70%, 80%, 90%, 95%, or 99%). In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by at most 50% (e.g., at most 45%, at most 40%, at most 38%, at most 37%, at most 35%, or at most 30%). In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by at most 99% (e.g., at most 98%, 95%, 90%, 85%, 80%, 70%, 60%, or 50%). In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by about 20% to about 99%. In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by about 20% to about 50%. In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by about 30% to about 50% (e.g., about 32% to about 50%, about 35% to about 50%, or about 37% to about 50%). In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by about 25%, 30%, 32%, 35%, 37%, 38%, or 40%. In some embodiments, administration of a compound or pharmaceutical composition provided herein improves the average VAS score in a subject by about 37%, such as shown in FIG. 5.

[0314] Subjects administered with the compound or pharmaceutical composition provided hereinmay experience improvements in Global Rating of Change (GRC) scale (also known as Global Impression of Change, Patient Global Impression of Change (PGIC)). The GRC scale may be a patient-reported metric for measurement of improvement in the subjects condition, such as the measurement described in Juniper et al. J Clin Epidemiol. 1994 Jan; 47(1):81-7, which is incorporated herein by reference in its entirety. Subjects assessed via the GRC scale may be classified as feeling “better”, “about the same”, or “worse”. In some embodiments, at least 40% (e.g., at least 42%, at least 45%, at least 47%, at least 50%, at least 52%, at least 55%, or at least 60%) of subjects feel “better” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, at least 60% (e.g., at least 70%, 80%, 85%, 90%, 95%, or 99%) of subjects feel “better” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, about 60% to about 99% (e.g., about 60% to about 95%, about 70% to about 90%, or about 80% to about 95%) of subjects feel “better” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some -53-WSGR Docket No. 68117-704.601 embodiments, about 40% to about 70% (e.g., about 45% to about 70%, about 50% to about 70%, or about 50% to about 60%) of subjects feel “better” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, about 58% of subjects feel “better” according to the GRC scale after administration, such as shown in FIG. 6A. In some embodiments, at least 20% (e.g., at least 22%, at least 25%, at least 27%, at least 30%, at least 32%, at least 35%, or at least 37%) of subjects feel “about the same” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, about 20% to about 45% (e.g., about 20% to about 40%, about 25% to about 40%, or about 30% to about 40%) of subjects feel “about the same” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, about 37% of subjects feel “about the same” according to the GRC scale after administration, such as shown in FIG. 6A. In some embodiments, at most 10% of subjects (e.g., at most 8%, at most 7%, at most 6%, or at most 5%) of subjects feel “worse” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, about 0% to about 8% (e.g., about 1% to about 7%, about 1% to about 6%, or about 2% to about 6%) of subjects feel “worse” according to the GRC scale after administration of a compound or pharmaceutical composition provided herein. In some embodiments, 5% of subjects feel “worse” according to the GRC scale after administration, such as shown in FIG. 6A.

[0315] In some embodiments, subjects are evaluated after administration of a compound orpharmaceutical composition provided herein using the Leicester Cough Questionnaire (LCQ). The LCQ assesses the impact of cough severity and provides specific metrics including physical, psychological, and social impact (in addition to a total score). LCQ may be measured as described in Birring et al Thorax 2003;58:339-343. In some embodiments, the impact of the compound or pharmaceutical composition provided herein is assessed compared to baseline (e.g., before treatment with the compound or pharmaceutical composition). In some embodiments, administration (e.g., treating) with a compound or pharmaceutical composition provided herein comprises improvement in LCQ. In some embodiments, administration with a compound or pharmaceutical composition provided herein comprises an improvement in LCQ of at least 0.5 points (e.g., at least 0.75 points, at least 1 point, at least 1.1 points, at least 1.25 points, at least 1.5 points, or at least 1.75 points). In some embodiments, administration with a compound or pharmaceutical composition provided herein comprises an improvement in LCQ of at least 2 points (e.g., at least 4 points, at least 6 points, at least 8 points, at least 10 points, at least 12 points, at least 16 points, or at least 18 points). In some embodiments, administration with a compound or -54-WSGR Docket No. 68117-704.601 pharmaceutical composition provided herein comprises an improvement in LCQ of from about 0.5 points to about 18 points, about 0.5 points to about 12 points, about 0.5 points to about 8 points, about 0.5 points to about 5 points, 0.5 points to about 2.5 points (e.g., about 0.5 points to about 2 points, about 0.75 points to about 2 points, or about 1 point to about 2 points). In some embodiments, the subject experiences an improvement in LCQ of about 0.5 points, 0.6 points, 0.7 points, 0.8 points, 0.9 points, 1 point, 1.1 points, 1.2 points, 1.3 points, 1.4 points, 1.5 points, 1.6 points, 1.7 points, 1.8 points, or 1.9 points. In other embodiments, the subject experiences an improvement in LCQ of about 2 points, 3 points, 4 points, 5 points, 6 points, 8 points, 10 points, 12 points, 14 points, 16 points, or 18 points. In some embodiments, the subject experiences an improvement in (e.g., total) LCQ of about 1.8 (e.g., 1.75) points, such as shown in FIG. 7.

[0316] In some embodiments, the methods provided herein may comprise reducing the severity ofthe refractory chronic cough. In some instances, reducing the severity of the refractory chronic cough comprises reducing the frequency of cough bouts, as described elsewhere herein. In some instances, reducing the severity of the refractory chronic cough comprises improvements in PGIC cough severity score.

[0317] The compound or pharmaceutical composition provided herein may be administered in anysuitable fashion according to one of skill in the art. In some embodiments, the compound or pharmaceutical composition is administered to the subject orally, intravenously, intranasally, intrathecally, intradermally, subcutaneously, intracerebroventricularly, intraperitoneally, intramuscularly, intravitreally, intracranially, intrabuccally, rectally, or sublingually. In specific embodiments, the compound or pharmaceutical composition is administered orally.

[0318] In some embodiments, the compound herein is administered in any suitable quantityaccording to one of skill in the art. In some embodiments, the compound provided herein may be administered in an amount of about 0.02 mg / kg to 3.5 mg / kg. In some embodiments, the compoundprovided herein is administered in an amount of at least 0.2 mg / kg (for instance, at least 0.3 mg / kg,0.5 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, or at least 3.3 mg / kg). In some embodiments, the compound provided herein are administered in an amount of about 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.5 mg / kg, 0.7 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.7 mg / kg, 1.9 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.7 mg / kg, 2.9 mg / kg, 3 mg / kg, 3.2 mg / kg, or 3.4 mg / kg. In some embodiments, the compoundprovided herein is administered in an amount of at most 5 mg / kg (for instance, at most 4.5 mg / kg,4 mg / kg, 3.5 mg / kg, 3 mg / kg, 2.5 mg / kg, 2 mg / kg, 1.8 mg / kg, 1.5 mg / kg, 1.3 mg / kg, 1 mg / kg, or at most 0.8 mg / kg). In some embodiments, the compound provided herein is administered in an amount of about 0.3 mg / kg. In some embodiments, the compound provided herein is administered -55-WSGR Docket No. 68117-704.601 in an amount of about 0.7 mg / kg. In some embodiments, the compound provided herein is administered in an amount of about 1 mg / kg. In some embodiments, the compound provided herein is administered in an amount of about 2 mg / kg.

[0319] In some embodiments, the compound herein is administered in any suitable quantityaccording to one of skill in the art. For example, the compound provided herein may be administered in an amount of about 1 mg to about 200 mg. In some embodiments, the compound provided herein are administered in an amount of at least 10 mg (e.g., at least 20 mg, 30 mg, 50 mg, 75 mg, 100 mg, 150 mg, or at least 200 mg). In some embodiments, the compound provided herein is administered in an amount of about 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. In some embodiments, the compound provided herein is administered in an amount of about 20 mg. In some embodiments, the compound provided herein is administered in an amount of about 40 mg. In some embodiments, the compound provided herein is administered in an amount 60 mg. In some embodiments, the compound provided herein is administered in an amount 120 mg.

[0320] In some embodiments, a total daily dose of the compound herein is at least 0.3 mg / kg (forinstance, at least 0.7 mg / kg, at least 1 mg / kg, at least 1.3 mg / kg, at least 1.7 mg / kg, at least 2 mg / kg, at least 2.5 mg / kg, at least 4.3 mg / kg, at least 5 mg / kg, at least 6 mg / kg, at least 6.7 mg / kg, at least 7.7 mg / kg, at least 8.3 mg / kg, at least 9.3 mg / kg, at least 10 mg / kg, at least 11 mg / kg, at least 11.7 mg / kg, at least 12.7 mg / kg, at least 13.3 mg / kg, at least 14.3 mg / kg, at least 15 mg / kg, or at least 16 mg / kg). In some embodiments, the total daily dose of the compound herein is at most 16 mg / kg (for example, at most 15 mg / kg, at most 14.3 mg / kg, at most 13.3 mg / kg, at most 12.7 mg / kg, at most 11.7 mg / kg, at most 11 mg / kg, at most 10 mg / kg, at most 9.3 mg / kg, at most 8.3 mg / kg, at most 7.7 mg / kg, at most 6.7 mg / kg, at most 6 mg / kg, at most 5 mg / kg, at most 4.3 mg / kg, at most 3.3 mg / kg, at most 3 mg / kg, at most 2.7 mg / kg, at most 2.5 mg / kg, at most 2.3 mg / kg, at most 2 mg / kg, or at most 1.7 mg / kg). In some embodiments, the total daily dose of the compound herein is from about 0.3 mg / kg to about 16 mg / kg (for example, about 0.3 mg / kg to about 16 mg / kg, about 4.3 mg / kg to about 15 mg / kg, about 5 mg / kg to about 14.3 mg / kg, about 6 mg / kg to about 13.3 mg / kg, or about 6.7 mg / kg to about 12.7 mg / kg).

[0321] In some embodiments, a total daily dose of the compounds herein is at least 20 mg (forinstance, at least 40 mg, at least 60 mg, at least 80 mg, at least 100 mg, at least 120 mg, at least 150 mg, at least 260 mg, at least 300 mg, at least 360 mg, at least 400 mg, at least 460 mg, at least 500 mg, at least 560 mg, at least 600 mg, at least 660 mg, at least 700 mg, at least 760 mg, at least 800 mg, at least 860 mg, at least 900 mg, or at least 960 mg). In some embodiments, the total daily -56-WSGR Docket No. 68117-704.601 dose of the compounds herein is at most 960 mg (for example, at most 900 mg, at most 860 mg, at most 800 mg, at most 760 mg, at most 700 mg, at most 660 mg, at most 600 mg, at most 560 mg, at most 500 mg, at most 460 mg, at most 400 mg, at most 360 mg, at most 300 mg, at most 260 mg, at most 200 mg, at most 180 mg, at most 160 mg, at most 150 mg, at most 140 mg, at most 120 mg, or at most 100 mg). In some embodiments, the total daily dose of the compounds herein is from about 20 mg to about 960 mg (for example, about 20 mg to about 960 mg, about 260 mg to about 900 mg, about 300 mg to about 860 mg, about 360 mg to about 800 mg, or about 400 mg to about 760 mg). In some embodiments, the total daily dose is about 60 mg, such as described in Examples 2 and 3. In some embodiments, the total daily dose is about 120 mg, such as described in Example 3.

[0322] The methods provided herein may comprise administering the pharmaceutical compositionor compound provided herein at any suitable frequency according to one of skill in the art. In some embodiments, the compound or pharmaceutical composition is administered to the subject (e.g., at least once) daily. In some embodiments, the compound or pharmaceutical composition is administered to the subject daily. In other embodiments, the compound or pharmaceutical composition is administered to the subject at least twice daily, e.g., twice daily, at least three times daily, at least four times daily, three times daily, or four times daily. In some embodiments, the compound or pharmaceutical composition is administered three times daily. In some embodiments, the compound or pharmaceutical composition is administered to the subject once, twice, three times, four times, or five times daily.

[0323] In some embodiments, such as described in Example 3, the compound is administered inan amount of about 20 mg three times per day. In some embodiments, such as described in Example 3, the compound is administered in an amount of about 40 mg per day. In some embodiments, the total daily dose of the compound is about 60 mg. In some embodiments, the total daily dose of the compound is about 120 mg. EXAMPLESExample 1: Ifenprodil Effect on Acute Cough in Guinea Pig Models

[0324] Ifenprodil (in this example ifenprodil hemitartrate) was evaluated in acute guinea pig citricacid models exposed to 1M aerosolized citric acid using clinically relevant doses of Ifenprodil compound (e.g., 1.5 mg / kg). The ability of Ifenprodil to reduce mean cough count and time to cough onset was compared to a vehicle treatment and gefapixant as a positive control. Results showed statistically significant decreases in mean cough count for animals administered with Ifenprodil compared to either the positive control or vehicle (FIG. 1). Results also showed -57-WSGR Docket No. 68117-704.601 statistically significant increases in time to cough onset compared to either the positive control or vehicle treatment (FIG. 2).

[0325] Changes in cough count (FIG. 8A-8B) and respiratory rate (FIG. 9) were also evaluated inguinea pigs. Changes in cough bouts were also evaluated in guinea pigs (FIG. 8C). Guinea pigs were dosed intraperitoneally with ifenprodil at 0, 1, 3, 10 and 30 mg / kg or with a vehicle control followed 30 min. later by 0.1M aerosolized citric acid for 10 min. and 5 min. later by 0.3M citric acid for 10’ followed by a 5’ washout. Cumulative coughs were measured using a Biopac acquisition system and Acknowledge software. The dose-ranging in guinea pigs may illustrate that it is possible to improve cough suppression at non-toxic doses.

[0326] Increasing the dose of ifenprodil reduced coughing in the guinea pig model in a dose-responsive manner (FIG. 8D-8E), to near complete cough suppression. The median cough count in controls (± interquartile range or IQR) is 14 (11, 17) vs. after 30 mg / kg ifenprodil treatment being 1 (0.25, 5.5) with p=0.036 (FIG. 8A). The cumulative number of coughs was 0, 0, 1 and 1 in 4 of 6 animals treated with 30 mg / kg ifenprodil. The cumulative number of coughs was 12, 9, 8, 6, and 1 in animals treated with vehicle or 1, 3, 10, or 30 mg / kg of ifenprodil, respectively (administered intraperitoneally about 30 minutes before cough challenges were initiated, n=5- 9 / treatment group). Statistically significant reductions in coughing were seen at 3 mg / kg, 10 mg / kg, and 30 mg / kg. The data may demonstrate near-complete cough suppression in a dose-dependent manner below the observed adverse effect level dose (NOAEL). Statistically significant reductions (p<0.05) in cough bouts were see at 3 mg / kg, 10 mg / kg, and 30 mg / kg (FIG. 8C).

[0327] In some instances, cumulative coughs may be referred to as cough bouts. In some cases,>90% of coughs evoked by citric acid occur as single coughs. In some cases, about 5% of coughs evoked by citric acid comprise 2 coughs in succession. In further instances, about 2% of coughs evoked by citric acid are paroxysms of coughing (e.g., multiple coughs over several seconds).

[0328] In FIG. 8B, cough count refers to the sum of total coughs. In FIG. 8C, cough bouts referto the sum of single coughs (spaced from other coughs by at least 3 seconds or more) and cough bouts (successive coughs spaced by intervals of less than 2 seconds or less than 3 seconds).

[0329] Effect sizes of cumulative cough count reductions and associated statistical significancewere high in lower cough count animals.

[0330] There was no respiratory depression observed at any dose, a concern clinically, and an issueseen preclinically with both codeine and baclofen (FIG.9). The guinea pig equivalent no observed adverse effect level (NOAEL) dose is 37 mg / kg (based on 52-week rat GLP toxicology data) translating to an HED of ~8 mg / kg or a total single daily dose of ~480 mg. -58-WSGR Docket No. 68117-704.601

[0331] NMDA receptor engagement may be important to the initiation of cough, and additionally,that the antitussive mechanism will be agnostic to peripheral stimulus. Increasing the doses of ifenprodil for RCC will likely improve the efficacy while staying within the therapeutic index. Example 2: Efficacy of Ifenprodil in Humans

[0332] Irrespective of the receptors in the lungs or trachea that are engaged by triggers of cough,these peripheral events can result in depolarization of the vagal afferent neurons sending a signal to the brain. Neuronal tracing and functional imaging studies have located the termination sites of these sensory neurons to the nucleus of the solitary tract (nTS) and the paratrigeminal nucleus (Pa5) in the medulla. The sustained and high-frequency signals from these afferent neurons are transmitted via glutamate release across synapses to N-methyl-D-aspartate (NMDA) receptors on neurons leading to the cough center in the brain. NMDA receptors may be a key node of signal transduction from heterogeneous peripheral inputs, culminating in depolarization of descending efferent motor neurons that may cause coughing. To understand which subunits of the hetero- tetrameric NMDA receptor were responsible for this transmission, the nTS region of the brain was microdissected and expression profiled in Guinea pigs (GP) leading to the observation that the GluN2A subunit of the NMDA receptor is not expressed, whereas the remaining GluN2 subunits are expressed. This may present an opportunity to identify selective inhibitors to certain receptor subtypes to attempt to reduce the well described dose-limiting adverse events (AEs) of general non-selective NMDA receptor blockers. Ifenprodil was identified as a molecule with >200x selectivity for GluN2B vs. the other GluN2 subtypes. Ifenprodil has a well-established human safety record and well-defined no adverse event levels (NOAEL) in multiple pre-clinical models after long-term repeat dosing. It was previously shown that a 1.5 mg / kg oral dose of ifenprodil reduced cough count in the GP model (1M citric acid exposure) by 40% (p<0.01) and resulted in an almost doubling of the time to cough (p<0.05). This translates to a human equivalent dose (HED) of ~20 mg.

[0333] The drug had no safety concerns and was well tolerated in our study. This profile promisesthe known anti-tussive effects of the non-selective NMDA receptor blockers without the neuropsychiatric side effects that have been shown to be dose limiting with these compounds.

[0334] An open-label human Phase 2a trial was performed at this dose (20 mg of ifenprodil orallythree times a day) in 20 patients with idiopathic pulmonary fibrosis (IPF) and associated refractory chronic cough (RCC). 24-hour cough count was measured using the VitaloJAK® device at 12 weeks. Subjects in the trial were administered 20 mg of ifenprodil three times per day (for a total daily dose of 60 mg). -59-WSGR Docket No. 68117-704.601

[0335] The demographics of the subject population are shown in Table 3. The population includedsubjects with an average age of about 73. 40% of subjects were undergoing antifibrotic therapy with nintedanib. 20% of subjects were undergoing antifibrotic therapy with pirfenidone. 5% of subjects were undergoing antifibrotic therapy with both nintedanib and pirfenidone. Table 3

[0336] The FDA-accepted endpoint for pivotal clinical trials of chronic cough is a reduction ingeometric mean cough count vs baseline. In addition, primary endpoints included no worsening of forced vital capacity (FVC) vs baseline (e.g., maintenance of lung function). Secondary endpoints in the study included diffusing capacity for carbon monoxide (DLCO), patient-reported outcomes of cough severity and quality of life, biomarkers for fibrosis, and drug safety.

[0337] The safety of the Ifenprodil was assessed during the trial. In some cases, the adverse eventsobserved during the trial were consistent with the clinical history of ifenprodil, established in post- marketing surveillance of over 15000 individuals. In limited instances, severe adverse effects, such as neuroendocrine tumors and moderate constipation were observed. In the study, one subject withdrew due to moderate adverse effects. Treatment compliance in the study was <90%.

[0338] After 12 weeks of treatment with ifenprodil, subjects experienced only a -1.7% FVC changeon average as compared to baseline. This may be consistent with 3-month FVC changes in studies of pirfenidone and nintedanib.

[0339] Subjects, after 12 weeks of treatment with ifenprodil, exhibited no change in DLCO frombaseline, consistent with lung function preservation.

[0340] After 4 and 12 weeks of treatment with Ifenprodil, reductions in geometric mean coughcount were observed (FIG. 3). A 32% reduction in geometric mean cough count was observed after 4 weeks of treatment (nominal p-value = 0.023). A 40% reduction in geometric mean cough count was observed after 12 weeks of treatment (nominal p-value < 0.01). For reference, the single largest and longest running IPF-RCC placebo arm (in a gefapixant trial) had an ~8% geometric mean cough count reduction. A post-hoc responder analysis using integrated historical placebo -60-WSGR Docket No. 68117-704.601 controls from all prior IPF-RCC trials illustrates significance across all response groups. In some instances, cough count is determined by use of a VitaloJAK® device.

[0341] After weeks 4 and 12 of treatment with Ifenprodil, reductions in geometric mean 24 hourcough count were observed (FIG. 11A-C), and is summarized in Table 4. A 31% reduction in geometric mean 24 hour cough count was observed after 4 weeks of treatment (p-value = 0.03). A 38% reduction in geometric mean 24 hour cough count was observed after 12 weeks of treatment (p-value <0.01). Subjects indicating improvement in cough frequency and severity as measured by PGIC demonstrate substantial reduction in 24 hour cough count (FIG. 11D and FIG. 11E).

[0342] After weeks 4 and 12 of treatment with Ifenprodil, reductions in geometric mean awakecough count were observed (FIG. 12A-C), and is summarized in Table 4. A 29% reduction in geometric mean awake cough count was observed after 4 weeks of treatment (p-value = 0.03). A 36% reduction in geometric mean awake cough count was observed after 12 weeks of treatment (p-value <0.01). Subjects indicating improvement in cough frequency and severity as measured by PGIC demonstrate substantial reduction in awake cough count (FIG. 12D and FIG. 12E). Table 4-61-WSGR Docket No. 68117-704.601

[0343] Cough response rates were evaluated in subjects administered placebo(s) and Ifenprodil.>30% of subjects in the Intent-to-Treat group experienced a >50% reduction in 24-hr cough, >15% of subjects experienced a >70% reduction in 24-hr cough, and >55% of subjects experienced a >30% reduction in 24-hr cough at 12 weeks of treatment (FIG.4A-B). With no control arm, a pre- estimated 25% placebo response rate was selected for comparison based on trials in refractory chronic cough, which may be greater than the actual placebo response rate based on similar trials in IPF-associated cough (e.g., ranging from 0% to 19% placebo response rate).

[0344] Patient-reported cough visual analog scores (VAS), a measure of cough severity, wereevaluated (FIG.5). Cough VAS scores showed a statistically significant improvement at 12 weeks of treatment compared to baseline (37.4% improvement, 23.6 mm, p = 0.001). In some instances, 90% of patients responded as measured by reductions in CS-VAS scores (p<0.001). In the Global Rating of Change Scale, 58% of subjects reported an improvement in cough frequency after 12 weeks of administration, whereas only 5% of subjects reported feeling worse (FIG. 6A). In the Global Rating of Change Scale, 47% of subjects reported an improvement in cough severity after 12 weeks of administration, whereas only 5% of subjects reported feeling worse (FIG. 6B). Subject quality of life (QOL) was measured with the Leicester Cough Questionnaire. In the Leicester Cough Questionnaire, subjects answer questions in three domains, each scored from 1- 7. Domains are summed to produce a score from 3-21 (higher numbers are better). Total scores from the questionnaire improved over 12 weeks by 1.75 points (p=0.017), as shown in FIG. 7.

[0345] Cough bouts (clustering of cough) was also evaluated as a metric to potentially capture theseverity of cough. A cough bout may be a series of coughs (2+) separated by a maximum pre- defined time period (<2 seconds or <3 seconds) between coughs). A single breath cluster (SBC) may refer to a series of coughs (2+) within a single inspiratory period.

[0346] After weeks 4 and 12 of treatment with Ifenprodil, reductions in geometric mean coughcount were observed (FIG. 13A). A 35% reduction in geometric mean cough count was observed after 4 weeks of treatment. A 33% reduction in geometric mean cough count was observed after 12 weeks of treatment. Treatment with ifenprodil demonstrated improvement in cough count compared to placebo (FIG. 13E).

[0347] After weeks 4 and 12 of treatment with Ifenprodil, reductions in geometric mean 2-secondcough bouts were observed (FIG.13B). A 35% reduction in geometric mean 2-second cough bouts was observed after 4 weeks of treatment. A 36% reduction in geometric mean 2-second cough bouts was observed after 12 weeks of treatment. Treatment with ifenprodil demonstrated improvement in 2-second cough bouts compared to placebo (FIG. 13E). -62-WSGR Docket No. 68117-704.601

[0348] After weeks 4 and 12 of treatment with Ifenprodil, reductions in geometric mean 3-secondcough bouts were observed (FIG.13C). A 34% reduction in geometric mean 3-second cough bouts was observed after 4 weeks of treatment. A 35% reduction in geometric mean 3-second cough bouts was observed after 12 weeks of treatment. Treatment with ifenprodil demonstrated improvement in 3-second cough bouts compared to placebo (FIG. 13E).

[0349] After weeks 4 and 12 of treatment with Ifenprodil, reductions in geometric mean singlebreath clusters were observed (FIG. 13D). A 44% reduction in geometric mean single breath clusters was observed after 4 weeks of treatment. A 37% reduction in geometric mean single breath clusters was observed after 12 weeks of treatment. Example 3: Phase 2b Refractory Cough Trial

[0350] The phase 2b refractory cough trial includes a 14 day subject screening period, 85 days oftreatment with ifenprodil or placebo, followed by a 7 day follow-up period. In the phase 2b trial, subjects are administered one of (a) a placebo three times per day, (b) an about 40 mg dose of ifenprodil three times per day (about 120 mg total daily dose), or (c) an about 150 mg dose of ifenprodil three times per day (about 450 mg total daily dose), and a 300mg dose of ifenprodil three times per day (900 mg total daily dose).

[0351] The study design mirrors previous phase 2b studies in chronic cough, such as inNCT02612610 and NCT04678206. These are protocols for which they FDA have indicated they are in agreement with. The study will be structured to include three dose arms and a placebo arm to evaluate the efficacy, safety, and tolerability of ifenprodil in approximately 240 adults with RCC. The study will be a placebo-controlled, parallel-arm trial randomized 1:1:1:1 with expected treatment arms of 40 mg three times per day (TID), 80 mg three times per day (TID), 120 mg three times per day (TID), and a placebo.

[0352] Primary endpoints for the study will include an average decrease from baseline in awakecough frequency at 12 weeks. An additional primary endpoint will include change from baseline to week 2, 4, and 12 weeks in the 24-hour cough frequency in subjects administered ifenprodil relative to placebo. A further additional endpoint will be 24-hour cough frequency measured at 12 weeks using the VitaloJAK® cough monitoring system in a patient population not stratified for baseline 24-hour cough frequency.

[0353] A secondary endpoint for the study will include reduction of cough as measured by smartwatch technology over several weeks. -63-WSGR Docket No. 68117-704.601

[0354] An exploratory efficacy endpoint will include the Cough Severity using Visual AnalogueScale (CS-VAS), the Leicester Cough Questionnaire (LCQ), and real time longitudinal cough monitoring.

[0355] Inclusion criteria include:a. Capable of giving signed informed consentb. Refractory chronic cough (including explained chronic cough) for at least one yearc. Women of child-bearing potential must use a highly effective contraception methodduring the study and for at least 14 days after the last dose

[0356] Exclusion criteria include:a. Current smoker / vaper (all forms of smoking and inhaled substances, including,cannabis / tobacco smoke and nicotine vapors) or individuals who have given up smoking within the last 6 months, or those with >20 pack-year smoking history) b. Diagnosis of chronic obstructive pulmonary disease (COPD), bronchiectasis,uncontrolled asthma c. Respiratory tract infection within 4 weeks before screeningd. Lab confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)infection at screening e. History of malignancy in the last 5 yearsf. History of alcohol or drug abuse within the last 3 yearsg. Has positive serological test for human immunodeficiency virus (HIV), hepatitisB virus surface antigen, or hepatitis C virus Example 4: Analysis of Records of Patients with Cough

[0357] In this example, clinical findings commonly used by expert physicians to arrive at an RCCdiagnosis from among a broader chronic cough population were analyzed. A total data set of 94,400,624 patients was analyzed for these cough-related diagnoses and treatments in the EHR Integrated Database from EVERSANA®, a nationally representative electronic health record dataset. Records from January 1, 2015, to December 31, 2023, were used. To ensure that sufficient follow-up data was included to articulate >8 weeks of coughing, the data set was restricted to patients who had more than 6 months of total follow-up in the record. Finally, the initial data set was restricted to adult patients aged 18-90. This resulted in 54,958,289 patients forming the initial analysis group.

[0358] Patients were considered to have chronic cough if they had a chronic cough diagnosis code,or if they had multiple cough diagnoses; multiple antitussive records; multiple inhaled -64-WSGR Docket No. 68117-704.601 corticosteroid records; or multiple expectorants over a span exceeding 8 weeks (FIG. 10A). Diagnoses were identified using ICD10 codes and medications identified by either RxNorm codes or ATC codes. Of this chronic cough population, patients were excluded that had underlying pathologies that cause cough as described in FIG. 10B to arrive at a RCC diagnosis in such patients.

[0359] Of the 54,958,289 patients who were aged 18-90, had associated gender data, and hadgreater than 6 months of follow-up data, 3,467,086 patients met the clinical criteria for diagnosis with chronic cough (6.31%). Of these patients, 1,024,624 patients, or 34.65% of chronic cough patients, met criteria that in the analysis defined them as RCC patients. For a different view of the data, also presented are metrics where the inclusion criteria are changed for a chronic cough diagnosis to narrow the time span for having received a chronic cough diagnosis code, multiple cough diagnoses; multiple antitussive records; multiple inhaled corticosteroid records; or multiple expectorants to between 8 weeks and 3 months. In either analysis, the proportion of chronic cough patients who are defined as RCC in this example ais consistent with estimates that generally hoverat ~40% from other studies. Data are reported in FIG. 10A, FIG. 10B as the number of distinctpatients at each step.

[0360] In this example, real world evidence was used in this analysis to define the prevalence ofchronic cough and RCC from among a large US-based EHR data set. The clinical criteria that have been applied to this data set in this example have resulted in a prevalence of chronic cough in adults of 6.31%, with 34.65% of these patients being identified as having RCC.

[0361] While preferred embodiments of the present invention have been shown and describedherein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. -65-

Claims

WSGR Docket No. 68117-704.601 CLAIMS WHAT IS CLAIMED IS:

1. A method of treating refractory chronic cough in a subject in need thereof, the methodcomprising administering to the subject a pharmaceutical composition comprising a selective N-methyl D-aspartate (NMDA) receptor inhibitor.

2. The method of claim 1, wherein the selective NMDA receptor inhibitor is specific for aGluN2B subunit.

3. The method of claim 1 or 2, wherein the selective N-methyl D-aspartate (NMDA) receptorinhibitor is a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X1is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cyclyl, or substituted or unsubstituted heterocyclyl; Y1is a substituted or unsubstituted straight chain or branched alkyl; Z1is CR’R’’, NR’, or OR’; each R1is independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; R' and R’’ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; n is an integer from 0 to 3; and -66-WSGR Docket No. 68117-704.601 m is an integer from 0 to 6.

4. The method of claim 3, wherein X1 is substituted or unsubstituted aryl.

5. The method of claim 3 or 4, wherein the selective N-methyl D-aspartate (NMDA) receptorinhibitor is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein, each R2is independently selected from the group consisting of hydrogen, halo, hydroxyl, sulfhydryl, amino, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl; or two R2are taken together with the atoms from which they are attached to form substituted or unsubstituted aryl, substituted or unsubstituted cyclyl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroaryl; and p is an integer from 0 to 5.

6. The method of any one of claims 3-5, wherein Y1 is substituted or unsubstituted alkyl.

7. The method of any one of claims 3-6, wherein R’ and R’’, when present, are eachindependently selected from hydrogen or alkyl substituted with substituted or unsubstituted aryl.

8. The method of any one of claims 3-7, wherein the selective N-methyl D-aspartate (NMDA)receptor inhibitor is a compound of Formula (III): -67-WSGR Docket No. 68117-704.601Formula (III) wherein, R3is hydrogen, halogen, or substituted or unsubstituted alkyl; R4is hydroxyl or hydrogen; R5is hydrogen; or R4and R5are taken together to form oxo; and R6is hydrogen or substituted or unsubstituted alkyl.

9. The method of claim 8, wherein R4 and R5 are taken together to form oxo.

10. The method of claim 8 or 9, wherein R6 is alkyl.

11. The method of any one of claims 3-10, wherein Z1 is CR’R’’ or NR’.

12. The method of any one of claim 5-11, wherein each R2, when present, is independentlyselected from the group consisting of hydrogen, halo, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl.

13. The method of any one of claims 8-12, wherein R6 is unsubstituted alkyl.

14. The method of any one of claims 5-13, wherein p is an integer from 0 to 3.

15. The method of any one of claims 3-14, wherein n is 1 or 2.

16. The method of any one of the preceding claims, wherein the selective N-methyl D-aspartate(NMDA) receptor inhibitor is selected from the compounds in Table 1.

17. The method of claim 1 or 2, wherein the selective N-methyl D-aspartate (NMDA) receptorinhibitor is selected from the group consisting of: ifenprodil, radiprodil, and pharmaceutically acceptable salts thereof.

18. The method of any one of the preceding claims, wherein the selective N-methyl D-aspartate(NMDA) receptor inhibitor is ifenprodil or a pharmaceutically acceptable salt thereof. -68-WSGR Docket No. 68117-704.60119. The method of claim 18, wherein the ifenprodil or a pharmaceutically acceptable saltthereof is ifenprodil hemitartrate, ifenprodil oleate, ifenprodil nicotinate, ifenprodil pamoate, ifenprodil fumarate, ifenprodil benzoate, or any combination thereof.

20. The method of any one of the preceding claims, wherein the selective N-methyl D-aspartate(NMDA) receptor inhibitor selectively reduces high frequency neuronal firing as measured by blockade of the NMDA pathway.

21. The method of any one of the preceding claims, wherein the selective N-methyl D-aspartate(NMDA) receptor inhibitor selectively reduces sustained neuronal firing.

22. The method of any one of the preceding claims, wherein the subject has been diagnosedwith a disease associated with cough, has been treated for the disease associated with cough, or both.

23. The method of claim 22, wherein the subject is resistant to a treatment that the subject hasreceived for the disease.

24. The method of claim 22 or 23, wherein the disease comprises idiopathic pulmonary fibrosis,asthma, chronic obstructive pulmonary disease, sarcoidosis, bronchiectasis, non-asthmatic eosinophilic bronchitis, gastroesophageal reflux disease (GERD), laryngeal dysfunction, or pneumonia.

25. The method of claim 22 or 23, wherein the disease comprises an interstitial lung disease.

26. The method of claim 22 or 23, wherein the disease comprises idiopathic pulmonary fibrosis.

27. The method of any one of claims 23-26, wherein the treatment comprises inhalablecorticosteroids, proton pump inhibitors, GABABagonists, antihistamines, decongestants, antibiotics, opiates, gabapentinoids, tricyclic antidepressants, or any combination thereof.

28. The method of any one of claims 23-27, wherein the treatment comprisesdextromethorphan, codeine, morphine, hydrocodone, codeine, benzonatate, guaifenesin, hydromorphone, promethazine, chlorpheniramine, diphenhydramine, or any combination thereof. -69-WSGR Docket No. 68117-704.60129. The method of any one preceding claims, wherein the subject is an adult human subject,and wherein the refractory chronic cough in the subject has lasted eight weeks or longer.

30. The method of any one of claims 1-28, wherein the subject is a child human subject, andwherein the refractory chronic cough in the subject has lasted four weeks or longer.

31. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition reduces mean cough count in the subject over a given time period by at least about 30%, at least about 35%, at least about 38%, or at least about 40%.

32. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition reduces mean cough count in the subject over a given time period by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

33. The method of claim 31 or 32, wherein the given time period is 5 minutes, 15 minutes, 30minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, 24 hours, or 72 hours.

34. The method of any one of claims 31-33, wherein the given time period is 24 hours.

35. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition increases average time to cough onset in the subject by at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%.

36. method of any one of the preceding claims, wherein administration of the pharmaceuticalcomposition increases average time to cough onset in the subject by at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

37. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition improves average visual analog score (VAS) by at least about 25%, at least about 30%, at least about 32%, at least about 35%, at least about 37%, at least about 38%, or at least about 40% as measured in a group of human subjects that suffer from refractory chronic cough. -70-WSGR Docket No. 68117-704.60138. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition improves average visual analog score (VAS) by at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99% as measured in a group of human subjects that suffer from refractory chronic cough.

39. The method of any one of the preceding claims, wherein the treating comprises animprovement in Global Rating of Change Scale for at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of subjects after 12 weeks of administration with the pharmaceutical composition.

40. The method of any one of the preceding claims, wherein the treating comprisesimprovements in Leicester Cough Questionnaire (LCQ) of at least 1 point, at least 1.25 points, or at least 1.5 points after 12 weeks of administration with the pharmaceutical composition.

41. The method of any one of the preceding claims, wherein the treating comprisesimprovements in Leicester Cough Questionnaire (LCQ) of at least 2 points, at least 5 points, at least 10 points, or at least 15 points.

42. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition reduces a geometric mean awake cough count by at least about 30%.

43. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition reduces a frequency of 2-second cough bouts by at least about 30%.

44. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition reduces a frequency of 3-second cough bouts by at least about 30%.

45. The method of any one of the preceding claims, wherein administration of thepharmaceutical composition reduces a frequency of single breath clusters by at least about 35%. -71-WSGR Docket No. 68117-704.60146. The method of any one of the preceding claims, wherein the pharmaceutical compositioncomprises 20 mg to about 960 mg of the selective NMDA receptor inhibitor.

47. The method of any one of the preceding claims, wherein the pharmaceutical compositioncomprises 20 mg or 40 mg of the selective NMDA receptor inhibitor.

48. The method of any one of the preceding claims, wherein the selective NMDA receptorinhibitor is administered to the subject in an amount of at least 20 mg, at least 40 mg, at least 60 mg, or at least 100 mg.

49. The method of any one of the preceding claims, wherein the selective NMDA receptorinhibitor is administered to the subject in an amount of about 20 mg, about 40 mg, about 60 mg, or about 100 mg.

50. The method of any one of the preceding claims, wherein the selective NMDA receptorinhibitor is administered in an amount of at least 0.3 mg / kg, at least 0.7 mg / kg, at least 1 mg / kg, or at least 1.2 mg / kg.

51. The method of any one of the preceding claims, wherein the selective NMDA receptorinhibitor is administered in an amount of about 0.3 mg / kg, about 0.7 mg / kg, about 1 mg / kg, or about 1.2 mg / kg.

52. The method of any one of the preceding claims, wherein a total daily dose of the selectiveNMDA receptor inhibitor is at least 60 mg, at least 120 mg, at least 180 mg, at least 200 mg, or at least 400 mg.

53. The method of any one of the preceding claims, wherein a total daily dose of the selectiveNMDA receptor inhibitor is about 60 mg, about 120 mg, about 180 mg, about 200 mg, or about 400 mg.

54. The method of any one of the preceding claims, wherein a total daily dose of the selectiveNMDA receptor inhibitor is at least 1 mg / kg, at least 2 mg / kg, at least 3 mg / kg, at least 3.3 mg / kg, or at least 6.6 mg / kg. -72-WSGR Docket No. 68117-704.60155. The method of any one of the preceding claims, wherein a total daily dose of the selectiveNMDA receptor inhibitor is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 3.3 mg / kg, or about 6.6 mg / kg.

56. The method of any one of the preceding claims, further comprising administering to thesubject one or more additional therapeutic agents.

57. The method of claim 56, wherein the one or more additional therapeutic agents is a P2X3receptor antagonist.

58. The method of claim 57, wherein the one or more additional therapeutic agents are selectedfrom camlipixant, Haduvio (nalbuphine ER), taplucainium, AX-8, and gefapixant.

59. The method of any one of the preceding claims, wherein the method comprisesadministering the pharmaceutical composition to the subject daily.

60. The method of any one of the preceding claims, wherein the method comprisesadministering the pharmaceutical composition to the subject once, twice, three times, four times, or five times daily.

61. The method of any one of the preceding claims, wherein the method comprisesadministering the pharmaceutical composition to the subject three times daily.

62. The method of any one of the preceding claims, wherein the pharmaceutical compositionis administered to the subject orally, intravenously, intranasally, intrathecally, intradermally, subcutaneously, intracerebroventricularly, intraperitoneally, intramuscularly, intravitreally, intracranially, intrabuccally, rectally, or sublingually.

63. The method of any one of the preceding claims, wherein the pharmaceutical compositionis administered to the subject orally. -73-

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