Fused pyrimidine compounds for treatment of tinnitus, hearing loss, and meniere's disease

Abstract

Methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere's disease, with a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, are provided. Also provided are therapeutic compositions that may be used to improve one or more symptoms of tinnitus, acute sensorineural hearing loss, or Meniere's disease. Formula (I): or pharmaceutically acceptable salts thereof, wherein R1, R2, R7 and ring A have any of the meanings herein defined in the description.

Description

Docket: 2262-122 PCTFUSED AMINO PYRIMIDINE COMPOUNDS FOR TREATMENT OF TINNITUS, ACUTE SENSORINEURAL HEARING LOSS, AGE-RELATED HEARING LOSS,AND MENIERE’S DISEASECROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit of and priority to the U. S. Provisional Application No.63 / 710,682, filed on October 23, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] Treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss, and Meniere’s disease with fused amino pyrimidine compounds.BACKGROUND

[0003] Tinnitus is characterized by an auditory sensation in the absence of external sound. In many cases tinnitus is subjectively perceptual, i.e., only the subject can perceive symptoms. Symptoms of tinnitus include ringing, roaring, static, buzzing, hissing, jackhammer sounds, and whistling in one or both ears. The noise may be intermittent or continuous. According to the National Institute on Deafness and other Communication Disorders (NIDCD) approximately 10 percent of the US adult population, or about 25 million Americans, have experienced some degree of tinnitus. According to the American Tinnitus Association, 20 million of these sufferers struggle with burdensome chronic tinnitus, while 2 million have extreme and debilitating cases. Severe tinnitus can lead to depression and other mental health challenges that severely affect the patient and the patient's family members. Therapies such as masking, sound therapy, electrical stimulation, and drugs have shown some benefit. Unfortunately, these treatments may be insufficient and many patients continue to suffer with tinnitus. Therefore, treatment of tinnitus remains a significant need.

[0004] Acute sensorineural hearing loss (ASNHL) is also known as sudden sensorineural hearing loss (SSNHL), sudden deafness and acute sensory hearing loss. Idiopathic acute sensorineural hearing loss is a form of acute sensorineural hearing loss in which no clear cause is known. The terms “acute sensorineural hearing loss” or “ASNHL” will be used herein for convenience and encompasses SSNHL, sudden deafness, acute sensory hearing loss andDocket: 2262-122 PCTidiopathic acute sensorineural hearing loss. In certain instances, acute sensorineural hearing loss may be defined as the onset of one-sided sensorineural hearing loss in less than 72 hours. It strikes an estimated 5-20 / 100,000 persons per year. In some instances, ASNHL may occur following various inner ear injuries. In certain instances, ASNHL may be provoked by exposure to excessive noise (acoustic trauma, acute or otherwise), viral or bacterial infections in the inner ear, disturbances of the inner ear blood supply, middle and inner ear surgery, exposure to ototoxic drugs, head trauma, a tumor on the nerve that connects the ear to the brain and a variety of other incidents. In certain instances, ASNHL may be associated with surgery induced acoustic trauma. The most common complaint in ASNHL is a feeling of aural fullness (sometimes described as pressure in the ear), followed by complaints of hearing loss and tinnitus. Aural fullness is a non-specific symptom. The most common treatment for ASNHL, especially in cases where the cause is unknown, is corticosteroids. Corticosteroids may be associated with lowered immune response, which could be detrimental in cases where ASNHL is caused by bacterial or viral infection.

[0005] Age-related hearing loss (also called presbycusis) is hearing loss that occurs gradually with age. See, National Institutes of Health, National Institute on Deafness and Other Communication Disorders, “Age Related Hearing Loss”, https: / / www.nidcd.nih.gov / health / age-related-hearing-loss. It is one of the most common conditions affecting aging adults.Approximately 15% of American adults (37.5 million) ages 18 and over report some trouble hearing, and about one in three people in the U. S. between the ages of 65 and 74 has hearing loss. Id. Nearly half of those older than 75 have difficulty hearing. Id. Hearing loss can range from a mild loss, in which a person misses certain high-pitched sounds, to a total loss of hearing. Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. Harris et al., Journal of Neuroscience 21 September 2022, 42 (38) 7201-7212. Treatment involves electric devices such as hearing aids which amplify sounds in the ear. While somewhat effective, hearing aids typically have reduced effectiveness in loud environments. There is a need for effective treatments for age-related hearing loss (ARHL).

[0006] Meniere's disease is a disorder of the inner ear that causes episodes of vertigo and fluctuating hearing loss with a progressive, ultimately permanent loss of hearing, ringing in the ear (tinnitus), and sometimes a feeling of fullness or pressure in the affected ear. A common symptom of Meniere's disease is hypersensitivity to sounds. In many cases, Meniere's diseaseDocket: 2262-122 PCTaffects only one ear, at least initially; however, over time both ears may become involved. The cause of Meniere's disease is unclear but may involve both genetic and environmental factors. Meniere's disease has been associated with an abnormal amount of fluid (endolymph) in the inner ear. Although there is no cure for Meniere's disease, medications to reduce nausea such as dimenhydrinate, meclizine or prochlorperazine may be administered. Anti-inflammatory medications such as NSAIDS or corticosteroids may also be administered.

[0007] Fused amino pyridine compounds and pharmaceutically acceptable salts thereof and methods of making them are disclosed in WO2021 / 180952, incorporated herein by reference. As described in WO2021 / 180952, these compounds and their pharmaceutically acceptable salts selectively modulate KCC2 and are used to treat or prevent KCC2 mediated disease, including neurological disorders. As described in the OMIM database, the LC12A5 gene encodes the neuronal KCC2 channel that is the major extruder of intracellular chloride in mature neurons. In the presence of low intraneuronal chloride, the binding of GABA and glycine to their ionotropic receptors results in chloride influx with subsequent hyperpolarization contributing to neuronal inhibition.

[0008] Hyperpolarizing GABAAR currents are critically dependent upon efficient Cl’ extrusion, which is facilitated by KCC2. Conditional inactivation of KCC2 in the hippocampus leads to neuronal Cl’ accumulation and depolarizing GABAAR currents. These deficits in inhibition parallel the development of spontaneous seizures, neuronal apoptosis and reactive astrocytosis (Kelley eta\., EBioMedicine 32, 62-71 (2018)). GABAA signaling is a major inhibitory neurotransmitter mechanism in the adult brain and consequently KCC2 has a key role in normal neurodevelopment and various neurological disorders. Decreased activity of KCC2 has been implicated in the pathogenesis of neurological disorders including epilepsy (Galanopoulou et al, Epilepsia 2007;48:14-18; Huberfield etal, The Journal of Neuroscience (2007) 27, 9866-9873), neuropathic pain (Price et al, Curr Top Med Chem 2005;5:547-555), Rett’s syndrome (Tang et al, 2019, Translational Medicine, 11(503)), autism (Tyzio et al, Science 343, 675-679, Memer et al, Frontiers in cellular neuroscience 9, 2015), mental disorders, spinal cord injury (Boulenguez etal, Nature Medicine 2010, 16, 302-307) and conditions in which there is neuronal hyperexcitability such as ALS (Fuchs et al, Journal of Neuropathology & Experimental Neurology, Volume 69, Issue 10, October 2010, Pages 1057-1070). KCC2 downregulation may play a strong role in the noise-induced neural hyperactivity. Parameshwarappa et al., Sci Rep 14,Docket: 2262-122 PCT10689 (2024).

[0009] Direct modulation of KCC2 by interaction with small molecules has been reported. Delpire etal (Proc Natl Acad Sci USA. 2009 Mar 31; 106(13): 5383-5388) describe an assay to identify small molecule inhibitors of KCC2 and Zhang et al (Journal of Biomolecular Screening 15(2): 2010) describe an assay used to identify positive modulators of KCC2.SUMMARY

[0010] Methods and compositions for treating tinnitus, acute sensorineural hearing loss (ASNHL), age-related hearing loss (ARHL) and Meniere’s disease are provided and, in embodiments, include administering to a subject experiencing tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease an effective amount of a compound according to Formula (I):

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] R1 is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C3-7cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-lOaryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -Cl-3alkyl, -Cl-8alkoxy and -C2-8alkynyloxy wherein -Cl-3alkyl, -Cl-8alkoxy and -C2-8alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Cl-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;Docket: 2262-122 PCT

[0013] R2 is selected from -H; -halo; and -Cl-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;

[0014] A is selected from

[0015] R3is selected from -H; -Ci-ealkyl; -C2-6alkenyl; -C2-6alkynyl; C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -Ci-3alkyl optionally substituted by 1 or 2 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9;

[0016] R4aand R4bare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;

[0017] R4cand R4dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3, or R4cand R4dtogether with the carbon to which they are attached represent carbonyl;

[0018] R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;

[0019] R6is selected from -H; -halo; -NH2; -CN; -Ci-salkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-Ci-3alkyl;

[0020] R7is selected from NR10R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -Ci-ealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-ealkyl; Cs-scycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they areDocket: 2262-122 PCTattached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H;

[0021] R8and R9are each independently selected from -H and -C1-6alkyl;

[0022] R10is -Ci-6alkyl;

[0023] R11is selected from -Ci-6alkyl optionally substituted with 1 or 2 substituents selected from -F and -Ci-3alkoxy; and -(CH2)nR12;

[0024] R12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;

[0025] m is 0 or l; and

[0026] n is i, 2 or 3

[0027] In embodiments, a subject having tinnitus has been diagnosed with tinnitus. In embodiments, a subject in need thereof has been diagnosed with tinnitus. In embodiments, methods of treating tinnitus include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in one or more symptoms of the tinnitus. In embodiments, methods of treating tinnitus include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in next day functioning of the subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating tinnitus in a subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in providing improvement in next day functioning of a subject with tinnitus. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of tinnitus. In embodiments, tinnitus is being treated.

[0028] In embodiments, a subject having acute sensorineural hearing loss has been diagnosed with acute sensorineural hearing loss. In embodiments, a subject in need thereof has been diagnosed with acute sensorineural hearing loss. In embodiments, methods of treating acute sensorineural hearing loss include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in one or more symptoms of the acute sensorineural hearing loss. In embodiments, methods of treating acute sensorineural hearing loss include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provideDocket: 2262-122 PCTimprovement in next day functioning of the subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating acute sensorineural hearing loss in a subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in providing improvement in next day functioning of a subject with acute sensorineural hearing loss. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of acute sensorineural hearing loss. In embodiments, acute sensorineural hearing loss is being treated.

[0029] In embodiments, a subject having age-related hearing loss has been diagnosed with age-related hearing loss. In embodiments, a subject in need thereof has been diagnosed with age-related hearing loss. In embodiments, methods of treating age-related hearing loss include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in one or more symptoms of the age-related hearing loss. In embodiments, methods of treating age-related hearing loss include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in next day functioning of the subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating age-related hearing loss in a subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in providing improvement in next day functioning of a subject with age-related hearing loss. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of age-related hearing loss. In embodiments, age-related hearing loss is being treated.

[0030] In embodiments, a subject having Meniere’s disease has been diagnosed with Meniere’s disease. In embodiments, a subject in need thereof has been diagnosed with Meniere’s disease. In embodiments, methods of treating Meniere’s disease include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in one or more symptoms of the Meniere’s disease. In embodiments, methods of treating Meniere’s disease include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in next day functioning of the subject. In embodiments, provided herein is aDocket: 2262-122 PCTcompound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating Meniere’s disease in a subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in providing improvement in next day functioning of a subject with Meniere’s disease. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of Meniere’s disease. In embodiments, Meniere’s disease is being treated.

[0031] In embodiments, methods of treating tinnitus are described herein which include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine. In embodiments, methods of treating tinnitus are described herein which include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine wherein the method provides improvement in the tinnitus. In embodiments the benzodiazepine is clobazam.

[0032] In embodiments, methods of treating acute sensorineural hearing loss described herein include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine. In embodiments, methods of treating acute sensorineural hearing loss described herein include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine wherein the method provides improvement in the acute sensorineural hearing loss. In embodiments the benzodiazepine is clobazam.

[0033] In embodiments, methods of treating age-related hearing loss are described herein which include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine. In embodiments, methods of treating age-related hearing loss are described herein which include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine wherein the method provides improvement in the age-related hearing loss. In embodiments the benzodiazepine is clobazam.

[0034] In embodiments, methods of treating Meniere's disease described herein include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine. In embodiments,Docket: 2262-122 PCTmethods of treating Meniere's disease described herein include administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a benzodiazepine wherein the method provides improvement in the Meniere's disease. In embodiments the benzodiazepine is clobazam.

[0035] In embodiments, a compound of Formula (I) is Compound A:

[0036] In embodiments, a compound of Formula (I) is Compound B:Compound B

[0037] In embodiments, a compound of Formula (I) is Compound C:Docket: 2262-122 PCTCompound C

[0038] In embodiments, a compound of Formula (I) is Compound D:Compound D

[0039] In embodiments, a compound of Formula (I) is Compound E:Docket: 2262-122 PCT

[0040] In embodiments, a compound of Formula (I) is Compound F:Compound F

[0041] In embodiments, a compound of Formula (I) is Compound G:

[0042] In embodiments, a compound of Formula (I) is Compound H:Docket: 2262-122 PCTBRIEF DESCRIPTION OF THE FIGURES

[0043] FIG. 1A is a drug screening workflow chart illustrating the steps taken to identify KCC2 direct activators, a multi-tiered program starting from a compound library of 1.3 million compounds. Identification of a subseries of fused pyrimidine ring compounds, denoted as subseries A (SSA) were identified as lead-hits from the compound library screen.

[0044] FIG. 1B depicts immunoblotting results for HEK-293 cells expressing KCC2 exposed to vehicle (-) or 30μM SSA1 (+) for 90 min and then heated to 37-58°C. Soluble fractions were subsequently immunoblotted with KCC2 and GAPDH antibodies.

[0045] FIG. 1C is a graph depicting thermal aggregation curves for KCC2 under control conditions and in the presence of SSA-0126. *=significantly different to control p<0.001; t-test; n=4 transfections. The level of remaining soluble native KCC2 at each temperature was normalized to that seen at 37°C (1x137°C).

[0046] FIG. 1D is a graph depicting isothermal dose response curves constructed for destabilization of KCC2 by SSA1 at 50°C, n=4 transfections

[0047] FIG. 1E shows the structure of Compound A (also referred to as CmpA).

[0048] FIG. 1F is a graph showing the effects of Compound A on KCC2 activity expressed in HEK-293 cells as measured using Tl flux. Data is normalized to values seen with vehicle (100%), n=3.

[0049] FIG. 1G is a chart showing the EC50 of Compound A for KCC2, KCC2-S940A, KCC3, KCC4 and NKCC1 as measured in expressing HEK-293 cells, n=4 transfections. In all panels p values were determined using unpaired t-tests with Welch’s correction.

[0050] FIG. 2A depicts three graphs showing EGly values versus time as measured from HEK-293 cells expressing KCC2 together with GlyRα1 using perforated patch clamp recordings. Individual shifts in EGly are shown for cells incubated with Compound A (0.3 and 3 μM) or vehicle (V) for 15min.

[0051] FIG 2B depicts a first bar graph showing AEoiy (mM) by concentration of vehicle and Compound A and a second bar graph showing reduction in [CF] (mM) by concentration of vehicle and Compound A. Mean shifts in Eoiy were determined for cells treated with vehicle, p=0.1227, Compound A 0.3pM (*p=0.0051), and 3pM (*p=0.0350), respectively, n=5 transfections. Compound A induced changes in [C1‘] were calculated from Eoiy using the Nemst equation for vehicle (V), (p=0.1227), 300nM, (*p=0.0051), or 3pM (*p=O. O35O) CmpA, n=5Docket: 2262-122 PCTtransfections.

[0052] FIG. 2C depicts immunoblotting results and a bar graph showing surface / total KCC2 (% cone.) by concentration of Compound A. HEK-293 cells (UT) or those expressing KCC2 were exposed to V, 0.3 μM, or 3 μM 350 for 1 min and biotinylated with NHS-biotin. Surface and total extracts were subsequently immunoblotted with KCC2 and actin antibodies. The ratio of surface / total KCC2 immunoreactivity was determined and normalized to V (100%) (n = 3 transfections).

[0053] FIG. 2D depicts immunoblotting results obtained by exposing untransfected HEK-293 cells (U) or those expressing KCC2 to vehicle (V), 0.3, or 3 μM, Compound A, for 15 min and biotinylated with NHS-Biotin. Surface and total extracts were subsequently immunoblotted with KCC2 and actin antibodies. The ratio of surface / total KCC2 immunoreactivity was determined and normalized to V (100%) for 0.3 (*p=0.659) or 3μM Compound A (*p=0.739), n=3 transfections.

[0054] FIG. 2E depicts a first bar graph showing pS940 / KCC2 (% concentration) of Compound A (pM) and a second bar graph showing pT1007 / KCC2 (% concentration) of Compound A (pM). HEK-293 cells were treated with V (-) or 3μM Compound A (+) for 15 min. Cell lysates were immunoblotted with KCC2, pS940, KCC2 and actin antibodies. The ratios of pS940 / KCC2 (p=0.491) and pT1007 / KCC2 (p=0.721) were then compared to V (100%), n=3 transfections. In all panels p values were determined using unpaired t-tests with Welch’s correction.

[0055] FIG. 3A depicts a graph showing current (pA) versus holding potential (mV) for vehicle and Compound A. 18-21 Div hippocampal neurons were subjected to gramicidin perforated patch clamp recordings in the presence of bumetanide (10μM) and TTX (500 nM). After attaining perforation, cultures were exposed to 300nM Compound A, or V (1%βCD) for 15 min. EGABA was then determine using voltage ramps protocols and representative current-voltage (I-V) plots are shown for neurons at 0 (blue) and 15 (red) min treatment for V and Compound A treated neurons.

[0056] FIG. 3B depicts a first bar graph showing neuronal EGABA values by exposure to vehicle (V) over time and a second bar graph defining neuronal EGABA values by exposure to Compound A over time. EGABA values were measured at 0 and 15 min following treatment with V (p = 0.2190) or 300nM Compound A (*p = 0.0104), n=5 cultures.Docket: 2262-122 PCT

[0057] FIG. 3C depicts a bar graph showing neuronal [Cl-] values by exposure to Compound A over time. [Cl-] values were calculated from EGABA values for V (p = 0.1646) or Compound A (*p = 0.0153) treated neurons, n=5 cultures.

[0058] FIG. 3D depicts a first bar graph showing neuronal Basal EGABA (mV) upon exposure to vehicle (V) and Compound A, and a second bar graph showing neuronal 1 IK A EGABA upon exposure to vehicle (V) and Compound A. 18-21 Div hippocampal neurons were incubated with 300nM Compound A or vehicle for Ih. Neurons were subject to whole cell recording using an intracellular solution containing 30 mM Cl’. 5 min later basal EGABA values were determined and compared between treatments, *p=0.0253, n=4 cultures. Neurons were subsequently exposed to 10 pM VU0463271 and the magnitude of the shift in EGABA (VU0463271 AEGABA) was then determined and compared between groups, *p = 0.040 n= 4 cultures.

[0059] FIG. 4A depicts a bar graph showing accumulation of Compound A in the mouse brain within 30 minutes after intravenous injection of 25mg / kg Compound A in 5% β-cyclodextrin (βCD). 15 and 60 minutes later drug levels were measured via LC-MS / MS, n=3 mice.

[0060] FIG. 4B depicts a bar graph showing accumulation of Compound A in the mouse brain after intravenous injection of 50mg / kg Compound A in 5% β-cyclodextrin (βCD). 1 and 2 h later drug levels were measured via LC-MS / MS, n=3 mice.

[0061] FIG. 4C is a graph showing accumulation of Compound A in the mouse brain within 30 minutes after subcutaneous injection of 50mg / kg Compound A in 5% β-cyclodextrin (βCD). Drug accumulation was then measured over a time course of 8h via LC-MS / MS, n=3-4 mice.

[0062] FIG. 4D depicts a first bar graph showing the effect of Compound A and vehicle (V) on distance traveled after mice were dosed with vehicle (V) or 50mg / kg Compound A and a second bar graph showing the effect of Compound A and vehicle (V) on time spent in a center zone after mice were dosed with vehicle or 50mg / kg Compound A. 2-3h after injection, the mice were placed in the center of a 60cm x 60cm open field and allowed to explore for 10min. The total distance traveled (p=0.365) and time in the center of the area (p=0.425) were then quantified and compared between treatments using t-tests; n=9 mice.Docket: 2262-122 PCTDETAILED DESCRIPTION

[0063] Described herein are methods and compositions for treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease which include administering to a subject in need thereof an effective amount of an effective amount of a compound according to Formula (I):or a pharmaceutically acceptable salt thereof, wherein:

[0064] R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C3-7cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -0-(CH2)m-C6-ioaryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -C1-3alkyl, -C1-8alkoxy and -C2-8alkynyloxy wherein -C1-3alkyl, -C1-8alkoxy and -C2-8alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-C1-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;

[0065] R2is selected from -H; -halo; and -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;

[0066] A is selected fromDocket: 2262-122 PCT

[0067] R3is selected from -H; -C1-6alkyl; -C2-6alkenyl; -C2-6alkynyl; C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -Ci-3alkyl optionally substituted by 1 or 2 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9;

[0068] R4aand R4bare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;

[0069] R4cand R4dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3, or R4cand R4dtogether with the carbon to which they are attached represent carbonyl;

[0070] R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;

[0071] R6is selected from -H; -halo; -NH2; -CN; -Ci-salkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-Ci-3alkyl;

[0072] R7is selected from NR10R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -Ci-ealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; Cs-scycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H;

[0073] R8and R9are each independently selected from -H and -C1-6alkyl;

[0074] R10is -C1-6alkyl;

[0075] R11is selected from -C1-6alkyl optionally substituted with 1 or 2 substituents selected from -F and -C1-3alkoxy; and -(CH2)nR12;

[0076] R12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;

[0077] m is 0 or l; andDocket: 2262-122 PCT

[0078] n is 1, 2 or 3.

[0079] It should be understood that, as used herein, “a compound of Formula (I)” and “a compound according to Formula (I)” are used interchangeably.

[0080] Described herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease with a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. Compositions including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, are described herein. Methods and compositions for treating tinnitus include administering to a subject in need thereof an effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. Methods and compositions for treating acute sensorineural hearing loss include administering to a subject in need thereof an effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. Methods and compositions for treating age-related hearing loss include administering to a subject in need thereof an effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. Methods and compositions for treating Meniere's disease include administering to a subject in need thereof an effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof.

[0081] In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease include administering a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof to provide improvement in next day functioning of the subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease in a subject. In embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in providing improvement in next day functioning of a subject with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. In embodiments, provided herein is a compound of Formula (I), or aDocket: 2262-122 PCTpharmaceutically acceptable salt thereof, for the manufacture of a medicament for treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease.

[0082] Without wishing to be bound by any particular theory, tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease can result from impairedCl⁻ transport. See, e.g., Parameshwarappa, V., Siponen, M L, Watabe, I. et al. Noise-induced hearing loss alters potassium-chloride cotransporter KCC2 and GABA inhibition in the auditory centers. Sci Rep 14, 10689 (2024) (“Parameshwarappa et al.”). KCC2 is a K+-Cl⁻ cotransporter and responsible for maintaining low Cl⁻ concentration in neurons of the central nervous system (CNS), essential for postsynaptic inhibition through GABAA and glycine receptors. As a result of their KCC2 activation activity, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, restore GABAergic function in patients experiencing tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease involving impaired Cl" transport, thereby relieving, alleviating or eliminating symptoms. For example, in age-related hearing loss, lower levels of cortical GABA were associated with greater central gain, which was predictive of poorer speech recognition in noise (SIN). See, Harris et al., Journal of Neuroscience 21 September 2022, 42 (38) 7201-7212, supra. Further, as stated in Parameshwarappa et al.KCC2 downregulation and chloride dysregulation offer new avenues of understanding the potential link between auditory symptoms (tinnitus and / or hyperacusis) and neurological and psychiatric diseases. Accordingly, administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, restores GABAergic function thereby improving, e g., relieving, alleviating or eliminating, tinnitus, acute sensorineural hearing loss, age-related hearing loss and / or Meniere’s disease.

[0083] In embodiments, provided herein are methods of treating tinnitus including administering to a patient in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of the tinnitus. Symptoms of tinnitus may include, but are not limited to, ringing, roaring, static, buzzing, hissing, whooshing, cricket noises, jackhammer noises and / or whistling in one or both ears. The symptoms may be intermittent or continuous.

[0084] In embodiments, provided herein are methods of treating acute sensorineural hearing loss including administering to a patient in need thereof a pharmaceutical compositionDocket: 2262-122 PCTincluding a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of the acute sensorineural hearing loss. Symptoms of acute sensorineural hearing loss may include, but are not limited to, hearing loss, aural fullness, and tinnitus.

[0085] In embodiments, provided herein are methods of treating age-related hearing loss including administering to a patient in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of the age-related hearing loss. Symptoms of age-related hearing loss may include, but are not limited to, difficulty hearing, reduced ability to perceive certain high-pitched sounds, reduced ability to perceive certain low-pitched sounds and a total loss of hearing.

[0086] In embodiments, provided herein are methods of treating Meniere's disease including administering to a patient in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of the Meniere's disease. Symptoms of Meniere's disease may include, but are not limited to, vertigo, hearing loss, tinnitus, hypersensitivity to sounds, and aural fullness in the affected ear.

[0087] As used herein, the terms "effective amount" or “therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and / or physiologic effect in connection with tinnitus. Likewise, the terms "effective amount" or “therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and / or physiologic effect in connection with acute sensorineural hearing loss. Likewise, the terms "effective amount" or “therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and / or physiologic effect in connection with age-related hearing loss. Likewise, the terms "effective amount" or “therapeutically effective amount” refer to an amount of a compound, material, composition, medicament, or other material that is effective to achieve a particular pharmacological and / or physiologic effect in connection with Meniere's disease.Docket: 2262-122 PCT

[0088] In embodiments, effective amount refers to an amount which may be suitable to prevent a decline in or exacerbation of any one or more of the above symptoms, or, in embodiments, to improve any one or more of the above symptoms. In embodiments, effective amount refers to an amount which may be suitable to prevent a decline in two or more of the above symptoms, or, in embodiments, to improve two or more of the above symptoms. In embodiments, effective amount refers to an amount which may be suitable to prevent a decline in three or more of the above symptoms, or, in embodiments, to improve three or more of the above symptoms. In embodiments, an effective amount may be suitable to reduce either the extent or rate of decline in a subject’s cognitive skills or functioning, and / or the effective amount may be suitable to delay the onset of such decline. Such effectiveness may be achieved, for example, by administering compositions described herein to an individual or to a population. In embodiments, the reduction, or delay of such a decline, or the improvement in an individual or population can be relative to a cohort, e.g., a control subject or a cohort population that has not received the treatment or been administered the composition or medicament. The terms “effective amount” and “therapeutically effective amount” are used interchangeably herein.

[0089] The effective amount can vary according to a variety of factors such as subjectdependent variables (e.g., age, immune system, health, etc.), the disease or disorder being treated, as well as the route of administration and the pharmacokinetics of the agent being administered.

[0090] Accordingly, an effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a subject having tinnitus. An effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a subject having acute sensorineural hearing loss. An effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a subject having age-related hearing loss. An effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is used to treat a subject having Meniere's disease.

[0091] Many pharmaceutical products are administered as a fixed dose, at regular intervals, to achieve therapeutic efficacy. Duration of action is typically reflected by a drug’s plasma half-life. Since efficacy is often dependent on sufficient exposure within the central nervous systemDocket: 2262-122 PCTadministration of CNS drugs with a short half-life may require frequent maintenance dosing. CNS drugs with a long half-life may require less frequent maintenance dosing.

[0092] The subject may be an animal, e.g., mammal, e.g., human, etc. As used herein, the terms “treat”, “treatment" or “treating” encompass any manner in which the symptoms or pathology of a condition, disorder or disease associated with tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere's disease are ameliorated or otherwise beneficially altered. In embodiments, “treat”, “treatment" or “treating” can refer to inhibiting a disease or condition, e.g., arresting or reducing its development or at least one clinical or subclinical symptom thereof. In embodiments, “treat”, “treatment" or “treating” can refer to relieving the disease or condition, e.g., causing regression of the disease or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject being treated may be statistically significant, mathematically significant, or at least perceptible to the subject and / or the physician.

[0093] It should be understood that in the context of Formula (I) and other Formulas disclosed herein that unless otherwise indicated, the term “alkyl” includes both linear and branched chain alkyl groups. The prefix Cp-qin Cp-qalkyl and other terms (where p and q are integers) indicates the range of carbon atoms that are present in the group, for example Ci-3alkyl includes Cialkyl (methyl), C2alkyl (ethyl) and C alkyl (propyl as / / -propyl and isopropyl).

[0094] The term “Cp.qalkoxy” comprises -O-Cp.qalkyl groups and -Cp.qalkyl groups where the O atom is within the alkyl chain, for example, -CH2-O-CH3.

[0095] The term “Cp.qalkenyl” includes both linear and branched chain alkyl groups containing at least two carbon atoms and at least one double carbon-carbon bond.

[0096] The term “Cp.qalkenyloxy” comprises -O-Cp.qalkenyl groups and -Cp.qalkenyl groups where the O atom is within the alkenyl chain.

[0097] The term “Cp.qalkynyl” includes both linear and branched chain alkyl groups containing at least two carbon atoms and at least one triple carbon-carbon bond.

[0098] The term “Cp.qalkynyloxy” comprises -O-Cp.qalkynyl groups and -Cp.qalkynyl groups where the O atoms is within the alkynyl chain.

[0099] Cp-qcycloalkyl refers to a cyclic non-aromatic group of p-q carbon atoms and no heteroatoms. For example, a 3 to 7 membered cycloalkyl refers to a ring containing 3 to 7 carbon atoms. Suitable C3-7cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Docket: 2262-122 PCT[000100] Aryl is a 6 to 10 membered monocyclic or bicyclic aromatic ring containing no heteroatoms. Aryl includes phenyl.[000101] Heterocycloalkyl is a monocyclic saturated or partially unsaturated, non-aromatic ring having, for example, 3 to 7 members, such as 3 to 6 members, 5 to 7 members such as 5 or 6 members, where at least one member and up to 4 members, particularly 1, 2 or 3 members of the ring are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms, in stable combinations known to those of skill in the art. Heterocycloalkyl ring nitrogen and sulphur atoms are optionally oxidised. Suitable heterocycloalkyl rings include morpholinyl, thiazolidinyl, homomorpholine, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and tetrahydrofuranyl. In embodiments, when R7is heterocycloalkyl, optionally two substituents on the same ring carbon together with the carbon to which they are attached form a 5 to 7 membered heterocycloalkyl ring, thereby creating a spirocyclic ring system. For example, in embodiments, R7is morpholinyl and two substituents on the same ring carbon together form a tetrahydropyran.[000102] Heteroaryl is a polyunsaturated, monocyclic 5 or 6 membered aromatic ring containing at least one and up to 3 heteroatoms, particularly, 1 or 2 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon atoms. Heteroaryl ring nitrogen and sulphur atoms are optionally oxidised. Suitable heteroaryl rings include pyridinyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazinyl, oxazolyl, thiophenyl and thiazolyl.[000103] The term “halo” is fluorine, chlorine or bromine.[000104] The use of the dashed bond “ - ” in rings A of Formula (I) represents the fusion of the pyrimidine ring.[000105] Where the term “optionally” is used, it is intended that the subsequent feature may or may not occur. As such, use of the term “optionally” includes instances where the feature is present, and also instances where the feature is not present. For example, a group “optionally substituted with 1, 2 or 3 -F substituents” includes group with and without an -F substituent.[000106] The term “substituted” means that one or more hydrogens (for example 1 or 2 hydrogens, or alternatively 1 hydrogen) on the designated group is replaced by the indicated substituent(s) (for example 1, 2 or 3 substituents, or alternatively 1 or 2 substituents, or alternatively 1 substituent), provided that any atom(s) bearing a substituent maintains a permitted valency. Substituent combinations encompass only stable compounds and stable synthetic intermediates. “Stable” means that the relevant compound or intermediate is sufficiently robustDocket: 2262-122 PCTto be isolated and have utility either as a synthetic intermediate or as an agent having potential therapeutic utility. If a group is not described as “substituted”, or “optionally substituted”, it is to be regarded as unsubstituted (i.e. that none of the hydrogens on the designated group have been replaced).[000107] The term “pharmaceutically acceptable” is used to specify that an object (for example a salt, dosage form or excipient) is suitable for use in patients. An example list of pharmaceutically acceptable salts can be found in the Handbook of Pharmaceutical Salts:Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, editors, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. In embodiments, a suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I), to said human or animal body.[000108] In embodiments, a suitable pharmaceutically acceptable salt of a compound of Formula (I) is, for example, an acid addition salt. An acid addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. In embodiments, compounds described herein may form base addition salts. A base-addition salt of a compound of Formula (I) may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person.[000109] In embodiments, a compound according to Formula (I) may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitter ion monohydrate. Acid addition salts, include but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethane-di sulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, pantothenic, p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acid addition salts, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. In embodiments, inorganic acid addition salts, including but not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric or nitric acid addition salts may be used.[000110] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (I). In embodiments there is provided a pharmaceutically acceptable salt of a compound of Formula (I).Docket: 2262-122 PCT[000111] Compounds and salts described herein may exist in solvated forms and unsolvated forms. For example, a solvated form may be a hydrated form, such as a hemi-hydrate, a monohydrate, a dihydrate, a trihydrate or an alternative quantity thereof. The description herein encompasses all such solvated and unsolvated forms of compounds of Formula (I), particularly to the extent that such forms possess KCC2 modulating activity, as for example measured using the tests described herein.[000112] The following embodiments of moiety A may be applied to the description of the compounds of Formula (I), provided herein:[000113] Moiety A is selected from:-oxide thereof.[000114] In embodiments, moiety[000115] In embodiments, moiety[000116] In embodiments, moietyDocket: 2262-122 PCT[000117] In embodiments, moiety[000118] In embodiments, moiety[000119] In embodiments, there is provided a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R4band R7are as defined for Formula (I).[000120] In embodiments, there is provided a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4a, R4band R7are as defined for Formula (I) and when R7is morpholinyl, either:[000121] R1is selected from Cs ealkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C3-?cycloalkyl; -O-Ca-ycycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; heteroaryl is optionally substituted with 1 or 2 substituents selected from -halo, -Ci-salkyl, -Ci-xalkoxy and -C2-salkynyloxy, wherein -Cnsalkyl, -Ci-xalkoxy and -CAxalkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-C1-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; and aryl is substituted with 1 or 2 substituents selected from -halo, -Cnsalkyl, -Cnsalkoxy and -C2-Docket: 2262-122 PCTsalkynyloxy, wherein -Ci-xalkyl, -Ci-salkoxy and -C2-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; and R2is selected from -H; -halo; and -C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; or [000122] R1is selected from C2-6alkyl; Cz-ealkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; Cs-ycycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; and heteroaryl is optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-xalkoxy and -C2-salkynyloxy, wherein -Ci-3alkyl, -Ci-xalkoxy and -C'2-xalkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; and R2is selected from -halo and -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3.[000123] In embodiments, there is provided a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein:[000124] R1is selected from -C2-6alkyl; -C2-6alkoxy; C -7cycloalkyl; -O-C -7cycloalkyl; phenyl optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-salkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; -O-phenyl optionally substituted with 1 or 2 -halo substituents; -O-C F-phenyl; and thiophenyl; wherein -C2-6alkyl and -C2-6alkoxy are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;[000125] R2is selected from -H, -F and -CH3;[000126] R3is selected from -C2-4alkynyl and -Ci-3alkyl optionally substituted with -NR8R9;[000127] R4aand R4bare both -H;[000128] R7is selected from -NR^R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy; cyclopropyl; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; or theDocket: 2262-122 PCTheterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 6 membered monocyclic heterocycloalkyl;[000129] R8and R9are each independently selected from -Ci-ealkyl;[000130] R10is selected from -Ci-salkyl;[000131] R11is selected from -Ci-salkyl optionally substituted with 1 or 2 substituents selected from -F and -Cioalkoxy; and -(CH2)nR12;[000132] R12is selected from a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;[000133] n is 1 or 2.[000134] In embodiments, there is provided a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein:[000135] R1is selected from -C2-ealkyl; -C2-6alkoxy; Cs-ycycloalkyl; -O-C3-7cycloalkyl; phenyl substituted with 1 or 2 substituents selected from -halo, -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy wherein -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; -O-phenyl optionally substituted with 1 or 2 -halo substituents; -O-CFF-phenyl; and thiophenyl; wherein -C2-6alkyl and -C2-6alkoxy are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; and R2is selected from -H, -F and -CH3; or[000136] R1is selected from -C2-6alkyl; -C2-6alkoxy; C3-7cycloalkyl; -O-C3-7cycloalkyl; unsubstituted phenyl; -O-phenyl optionally substituted with 1 or 2 -halo substituents; -O-CH2-phenyl; and thiophenyl; wherein -C2-6alkyl and -C2-6alkoxy are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; and R2is selected from -F and -CH3;[000137] R3is selected from -C2-4alkynyl and -Ci-3alkyl optionally substituted with -NR8R9;[000138] R4aand R4bare both -H;[000139] R7is selected from -NR^R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy; cyclopropyl; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; or theDocket: 2262-122 PCTheterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 6 membered monocyclic heterocycloalkyl;[000140] R8and R9are each independently selected from -Ci-ealkyl;[000141] R10is selected from -Ci-salkyl;[000142] R11is selected from -Ci-salkyl optionally substituted with 1 or 2 substituents selected from -F and -Cioalkoxy; and -(CH2)nR12;[000143] R12is selected from a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl; and[000144] n is 1 or 2.[000145] In embodiments, there is provided a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein R1, R2, R5a, R5b, R5c, R5dand R7are as defined for Formula (I).[000146] In embodiments, there is provided a compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein:[000147] R1is selected from C3-7cycloalkyl and C6-10aryl, wherein the aryl is optionally substituted with a -C2-salkoxy substituent wherein the alkoxy is optionally substituted with 1 or 2 -CF3 substituents;[000148] R2is -H;[000149] R5a, R5b, R5cand R5dare each -H;[000150] R7is selected from -NR10Rn; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -Ci-ealkyl optionally substitutedDocket: 2262-122 PCTwith 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-salkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; and C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H.[000151] In embodiments, there is provided a compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein:[000152] R1is selected from C3-7cycloalkyl and Cs-ioaryl, wherein the aryl is optionally substituted with a -C'2-xalkoxy substituent wherein the alkoxy is optionally substituted with 1 or 2 -CF3 substituents;[000153] R2is -H;[000154] R5a, R5b, R5cand R5dare each -H;[000155] R7is selected from a 5 to 7 membered monocyclic heterocycloalkyl and a 5 or 6 membered monocyclic heteroaryl, wherein the heterocycloalkyl and heteroaryl are optionally substituted with a substituent selected from -Ci- alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -OH; and cyclopropyl.[000156] In embodiments, there is provided a compound of Formula (IV):or aN-oxide or pharmaceutically acceptable salt thereof, wherein R1, R2, R6and R7are as defined for Formula (I).[000157] In embodiments, there is provided a compound of Formula (IV), or a N-oxide or pharmaceutically acceptable salt thereof, wherein:[000158] R1selected from C3-7cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;Docket: 2262-122 PCT[000159] R2is selected from -H; -halo; and -Ci-salkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;[000160] R6is selected from -H; -halo; -NH2; -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-Ci-3alkyl;[000161] R7is selected from -NR10Rn; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -Cnealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; and C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl;[000162] R8and R9are each independently selected from -H and -C1-6alkyl;[000163] R10is -Ci-6alkyl;[000164] R11is selected from -Ci-6alkyl optionally substituted with 1 or 2 substituents selected from -F and -Cioalkoxy; and -(CH2)nR12;[000165] R12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;[000166] n is 1, 2 or 3.[000167] In embodiments, there is provided a compound of Formula (IV), or a N-oxide or pharmaceutically acceptable salt thereof, wherein:[000168] R1selected from C3-7cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;[000169] R2is -H;[000170] R6is selected from -H; -halo; -NH2; -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-Ci.3alkyl;Docket: 2262-122 PCT[000171] R7is selected from a 5 to 7 membered monocyclic heterocycloalkyl optionally substituted with 1, 2 or 3 groups selected from -Ci-ealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; and Cs-scycloalkyl;[000172] R8and R9are each independently selected from -H and -Ci-ealkyl.[000173] The following embodiments of moieties R1, R2, R3, R4a, R4b, R4c, R4d, R5, R6a, R6b, R7, R8, R9, R10, R11, R12, m and n may be applied, alone or in combination, to the description of the compounds of Formula (I) provided herein. The following embodiments of moieties R1, R2, R3, R4a, R4b, R7, R8, R9, R10, R11, R12, m and n may be applied, alone or in combination, to the description of the compounds of Formula (II) provided herein. The following embodiments of moieties R1, R2, R5a, R5b, R5c, R5d, R7, R8, R9, R10, R11, R12, m and n may be applied, alone or in combination, to the description of the compounds of Formula (III) provided herein. The following embodiments of moieties R1, R2, R6, R7, R8, R9, R10, R11, R12, m and n may be applied, alone or in combination, to the descriptions of the compounds of Formula (IV) provided herein.[000174] R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C3-7cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -C2-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl.[000175] In embodiments, R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C3-7cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-loaryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein -0-(CH2)m-C6-ioaryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy wherein -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; and C6-10aryl is substitutedDocket: 2262-122 PCTwith 1 or 2 substituents selected from -halo, -Ci-salkyl, -Ci-salkoxy and -Cs-salkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -C2-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl[000176] In embodiments, R1is selected from C2-6alkyl; C2-6alkoxy; C3-?cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl and thiophenyl; wherein alkyl, alkoxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl is optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -Cz-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-C1-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl.[000177] In embodiments, R1is selected from C2-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; C2-4alkoxy; C4-6cycloalkyl; -O-C4-6cycloalkyl; phenyl; -O-(CH2)m-phenyl; and thiophenyl; wherein phenyl is optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Ci-jalkyl, -Ci-salkoxy and -C2-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl.[000178] In embodiments, R1is selected from C2-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; C2-4alkoxy; C4-ecycloalkyl; -O-C4-6cycloalkyl; phenyl; -O-(CH2)m-phenyl; and thiophenyl; wherein -O-(CH2)m-phenyl is optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl; and phenyl is substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Cualkyl, -Ci-salkoxy and -C2-8alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3 and -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl.[000179] In embodiments, R1is selected from -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; thiophenyl; phenyl; -O-phenyl; -O-CFh-phenyl; whereinDocket: 2262-122 PCTphenyl is optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C=CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C=CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C=CH, -O-(CH2)5CF3and -O-(CH2)7.[000180] In embodiments, R1is selected from -CF2CF3; propyl; butyl; pentyl; propoxy; cyclobutyl; cyclohexyl; -O-cyclopentyl; thiophenyl; phenyl substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C=CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C=CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C=CH, -O-(CH2)5CF3and -O-(CH2)7.; -O-phenyl; -O-CH2-phenyl; wherein -O-phenyl and -O-CH2-phenyl is optionally substituted with 1 or 2 substituents selected from -F, -Cl, -CH3, -O-(CH2)5C=CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C=CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C=CH, -O-(CH2)5CF3and -O-(CH2)7.[000181] In embodiments, R1is cyclohexyl. In another embodiment, R1is phenyl substituted with -F, -Cl, -CH3, -O-(CH2)5C=CH, -O-(CH2)7, -O-(CH2)2C(N=N)(CH2)2C=CH, -O-(CH2)2NHC(O)OC(CH3)3, -O-CH2C=CH, -O-(CH2)5CF3and -O-(CH2)7. In embodiments, R1is phenyl.[000182] R2is selected from -H, -halo and -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3. In embodiments, R2is -H. In embodiments, R2is -halo. In embodiments, R2is -F. In embodiments, R2is -Cusalkyl. In embodiments, R2is methyl.[000183] R3is selected from -H; -Ci-ealkyl; -C2-ealkenyl; -C2-6alkynyl; -C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted by 1, 2 or 3 groups, for example 1 or 2 groups, selected from -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9.[000184] In embodiments, R3is selected from -H; -C2-4alkynyl; -Ci-3alkyl optionally substituted with -C(O)NR8R9or -NR8R9; and a 5 or 6 membered heterocycloalkyl optionally substituted with Ci.3alkyl.[000185] In embodiments, R3is selected from -H; -C2-4alkynyl; -Cioalkyl optionally substituted with -C(O)NR8R9or -NR8R9; and a 5 or 6 membered nitrogen containing heterocycloalkyl optionally substituted with Ci-3alkyl.[000186] In embodiments, R3is selected from -H; -C2-4alkynyl; -Ci^alkyl optionally substituted with -C(O)NR8R9or -NR8R9; and piperidinyl optionally substituted with Ci-3alkyl.Docket: 2262-122 PCT[000187] In embodiments, R3is selected from methyl, ethyl, z-propyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2, -CH2C=CH, -CH2C(O)N(CH3)2and N-methylpiperidine. In embodiments, R3is selected from ethyl, z-propyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2, -CH2C=CH, -CH2C(O)N(CH3)2and N-methylpiperidine.[000188] In embodiments, R3is selected from -C2-4alkynyl and -Ci-3alkyl optionally substituted with -NR8R9.[000189] In embodiments, R3is selected from ethyl, z-propyl, -(CH2)2N(CH3)2, -(CH2)3N(CH3)2and -CH2C=CH.[000190] In embodiments, R3is z-propyl.[000191] R4aand R4bare each independently selected from -H and -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3. In embodiments, R4ais methyl and R4bis -H. In embodiments, R4aand R4bare both -H.[000192] R4cand R4dare each independently selected from -H and C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; or R4cand R4dtogether with the carbon to which they are attached represent carbonyl. In embodiments, R4cand R4dtogether with the carbon to which they are attached represent carbonyl. In embodiments, R4cand R4dare each independently selected from -H and C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3. In embodiments, R4cand R4dare both -H or together with the carbon to which they are attached represent carbonyl. In embodiments, R4cand R4dare both -H.[000193] R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3. In embodiments, R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3. In embodiments, R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl. In embodiments, R5ais methyl and R5b, R5cand R5dare each -H. In embodiments, R5a, R5band R5care each -H and R5dis methyl. In embodiments, R5a, R5b, R5cand R5deach represent -H.[000194] R6is selected from -H; -halo; -NH2; -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-Ci-3alkyl. In embodiments, R6is selected from -H; -Br; -NH2; -CN; methoxy; ethyl; -C(O)OCH3; -C(O)NH2; -C(O)OH; and -NHC(O)CH3.Docket: 2262-122 PCT[000195] R7is selected from -NR10Rn; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 (for example, 1 or 2) groups selected from -CN; -Ci-ealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; and C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl.[000196] In embodiments, R7is selected from NR10R11; a 5 to 7 membered monocylic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5 or 6 membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, oxazolyl, imidazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 (for example, 1 or 2) groups selected from -CN; -Ci-ealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-3alkylene-NHC(O)OCi-6alkyl; and C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl.[000197] In embodiments, R7is selected from NR10R11; a 5 to 7 membered monocylic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5 or 6 membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, oxazolyl, imidazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 (for example, 1 or 2) groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH2CF3, -CH2OH, -CH2CH2OH, -C(O)OH, -(CH2)2NHC(O)CH3and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 6 membered monocyclic heterocycloalkyl.[000198] In embodiments, R7is selected from NR10R11wherein R10is selected from methyl, ethyl or propyl and R11is selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -Docket: 2262-122 PCT(CH2)PR12; a 5 to 7 membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl; a 5 or 6 membered monocyclic heteroaryl selected from pyridinyl, dihydropyranyl, oxazolyl, imidazolyl and thiazolyl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1 or 2 groups selected from -CN, methyl, ethyl, propyl, cyclopropyl, methoxy, -CH2CF3, -CH2OH, -CH2CH2OH, -C(O)OH, -(CH2)2NHC(O)CH3and -CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form tetrahydropyranyl.[000199] In embodiments, R7is selected from NR10R11wherein R10is selected from methyl, ethyl or propyl and R11is selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2)nR12.[000200] In embodiments, R7is selected from NR10R11wherein R10is selected from methyl, ethyl or propyl; R11is selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3and -(CH2)nR12; n is 1 or 2; and R12is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.[000201] In embodiments, R7is selected from a 5 to 7 membered monocyclic heterocycloalkyl optionally substituted with 1, 2 or 3 (for example, 1 or 2) groups selected from -CN; -Ci-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)OH; — Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci.3alkylene-NHC(O)OCi-6alkyl and C3.5cycloalkyl; or the heterocycloakyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl.[000202] In embodiments, R7is a 5 to 7 membered monocyclic heterocycloalkyl selected from morpholinyl, thiazolidinyl, tetrahydropyranyl, pyrrolyl, thiomorpholinyl and 3,4-dihydro-2H-pyranyl wherein the heterocycloalkyl is optionally substituted with 1 or 2 groups selected from -CN; -Ci-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)OH; -CH2NHC(O)CH3; -CH2NHC(O)OC(CH3)3; and C3.5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon whichDocket: 2262-122 PCTtogether with the carbon atom to which they are attached form a 6 membered monocyclic heterocycloalkyl.[0002031 In embodiments, R7is a 5 to 7 membered monocyclic heterocyclalkyl optionally substituted with 1 or 2 substituents selected from methyl, ethyl, propyl, cyclopropyl, -CH2CH2OH, -CH2OH, -C(O)OH, -CH2CF3, and - CH2NHC(O)OC(CH3)3; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form tetrahydropyran.[000204] In embodiments, R7is morpholinyl optionally substituted with 1 or 2 substituents selected from methyl, ethyl, propyl, cyclopropyl, -CH2CH2OH, -CH2OH, -C(O)OH, -CH2CF3, and - CH2NHC(O)OC(CH3)3; or optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form tetrahydropyran (i.e. R7becomes a spirocyclic group).[000205] In embodiments, R7is 2-methylmorpholin-4-yl.[000206] R8is selected from -H and -Ci-ealkyl. In embodiments, R8is selected from -H and -Ci-3alkyl. In embodiments, R8is -H. In embodiments, R8is -Ci-3alkyl. In embodiments, R8is methyl.[000207] R9is selected from -H and -Ci-6alkyl. In embodiments, R9is selected from -H and -Cisalkyl. In embodiments, R9is -H. In embodiments, R9is -Ci-salkyl. In embodiments, R9is methyl.[000208] R10is -Ci-salkyl. In embodiments, R10is -Ci-3alkyl. In embodiments, R10is methyl. In another embodiment, R10is ethyl. In embodiments, R10is propyl.[000209] R11is selected from -Ci-ealkyl optionally substituted with 1 or 2 substituents selected from -F and -Ci-3alkoxy; or -(CH2)nR12. In embodiments, R11is selected from -Ci-ealkyl optionally substituted with 1 or 2 substituents selected from -F and ethoxy. In embodiments, R11is selected from ethyl, propyl, CH2CHF2, CH2CH2OCH2CH3 and -(CH2)nR12In embodiments, R11is selected from -(CH2)nR12.[000210] R12is selected from a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl. In embodiments, R12is selected from isoxazolyl, oxadiazolyl, cyclopropyl, pyrazinyl, tetrahydrofuranyl and pyridinyl.[000211] m is 0 or 1. In embodiments, m is 0. In embodiments, m is 1.Docket: 2262-122 PCT[000212] n is 1, 2 or 3. In embodiments, n is 1 or 2. In embodiments, n is 1. In embodiments, n is 2. In embodiments, n is 3.[000213] In embodiments, the compound of Formula (I) is selected from:[000214] 2-(diethylamino)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000215] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000216] 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(l,3-thiazolidin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000217] 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4- { [4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000218] 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(thiomorpholin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000219] 2-[(2S)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000220] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000221] 2-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000222] 2-(3-methylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000223] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000224] 4-[(4-cyclohexylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000225] 4-[(4-cyclohexylphenyl)amino]-2-(2-methylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000226] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000227] 4-[(4-cyclohexylphenyl)amino]-2-((2R)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;Docket: 2262-122 PCT[000228] 4-[(4-cyclohexylphenyl)amino]-2-((2S)-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000229] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(2,2,2-trifluoroethyl)morpholin- 4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000230] tert-butyl {[(2R)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl]methyl}carbamate;[000231] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-[2-(propan-2-yl)morpholin-4-yl]- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000232] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(l,3-thiazolidin-3-yl)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000233] 4-[(4-cyclohexylphenyl)amino]-2-[(2-ethoxyethyl)(methyl)amino]-6-(propan-2-yl)- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000234] 4-[(4-cyclohexylphenyl)amino]-2-(2-ethylmorpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000235] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(l,2-oxazol-3-yl)methyl]amino}-6- (propan-2 -yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000236] 4-[(4-cy cl ohexylphenyl)amino]-2-{ methyl [2-(l,2,4-oxadiazol-3-yl)ethyl]amino}-6- (propan-2 -yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000237] 4-[(4-cyclohexylphenyl)amino]-2-(l,4-oxazepan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000238] 4-[(4-cyclohexylphenyl)amino]-2-(l,9-dioxa-4-azaspiro[5.5]undecan-4-yl)-6-(propan- 2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000239] 4-[(4-cyclohexylphenyl)amino]-2-(3-methoxypyrrolidin-l-yl)-6-(propan-2-yl)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000240] 4-[(4-cyclohexylphenyl)amino]-2-[2-(2-hydroxyethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000241] 4-[(4-cyclohexylphenyl)amino]-2-(dipropylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000242] 4-[(4-cyclohexylphenyl)amino]-2-[(cyclopropylmethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;Docket: 2262-122 PCT[000243] 4-[(4-cyclohexylphenyl)amino]-2-[2-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000244] 4-[(4-cyclohexylphenyl)amino]-2-[3-(hydroxymethyl)morpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000245] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(pyrazin-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000246] 4-[(4-cyclohexylphenyl)amino]-2-(diethylamino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000247] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[(oxolan-2-yl)methyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000248] 4-[(4-cyclohexylphenyl)amino]-2-[(2,2-difluoroethyl)(methyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000249] 4-[(4-cyclohexylphenyl)amino]-2-{methyl[2-(pyridin-2-yl)ethyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000250] (3S)-4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholine-3-carboxylic acid;[000251] N-[2-(4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}morpholin-2-yl)ethyl]acetamide;[000252] 6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000253] 6-isopropyl-4-((4-isopropylphenyl)amino)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo [3,4-d]pyrimidin-7-one (Compound B);[000254] 4-{4-[(4-cyclohexylphenyl)amino]-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl}pyridine-2-carbonitrile;[000255] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000256] 4-[(4-cyclohexylphenyl)amino]-2-(2-methoxypyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000257] 4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one (Compound C);Docket: 2262-122 PCT[000258] 4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000259] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(pyridin-4-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000260] 4-[(4-cyclohexylphenyl)amino]-2-(l-methyl-lH-pyrazol-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000261] 4- [(4-cy cl ohexylphenyl)amino] -2-( 1, 3 -oxazol-5 -yl)-6-(propan-2-yl)-5,6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000262] 4-[(4-cyclohexylphenyl)amino]-6-(propan-2-yl)-2-(l,3-thiazol-5-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000263] 2-(3,6-dihydro-2H-pyran-4-yl)-6-(propan-2-yl)-4-{[4-(propan-2-yl)phenyl]amino}- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000264] 4-{[4-(4-fluorophenoxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000265] 2-(2-cyclopropylmorpholin-4-yl)-4-({4'-[(hept-6-yn-l-yl)oxy][l,l'-biphenyl]-4-yl}amino)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000266] 2-(2-cyclopropylmorpholin-4-yl)-4-{[4'-(heptyloxy)[l,l'-biphenyl]-4-yl]amino}-6- (propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000267] 4-[(4'-{2-[3-(but-3-yn-l-yl)-3H-diaziren-3-yl]ethoxy}[l,r-biphenyl]-4-yl)amino]-2-(2-cyclopropyl-morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000268] 2-[(2R)-2-methylmorpholin-4-yl]-4-[(4-pentylphenyl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000269] 4-{[4-(butan-2-yl)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000270] 4-{[4-(benzyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000271] 2-(2-cyclopropylmorpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000272] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;Docket: 2262-122 PCT[000273] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-[(4-propylphenyl)amino]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000274] 2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan- 2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000275] 2-(2-cyclopropylmorpholin-4-yl)-6-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000276] 4-[(4-cyclobutylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000277] 4-{[4-(cyclopentyloxy)phenyl]amino}-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000278] 2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-4-{[4-(2,2,2-trifluoroethyl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000279] / c77-butyl {2-[(4'-{[2-(2-cyclopropylmorpholin-4-yl)-7-oxo-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino} [ 1, 1 '-biphenyl]-4-yl)oxy]ethyl } carbamate;[000280] 6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-4-{[4-(propan-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000281] 4-[(4-cyclohexylphenyl)amino]-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000282] tert-butyl { 2- [(4' - { [2-(morpholin-4-y l)-7 -oxo-6-(propan-2-yl)-6, 7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]amino}[l,r-biphenyl]-4-yl)oxy]ethyl}carbamate;[000283] 4-[(4'-{2-[3-(but-3-yn-l-yl)-3H-diaziren-3-yl]ethoxy}[l,l'-biphenyl]-4-yl)amino]-2- (morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000284] 2-(morpholin-4-yl)-6-(propan-2-yl)-4-({4'-[(prop-2-yn-l-yl)oxy][l, T-biphenyl]-4-yl}amino)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000285] 4-[(4-cyclohexylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000286] 4-[(4-cyclohexylphenyl)amino]-6-[2-(dimethylamino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000287] 4-[(4-cyclobutylphenyl)amino]-6-[3-(dimethylamino)propyl]-2-[(2R)-2-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;Docket: 2262-122 PCT[000288] 4-[(4-cyclobutylphenyl)amino]-6-[2-(dimethylarnino)ethyl]-2-[(2R)-2-methylmorpholin-4-yl]-5, 6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000289] 2-(morpholin-4-yl)-4-{[4-(propan-2-yl)phenyl]amino}-6-(prop-2-yn-l-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000290] 4-[(4-cyclohexylphenyl)amino]-2-(oxan-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000291] 4- [(4-cy cl ohexylphenyl)amino] -2-( 1 H-imidazol- 1 -yl)-6-(propan-2-yl)-5, 6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000292] 2-(3, 6-dihy dro-2H-pyran-4-yl)-4-[(2'-methyl[ 1, T-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5, 6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000293] 4-[(4'-{2-[3-(but-3-yn-l-yl)-3H-diaziren-3-yl]ethoxy)[l,r-biphenyl]-4-yl)amino]-2- (3, 6-dihy dro-2H-pyran-4-yl)-6-(propan-2-yl)-5, 6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000294] 2-(3,6-dihydro-2H-pyran-4-yl)-4-[(2-fluoro[l J'-biphenyl]-4-yl)amino]-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000295] 2-(morpholin-4-yl)-4-{[4-(pentafluoroethyl)phenyl]amino}-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000296] 4-[(2-fluoro[l,l'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000297] 4-[(3',4'-dichloro[l,r-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000298] 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{ [4-(propan-2-yl)phenyl]amino}-5, 6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000299] 4-[(4-tert-butylphenyl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5, 6-dihy dro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000300] 4-[(2-methyl[l,l'-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000301] 4-[(4'-chloro[l,r-biphenyl]-4-yl)amino]-2-(morpholin-4-yl)-6-(propan-2-yl)-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000302] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;Docket: 2262-122 PCT[000303] N-(4-cyclobutylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;[000304] N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;[000305] 2-(2-cyclopropylmorpholin-4-yl)-N-[4'-(heptyloxy)[l,l'-biphenyl]-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;[000306] 2-[(2R)-2-methylmorpholin-4-yl]-N-{4'-[(6,6,6-trifluorohexyl)oxy][l,r-biphenyl]-4-yl}-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;[000307] N-(4-cyclohexylphenyl)-2-(2-methylpyridin-4-yl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine;[000308] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine (Compound D);[000309] 6 -bromo-N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;[000310] N-(4-cyclohexylphenyl)-2-(3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine;[000311] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-8-oxo-81ambda~5 — pyrido[2,3-d]pyrimidin-4-amine;[000312] N-(4-cyclohexylphenyl)-6-ethyl-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;[000313] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carbonitrile (Compound H);[000314] methyl 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylate;[000315] methyl (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido[2,3-d]pyrimidine-6-carboxylate (Compound E);[000316] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxylic acid;[000317] 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carboxamide;Docket: 2262-122 PCT[000318] 4-[(4-cyclohexylphenyl)amino]-2-(2-cyclopropylmorpholin-4-yl)pyrido[2,3-d]pyrimidine-6-carboxamide;[000319] N-(4-cyclohexylphenyl)-6-methoxy-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine;[000320] (7?)-N-(4-cyclohexylphenyl)-6-methoxy-2- (2-methylmorpholino)pyrido[2,3-d]pyrimidin-4-amine (Compound F);[000321] N-{4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-rnethylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-6-yl } acetamide;[000322] N-4-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine- 4.6-diamine;[000323] N-(4-cyclohexylphenyl)-2-(morpholin-4-yl)-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;[000324] N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-6-(propan-2-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;[000325] 2-{4-[(4-cyclohexylphenyl)amino]-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl}-N, N-dimethylacetamide (Compound G);[000326] N-(4-cyclohexylphenyl)-2-(2-cyclopropylmorpholin-4-yl)-6-(l-methylpiperidin-4-yl)- 6.7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-amine;[000327] 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-2-yl)phenyl]amino}-5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-one;[000328] 2-(morpholin-4-yl)-6-(propan-2-yl)-4-{[4-(thiophen-3-yl)phenyl]amino}-5,6-dihydro- 7H-pyrrolo[3,4-d]pyrimidin-7-one;[000329] and pharmaceutically acceptable salts thereof.[000330] In embodiments, the compound of Formula (I) is Compound A:Docket: 2262-122 PCTalso known as (R)-N-(4-cyclohexylphenyl)-2-(2-methylmorpholino)-5,7- dihydrofuro[3,4-d]pyrimidin-4-amine (also referred herein to as N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine, or also referred to herein as Compound A or CmpA), or a pharmaceutically acceptable salt thereof.[000331] In embodiments, the compound of Formula (I) is Compound B:6-isopropyl-4-((4-isopropylphenyl)amino)-2-(pyridin-4-yl)-5,6-dihydro- 7H-pyrrolo [3,4-d]pyrimidin-7-oneCompound B[000332] In embodiments, the compound of Formula (I) is Compound C:Docket: 2262-122 PCT4-[(4-cyclohexylphenyl)amino]-2-(2-methylpyridin-4-yl)-6-(propan-2-yl)- 5,6-dihydro-7H-pyrrolo[3,4-d]pyrimidin-7-oneCompound C[000333] In embodiments, the compound of Formula (I) is Compound D:N-(4-cyclohexylphenyl)-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-4-amine Compound D[000334] In embodiments, the compound of Formula (I) is Compound E:Docket: 2262-122 PCTmethyl (J?)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino) pyrido[2,3-d]pyrimidine-6-carboxylateCompound E[000335] In embodiments, the compound of Formula (I) is Compound F:(7?)-N-(4-cyclohexylphenyl)-6-methoxy-2- (2-methylmorpholino) pyrido[2,3 -d]pyrimidin-4-amineCompound F[000336] In embodiments, the compound of Formula (I) is Compound G:Docket: 2262-122 PCT2-(4-((4-cyclohexylphenyl)amino)-2-(3,6-dihydro-2H-pyran-4-yl)-5,7-dihydro- 6H-pyrrolo[3,4-d]pyrimidin-6-yl)-N, N-dimethylacetamideCompound G[000337] In embodiments, the compound according to Formula (I) is:known as (R)-4-((4-cyclohexylphenyl)amino)-2-(2-methylmorpholino)pyrido [2,3-d]pyrimidine-6-carbonitrile (also referred to as 4-[(4-cyclohexylphenyl)amino]-2-[(2R)-2-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidine-6-carbonitrile or Compound H), or a pharmaceutically acceptable salt thereof.[000338] Atoms of the compounds and salts described herein may exist as their isotopes. All compounds of Formula (I) where an atom is replaced by one or more of its isotopes (for example a compound of Formula (I) where one or more carbon atom is annC or13C carbon isotope, or where one or more hydrogen atoms is a2H or3H isotope, or where one or more nitrogen atoms is a15N isotope or where one of more oxygen atoms is an17O or18O isotope) are encompassed herein.[000339] Compounds herein may exist in one or more geometrical, optical, enantiomeric, and diastereomeric forms, including, but not limited to, cis- and trans-forms, E- and Z-forms, and R-,Docket: 2262-122 PCTS- and meso-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g., chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application or adaptation of known methods. In embodiments, a single stereoisomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation. In embodiments, a single stereoisomer is obtained through direct synthesis from, for example, a chiral starting material.[000340] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, which is a single optical isomer being in an enantiomeric excess (% e.e.) of > 95%, > 98% or > 99%. In embodiments, the single optical isomer is present in an enantiomeric excess (% e.e.) of > 99%.[000341] In embodiments, there is provided an N-oxide of a compound of Formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.[000342] Compounds of Formula (I), where R7is -NR10Rn(z.e., R7is linked by an aliphatic N atom), may for example be prepared as described in WO2021 / 180952.[000343] As a result of their KCC2 activation activity, the compounds of Formula (1), or pharmaceutically acceptable salts thereof are useful in therapy, for example, in the treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease mediated at least in part by KCC2. In embodiments, the compounds of Formula (I), or pharmaceutically acceptable salts thereof, increase KCC2 activity, diminish neuronal hyperexcitabilty, and provide a GABAergic effect, resulting in beneficial therapeutic effects on tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease.[000344] The term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. In embodiments, the term "therapy" may also include "prophylaxis" if “prophylaxis” is specifically referred to. The term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease or disorder has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease. Nonetheless,Docket: 2262-122 PCTprophylactic (preventive) and therapeutic treatment are two separate embodiments of the disclosure herein. In embodiments, the term “treatment” can be used synonymously with “therapy”. Similarly, the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein. As used herein, the terms “treat”, “treatment" or “treating” as applied to tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease encompass any manner in which the symptoms or pathology of a condition, disorder or disease associated with tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease are ameliorated or otherwise beneficially altered. In embodiments, “treat”, “treatment" or “treating” can refer to inhibiting a disease, disorder or condition, e.g., arresting or reducing its development or at least one clinical or subclinical symptom thereof. In embodiments, “treat”, “treatment" or “treating” can refer to relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder or condition or at least one of its clinical or subclinical symptoms. The terms “treat”, “treatment" or “treating” may be used interchangeably herein. The benefit to a subject being treated may be statistically significant, mathematically significant, or at least perceptible to the subject and / or the physician.[000345] In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy for tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. For example, in embodiments, Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutically acceptable salt of any of the foregoing, is for use in therapy for tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. In embodiments, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutically acceptable salt of any of the foregoing, for the manufacture of a medicament for tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease.[000346] The term "therapeutically effective amount" refers to an amount of a compound of Formula (I) as described herein which is effective to provide “therapy” in a subject, or to “treat” a disease or disorder in a subject. In the case of tinnitus, acute sensorineural hearing loss, age-related hearing loss and Meniere’s disease, the therapeutically effective amount may cause any of the changes observable or measurable in a subject as described in the definition of “therapy”,Docket: 2262-122 PCT“treatment” and “prophylaxis” above. As recognized by those skilled in the art, effective amounts may vary depending on route of administration, excipient usage, and co-usage with other agents. For example, where a combination therapy is used, the amount of the compound of Formula (I) or pharmaceutically acceptable salt described in this specification and the amount of the other pharmaceutically active agent(s) are, when combined, jointly effective to treat a targeted disease or disorder in the patient. In this context, the combined amounts are in a “therapeutically effective amount” if they are, when combined, sufficient to decrease the symptoms of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease responsive to activation of KCC2 as described herein. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of Formula (I) or pharmaceutically acceptable salt thereof and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s). “Subjects” or “patients” include mammals, for example, humans. The terms “subjects” and “patients” may be used interchangeably herein.[000347] The compounds of Formula (I), or pharmaceutically acceptable salts thereof, may be administered as pharmaceutical compositions, including one or more pharmaceutically acceptable excipients. Therefore, in embodiments, there is provided a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.[000348] The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian. Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, stabilizers, flavorings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.Docket: 2262-122 PCT[000349] The pharmaceutical compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, films, dragees, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, lotions, transdermal patches, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution or suspension for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. The compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.[000350] In embodiments, a pharmaceutical composition herein may contain a compound according to Formula (I) in any of the amounts set forth herein and a diluent in an amount from 30% to 90%. Examples of diluents include lactose, microcrystalline cellulose, starch, calcium phosphate, calcium carbonate, sucrose, mannitol, maltodextrin and sorbitol. In embodiments, a pharmaceutical composition herein may contain a compound according to Formula (I) and a lubricant in an amount, e.g., from 0.25% to 5.0%. Examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, talc, polyethylene glycols and silicon dioxide. Examples of water-soluble lubricants include sodium benzoate, polyethylene glycol, and adipic acid. In embodiments, a pharmaceutical composition herein may contain a compound according to Formula (I) and a disintegrant in an amount, e.g., from 1.0% to 10.0%. There are two classes of disintegrants: traditional disintegrants, such as starch, and super disintegrants, which include croscarmellose sodium, crospovidone, and sodium starch glycolate.[000351] The compound of Formula (I) will normally be administered to a subject, e.g., a warm-blooded animal at a unit dose within the range 2.5-5000 mg / m2body area of the animal, or approximately 0.05-100 mg / kg, and this normally provides a therapeutically-effective dose. A unit dose form such as a tablet, capsule, film, patch, vial will can contain, for example 0.1-500 mg of active ingredient. The daily dose will necessarily be varied depending upon the host treated, the particular route of administration, any therapies being co-administered, and the severity of the illness being treated.Docket: 2262-122 PCT[000352] The pharmaceutical compositions described herein include compounds of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy for tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease.[000353] As such, in embodiments, there is provided a pharmaceutical composition for use in therapy for tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.[000354] In embodiments, there is provided a pharmaceutical composition for use in the treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease in which activation of KCC2 is beneficial, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.[000355] In embodiments, treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease is implemented by administering to a subject, e.g., a human, in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, about 0.01 mg to about 1500 mg of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, such as Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutically acceptable salt of any of the foregoing. In embodiments, methods include treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease by administering to a subject, e.g., a human, in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease about 0.01 mg to about 1500 mg of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. In embodiments, the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, can be, e.g., between 0.1 and 1500 mg / day, or 0.01 mg / kg / day to 15 mg / kg / day, for treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. For example, the daily dosage can be, e.g., in the range of about 0.01 to 1500 mg, 0.1 to 1250 mg, 0.1 to 1000 mg, 0.1 to 750 mg, 0.1 to 500 mg, 0.1 to 450 mg, 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 175 mg, 0.1 to 150 mg, 0.1 to 125 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1mg, 1 to 1500 mg, 1 to 1000 mg, 1 to 500 mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to 175 mg, 1 to 150 mg, 1 to 125 mg, 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1 to 30 mg, 1 toDocket: 2262-122 PCT25 mg, 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 1500 mg, 5 to 1000 mg, 5 to 500 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 175 mg, 5 to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 1500 mg, 10 to 1000 mg, 10 to 500 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 175 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50 mg, 10 to 30 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 15 to 1500 mg, 15 to 1000 mg, 15 to 500 mg, 15 to 300 mg, 15 to 250 mg, 15 to 200 mg, 15 to 175 mg, 15 to 150 mg, 15 to 125 mg, 15 to 100 mg, 15 to 75 mg, 15 to 50 mg, 15 to 30 mg, 15 to 25 mg, 15 to 20 mg, 20 to 1500 mg, 20 to 1000 mg, 20 to 500 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 175 mg, 20 to 150 mg, 20 to 125 mg, 20 to 100 mg, 20 to 75 mg, 20 to 50 mg, 20 to 30 mg, 20 to 25 mg, 25 to 1500 mg, 25 to 1000 mg, 25 to 500 mg, 25 to 300 mg, 25 to 250 mg, 25 to 200 mg, 25 to 175 mg, 25 to 150 mg, 25 to 125 mg, 25 to 100 mg, 25 to 75 mg, 25 to 50 mg, 25 to 30 mg, 30 to 1500 mg, 30 to 1000 mg, 30 to 500 mg, 30 to 300 mg, 30 to 250 mg, 30 to 200 mg, 30 to 175 mg, 30 to 150 mg, 30 to 125 mg, 30 to 100 mg, 30 to 75 mg, 30 to 50 mg, 35 to 1500 mg, 35 to 1000 mg, 35 to 500 mg, 35 to 300 mg, 35 to 250 mg, 35 to 200 mg, 35 to 175 mg, 35 to 150 mg, 35 to 125 mg, 35 to 100 mg, 35 to 75 mg, 35 to 50 mg, 40 to 1500 mg, 40 to 1000 mg, 40 to 500 mg, 40 to 300 mg, 40 to 250 mg, 40 to 200 mg, 40 to 175 mg, 40 to 150 mg, 40 to 125 mg, 40 to 100 mg, 40 to 75 mg, 40 to 50 mg, 50 to 1500 mg, 50 to 1000 mg, 50 to 500 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 175 mg, 50 to 150 mg, 50 to 125 mg, 50 to 100 mg, 50 to 75 mg, 75 to 1500 mg, 75 to 1000 mg, 75 to 500 mg, 75 to 300 mg, 75 to 250 mg, 75 to 200 mg, 75 to 175 mg, 75 to 150 mg, 75 to 125 mg, 75 to 100 mg, 100 to 1500 mg, 100 to 1000 mg, 100 to 500 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg, 100 to 175 mg, 100 to 150 mg, 100 to 125 mg, 125 to 1500 mg, 125 to 1000 mg, 125 to 500 mg, 125 to 300 mg, 125 to 250 mg, 125 to 200 mg, 125 to 175 mg, 125 to 150 mg, 150 to 1500 mg, 150 to 1000 mg, 150 to 500 mg, 150 to 300 mg, 150 to 250 mg, 150 to 200 mg, 150 to 175 mg, 175 to 1500 mg, 175 to 1000 mg, 175 to 500 mg, 175 to 300 mg, 175 to 250 mg, 175 to 200 mg, 200 to 1500 mg, 200 to 1000 mg, 200 to 500 mg, 200 to 300 mg, 200 to 250 mg, 250 to 1500 mg, 250 to 1000 mg, 250 to 500 mg, 250 to 300 mg, 7.5 to 15 mg, 2.5 to 5 mg, 1 to 5 mg, with doses of, e.g., about 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 400 mg and 500 mg beingDocket: 2262-122 PCTexamples.[000356] In embodiments, pharmaceutical compositions for treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease may include a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in an amount of, e.g., about 0.01 to 1500 mg, 0.01 to 1250 mg, 0.01 to 1000 mg, 0.01 to 750 mg, 0.01 to 500 mg, 0.01 to 250 mg, 0.01 to 100 mg, 0.01 to 50 mg, 0.01 to 25 mg, 0.01 to 10 mg, 0.01 to 5 mg, 0.01 to 1 mg, 0.1 to 500 mg, 0.1 to 450 mg, 0.1 to 300 mg, 0.1 to 250 mg, 0.1 to 200 mg, 0.1 to 175 mg, 0.1 to 150 mg, 0.1 to 125 mg, 0.1 to 100 mg, 0.1 to 75 mg, 0.1 to 50 mg, 0.1 to 30 mg, 0.1 to 25 mg, 0.1 to 20 mg, 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 5 mg, 0.1 to 1mg, 0.5 to 500 mg, 0.5 to 450 mg, 0.5 to 300 mg, 0.5 to 250 mg, 0.5 to 200 mg, 0.5 to 175 mg, 0.5 to 150 mg, 0.5 to 125 mg, 0.5 to 100 mg, 0.5 to 75 mg, 0.5 to 50 mg, 0.5 to 30 mg, 0.5 to 25 mg, 0.5 to 20 mg, 0.5 to 15 mg, 0.5 to 10 mg, 0.5 to 5 mg, 0.5 to 1mg, 1 to 500 mg, 1 to 450 mg, 1 to 300 mg, 1 to 250 mg, 1 to 200 mg, 1 to 175 mg, 1 to 150 mg, 1 to 125 mg, 1 to 100 mg, 1 to 75 mg, 1 to 50 mg, 1 to 30 mg, 1 to 25 mg, 1 to 20 mg, 1 to 15 mg, 1 to 10 mg, 1 to 5 mg, 5 to 500 mg, 5 to 450 mg, 5 to 300 mg, 5 to 250 mg, 5 to 200 mg, 5 to 175 mg, 5 to 150 mg, 5 to 125 mg, 5 to 100 mg, 5 to 75 mg, 5 to 50 mg, 5 to 30 mg, 5 to 25 mg, 5 to 20 mg, 5 to 15 mg, 5 to 10 mg, 10 to 500 mg, 10 to 450 mg, 10 to 300 mg, 10 to 250 mg, 10 to 200 mg, 10 to 175 mg, 10 to 150 mg, 10 to 125 mg, 10 to 100 mg, 10 to 75 mg, 10 to 50 mg, 10 to 30 mg, 10 to 25 mg, 10 to 20 mg, 10 to 15 mg, 15 to 500 mg, 15 to 450 mg, 15 to 300 mg, 15 to 250 mg, 15 to 200 mg, 15 to 175 mg, 15 to 150 mg, 15 to 125 mg, 15 to 100 mg, 15 to 75 mg, 15 to 50 mg, 15 to 30 mg, 15 to 25 mg, 15 to 20 mg, 20 to 500 mg, 20 to 450 mg, 20 to 300 mg, 20 to 250 mg, 20 to 200 mg, 20 to 175 mg, 20 to 150 mg, 20 to 125 mg, 20 to 100 mg, 20 to 75 mg, 20 to 50 mg, 20 to 30 mg, 20 to 25 mg, 25 to 500 mg, 25 to 450 mg, 25 to 300 mg, 25 to 250 mg, 25 to 200 mg, 25 to 175 mg, 25 to 150 mg, 25 to 125 mg, 25 to 100 mg, 25 to 80 mg, 25 to 75 mg, 25 to 50 mg, 25 to 30 mg, 30 to 500 mg, 30 to 450 mg, 30 to 300 mg, 30 to 250 mg, 30 to 200 mg, 30 to 175 mg, 30 to 150 mg, 30 to 125 mg, 30 to 100 mg, 30 to 75 mg, 30 to 50 mg, 40 to 500 mg, 40 to 450 mg, 40 to 400 mg, 40 to 250 mg, 40 to 200 mg, 40 to 175 mg, 40 to 150 mg, 40 to 125 mg, 40 to 100 mg, 40 to 75 mg, 40 to 50 mg, 50 to 500 mg, 50 to 450 mg, 50 to 300 mg, 50 to 250 mg, 50 to 200 mg, 50 to 175 mg, 50 to 150 mg, 50 to 125 mg, 50 to 100 mg, 50 to 75 mg, 75 to 500 mg, 75 to 450 mg, 75 to 300 mg, 75 to 250 mg, 75 to 200 mg, 75 to 175 mg, 75 to 150 mg, 75 to 125 mg, 75 to 100 mg, 100 to 500 mg, 100 to 450 mg, 100 to 300 mg, 100 to 250 mg, 100 to 200 mg, 100 to 175 mg, 100 to 150 mg,Docket: 2262-122 PCT100 to 125 mg, 125 to 500 mg, 125 to 450 mg, 125 to 300 mg, 125 to 250 mg, 125 to 200 mg, 125 to 175 mg, 125 to 150 mg, 150 to 500 mg, 150 to 450 mg, 150 to 300 mg, 150 to 250 mg, 150 to 200 mg, 200 to 500 mg, 200 to 450 mg, 200 to 300 mg, 200 to 250 mg, 250 to 500 mg, 250 to 450 mg, 250 to 300 mg, 300 to 500 mg, 300 to 450 mg, 300 to 400 mg, 300 to 350 mg, 350 to 500 mg, 350 to 450 mg, 350 to 400 mg, 400 to 500 mg, 400 to 450 mg, with 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, and 500 mg being examples.[000357] Typically, dosages may be administered to a subject experiencing tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease once, twice, three or four times daily, every other day, once weekly, or once a month. In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject experiencing tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease once a day (e.g., morning or night), or twice a day, (e.g., morning and evening), three times a day (e.g., at breakfast, lunch, and dinner, or every 8 hours), or four times a day (e.g., breakfast, lunch, dinner and at bedtime) at a dose of 0.01-1000 mg / admini strati on. In embodiments, the pharmaceutical compositions described herein may be administered by continuous infusion.[000358] In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered to a subject experiencing tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease in an amount of 1500 mg / per day, 1400 mg / per day, 1300 mg / per day, 1200 mg / per day, 1000 mg / per day, 900 mg / per day, 800 mg / per day, 700 mg / per day, 600 mg / per day, 500 mg / per day, 400 mg / per day, 300 mg / per day, 200 mg / per day, 100 mg / per day, 95 mg / per day, 90 mg / per day, 85 mg / per day, 80 mg / per day, 75 mg / per day, 70 mg / per day, 65 mg / per day, 60 mg / per day, 55 mg / per day, 50 mg / per day, 45 mg / per day, 40 mg / per day, 35 mg / per day, 30 mg / per day, 25 mg / per day, 20 mg / per day, 15 mg / per day, 10 mg / per day, 5 mg / per day, 4 mg / per day, 3 mg / per day, 3 mg / per day, 2 mg / per day, 1 mg / per day, in one or more doses. Dosages can be lower for infants and children than for adults. In embodiments, an infant or pediatric dose can be about 0.1 to 1500 mg per day once or in 2, 3 or 4 divided doses. In embodiments, a pediatric dose can be 0.05 mg / kg / day to 1500Docket: 2262-122 PCTmg / kg / day. In embodiments, the subject may be started at a low dose and the dosage is escalated over time. It should be understood that the above amounts are exemplary and doses of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, can include different amounts and varying ranges within a continuum between the minimum or maximum amounts described above in connection with a compound according to Formula (I), or a pharmaceutically acceptable salt thereof.[000359] In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease are provided which include administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 1 hour after administration to the subject. In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease are provided which include administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (1), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 2 hours after administration to the subject. In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease are provided which include administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 3 hours after administration to the subject. In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease are provided which include administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or aDocket: 2262-122 PCTpharmaceutically acceptable salt thereof, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 4 hours after administration to the subject. In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease are provided which include administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 6 hours after administration to the subject. In embodiments, methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease are provided which include administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 8, 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration to the subject. In embodiments, improvement in at least one or two or more symptoms for 12 hours after administration of the pharmaceutical composition to the subject is provided in accordance with the present disclosure. In embodiments, the pharmaceutical compositions provide improvement in next day functioning of the subject. For example, the pharmaceutical compositions may provide improvement in one or more symptoms of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours after administration and waking from a night of sleep.[000360] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in an effective amount, after an early sign of one or more symptoms of tinnitus, acute sensorineural hearing loss, age-related hearing loss orDocket: 2262-122 PCTMeniere’s disease is detected to reduce or prevent further symptoms. In embodiments, a continuing regimen of administration of active agents herein according to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is effective to reduce or prevent occurrence of symptoms associated with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease.[000361] In embodiments, the methods described herein are effective to reduce, delay, or prevent one or more other clinical symptoms of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. For example, the effect of a composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, on a particular symptom, pharmacologic, or physiologic indicator can be compared to an untreated subject, or the condition of the subject prior to treatment. In embodiments, the symptom, pharmacologic, and / or physiologic indicator is measured in a subject prior to treatment, and again one or more times after treatment is initiated. In embodiments, the control is a reference level, or average determined based on measuring the symptom, pharmacologic, or physiologic indicator in one or more subjects that do not have the disease, disorder or condition to be treated (e.g., healthy subjects). In embodiments, the effect of the treatment is compared to a conventional treatment that is known the art.[000362] Indeed, clinical efficacy of treatment can be monitored using any method known in the art. Measurable parameters to monitor efficacy will depend on the condition being treated. For monitoring the status or improvement of symptoms of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease various scales and tools are known. For example, some subjects can undergo audiometry with tympanometry, while some can undergo neuroimaging or assessment of vestibular function with electronystagmography. Audiometry testing measures hearing ability across different volume and frequencies. Tympanometry is a middle ear test that evaluates the function of the eardrum and the bones in the middle ear to see how well they’re conducting sound. A small probe blows air into the ears to see how these structures move. Then, sound is used to evaluate the muscle that protects the ear from loud noises. Neuroimaging, such as MRI scan, CT scan or ultrasound, may be used when tinnitus or hearing loss is unilateral, or only affecting one ear. Electronystagmography can uncover a variety of audiological problems, including both balance issues and tinnitus. This test involves insertionDocket: 2262-122 PCTof electrodes into the brain and measuring reactions to light, motion, depth perception and the effects of placing fluids in the ear canals.[000363] Effective treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease herein may be established by showing reduction in the frequency or severity of symptoms (e.g., more than, e.g., 10%, 20%, 30% 40%, 50% or more) after a period of time compared with baseline. For example, after a baseline period of 1 month, the subjects may be randomly allocated a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, or placebo as add-on therapy to standard therapies, during a double-blind period of, e.g., 2 months.[000364] In embodiments, primary outcome measurements may include the percentage of responders on a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and on placebo, defined as having experienced at least a 10% to 50% or more reduction of symptoms during the second month of the double-blind period compared with baseline.[000365] Cognitive impairment (aka impairment of cognition) may be associated with subjects experiencing tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. Cognitive impairment may be measured against normal cognitive function, which refers to the normal physiologic activity of the brain, including, but not limited to, one or more of the following: mental stability, memory / recall abilities, problem solving abilities, reasoning abilities, thinking abilities, judging abilities, ability to discriminate or make choices, capacity for learning, ease of learning, perception, intuition, attention, and awareness, as measured by any criteria suitable in the art.[000366] In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered via a pharmaceutical composition for treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease.Pharmaceutical compositions herein encompass dosage forms. Dosage forms herein encompass unit doses. In embodiments, as discussed below, various dosage forms including conventional formulations and modified release formulations can be administered one or more times daily. Any suitable route of administration may be utilized, e.g., enteral or parenteral including oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal and subcutaneous routes. As mentioned previously, suitableDocket: 2262-122 PCTdosage forms include tablets, capsules, oral liquids, powders, aerosols, transdermal modalities such as topical liquids, patches, creams and ointments, parenteral formulations and suppositories.[0003671 In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile of the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the in vivo plasma profile of the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 50% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration.[000368] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 55% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 55% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration.Docket: 2262-122 PCT[000369] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 60% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 60% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration, in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration.[000370] In embodiments, provided herein are methods of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 65% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration. In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss orDocket: 2262-122 PCTMeniere’s disease a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, which provides an in vivo plasma profile, wherein the in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in the subject 10 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is reduced by more than 65% and the method provides improvement in the subject for more than 10, 12, 14, 16, 18, 20, 22 or 24 hours after administration.[000371] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease wherein the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, within the subject about 4 hours after administration of the pharmaceutical composition is less than about 75% of the administered dose. In embodiments, provided herein are methods wherein the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, within the subject about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition is less than about 75%.[000372] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease wherein the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, within the subject about 4 hours after administration of the pharmaceutical composition is less than about 80% of the administered dose. In embodiments, provided herein are methods wherein the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, within the subject about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition is less than about 80% of the administered dose.[000373] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease wherein the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, within the subject about 4 hours after administration of the pharmaceutical composition is between about 65% to about 85% of the administered dose. In embodiments, the amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, within the subject after about, e.g., 6 hours, 8 hours, 10 hours, 12 hours, 15 hours, or 20 hours after administration of the pharmaceutical composition is between about 65% to about 85% of the administered dose.Docket: 2262-122 PCT[000374] In embodiments, as mentioned previously, pharmaceutical compositions herein may be provided with conventional release or modified release profiles. Pharmaceutical compositions may be prepared using a pharmaceutically acceptable “carrier” or “excipient” composed of materials that are considered safe and effective. The “carrier” includes all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions. Those with skill in the art are familiar with such pharmaceutical carriers and methods of compounding pharmaceutical compositions using such carriers. “Carrier” and “excipient” are used interchangeably herein.[000375] In embodiments, pharmaceutical compositions herein are modified release dosage forms which provide modified release profiles. Modified release profiles may exhibit immediate release, delayed release, or extended release profiles. Conventional (or unmodified) release oral dosage forms such as tablets, capsules, suppositories, syrups, solutions and suspensions typically release medications into the mouth, stomach or intestines as the tablet, capsule shell or suppository dissolves, or, in the case of syrups, solutions and suspensions, when they are swallowed. The pattern of drug release from modified release (MR) dosage forms is deliberately changed from that of a conventional dosage form to achieve a desired therapeutic objective and / or better patient compliance. Types of MR drug products include orally disintegrating dosage forms (ODDFs) which provide immediate release, extended release dosage forms, delayed release dosage forms (e g., enteric coated), and pulsatile release dosage forms.[000376] An ODDF is a solid dosage form containing a medicinal substance or active ingredient which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue. The disintegration time for ODDFs generally range from one or two seconds to about a minute. ODDFs are designed to disintegrate or dissolve rapidly on contact with saliva. Super disintegrants may form a majority of the dosage form. This mode of administration can be beneficial to people who may have problems swallowing tablets whether it be from physical infirmity or psychiatric in nature. Subjects with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease may exhibit such behavior. ODDF’s can provide rapid delivery of medication to the blood stream through mucosa resulting in a rapid onset of action. Examples of ODDFs include orally disintegrating tablets, capsules and rapidly dissolving films and wafers.Docket: 2262-122 PCT[000377] Extended release dosage forms (ERDFs) have extended release profdes and are those that allow a reduction in dosing frequency as compared to that presented by a conventional dosage form, e.g., a solution or unmodified release dosage form. ERDFs provide a sustained duration of action of a drug. Suitable formulations which provide extended release profiles are well-known in the art. For example, coated slow release beads or granules (“beads” and “granules” are used interchangeably herein) in which a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release retarding materials such as waxes, enteric coatings and the like. In embodiments, beads can be formed in which a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is mixed with a material to provide a mass from which the drug leaches out. In embodiments, the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. Beads having different rates of release may be combined into a single dosage form to provide variable or continuous release. The beads can be contained in capsules or compressed into tablets.[000378] In embodiments, modified dosage forms herein incorporate delayed release dosage forms having delayed release profiles. Delayed release dosage forms can include delayed release tablets or delayed release capsules. A delayed release tablet is a solid dosage form which releases a drug (or drugs) such as a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, at a time other than promptly after administration. A delayed release capsule is a solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) at a time other than promptly after administration. For example, enteric-coated tablets, capsules, particles and beads are well-known examples of delayed release dosage forms. Enteric coated tablets, capsules and particles and beads pass through the stomach and release the drug in the intestine. In embodiments, a delayed release tablet is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at a time other than promptly after administration. In embodiments, the conglomerate of medicinal particles are covered with a coating which delays release of the drug. In embodiments, a delayed release capsule is a solid dosage form containing a conglomerate of medicinal particles that releases a drug (or drugs) at aDocket: 2262-122 PCTtime other than promptly after administration. In embodiments, the conglomerate of medicinal particles is covered with a coating which delays release of the drug.[000379] Delayed release dosage forms are known to those skilled in the art. For example, coated delayed release beads or granules in which a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is applied to beads, e.g., confectioners nonpareil beads, and then coated with conventional release delaying materials such as waxes, enteric coatings and the like. In embodiments, beads can be formed in which a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is mixed with a material to provide a mass from which the drug leaches out. In embodiments, the beads may be engineered to provide different rates of release by varying characteristics of the coating or mass, e.g., thickness, porosity, using different materials, etc. In embodiments, enteric coated granules of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, can be contained in an enterically coated capsule or tablet which releases the granules in the small intestine. In embodiments, the granules have a coating which remains intact until the coated granules reach at least the ileum and thereafter provide a delayed release of the drug in the colon. Suitable enteric coating materials are well known in the art, e.g., Eudragit® coatings such methacrylic acid and methyl methacrylate polymers and others. The granules can be contained in capsules or compressed into tablets.[000380] In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is incorporated into porous inert carriers that provide delayed release profdes. In embodiments, the porous inert carriers incorporate channels or passages from which the drug diffuses into surrounding fluids. In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is incorporated into an ion-exchange resin to provide a delayed release profile. Delayed action may result from a predetermined rate of release of the drug from the resin when the drug-resin complex contacts gastrointestinal fluids and the ionic constituents dissolved therein. In embodiments, membranes are utilized to control rate of release from drug containing reservoirs. In embodiments, liquid preparations may also be utilized to provide a delayed release profile. For example, a liquid preparation consisting of solid particles dispersed throughout a liquid phase in which the particles are not soluble. The suspension is formulated to allow at least a reduction in dosing frequency as compared to that drug presented asDocket: 2262-122 PCTa conventional dosage form (e.g., as a solution or a prompt drug-releasing, conventional solid dosage form). For example, a suspension of ion-exchange resin constituents or microbeads.[000381] In embodiments, pharmaceutical compositions described herein are suitable for parenteral administration, including, e.g., intramuscular (i.m.), intravenous (i.v.), subcutaneous (s.c.), intraperitoneal (i.p.), or intrathecal (i.t.). Parenteral compositions must be sterile for administration by injection, infusion or implantation into the body and may be packaged in either single-dose or multi-dose containers. In embodiments, liquid pharmaceutical compositions for parenteral administration to a subject include a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in any of the respective amounts described above. In embodiments, the pharmaceutical compositions for parenteral administration are formulated as a total volume of about, e.g., 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml, or 500 ml. In embodiments, the compositions are contained in a bag, a glass vial, a plastic vial, or a bottle.[000382] In embodiments, pharmaceutical compositions for parenteral administration include respective amounts described above for a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. In embodiments, pharmaceutical compositions for parenteral administration include about 0.05 mg to about 500 mg a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. In embodiments, pharmaceutical compositions for parenteral administration to a subject include a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, at a respective concentration of about 0.005 mg / ml to about 500 mg / ml. In embodiments, the pharmaceutical composition for parenteral administration includes a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, at a respective concentration of, e.g., about 0.05 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 25 mg / ml, about 0.05 mg / ml to about 10 mg / ml, about 0.05 mg / ml to about 5 mg / ml, or about 0.05 mg / ml to about 1 mg / ml. In embodiments, the pharmaceutical composition for parenteral administration includes a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, at a respective concentration of, e.g., about 0.05 mg / ml to about 15 mg / ml, about 0.5 mg / ml to about 10 mg / ml, about 0.25 mg / ml to about 5 mg / ml, about 0.5 mg / ml to about 7 mg / ml, about 1 mg / ml to about 10 mg / ml, about 5 mg / ml to about 10 mg / ml, or about 5 mg / ml to about 15 mg / ml.Docket: 2262-122 PCT[000383] In embodiments, a pharmaceutical composition for parenteral administration is provided wherein the pharmaceutical composition is stable for at least six months. In embodiments, the pharmaceutical compositions for parenteral administration exhibit no more than about 5% decrease in a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., 3 months or 6 months. In embodiments, the amount of a compound according to a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, degrades at no more than about, e.g., 2.5%, 1%, 0.5% or 0.1%. In embodiments, the degradation is less than about, e.g., 5%, 2.5%, 1%, 0.5%, 0.25%, 0.1%, for at least six months.[000384] In embodiments, pharmaceutical compositions for parenteral administration are provided wherein the pharmaceutical composition remains soluble. In embodiments, pharmaceutical compositions for parenteral administration are provided that are stable, soluble, local site compatible and / or ready-to-use. In embodiments, the pharmaceutical compositions herein are ready-to-use for direct administration to a subject in need thereof.[000385] The pharmaceutical compositions for parenteral administration provided herein may include one or more excipients, e.g., solvents, solubility enhancers, suspending agents, buffering agents, isotonicity agents, stabilizers or antimicrobial preservatives. When used, the excipients of the parenteral compositions will not adversely affect the stability, bioavailability, safety, and / or efficacy of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, used in the composition. Thus, parenteral compositions are provided wherein there is no incompatibility between any of the components of the dosage form.[000386] In embodiments, parenteral compositions including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, include a stabilizing amount of at least one excipient. For example, excipients may be selected from the group consisting of buffering agents, solubilizing agents, tonicity agents, antioxidants, chelating agents, antimicrobial agents, and preservatives. One skilled in the art will appreciate that an excipient may have more than one function and be classified in one or more defined group.[000387] In embodiments, parenteral compositions including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and an excipient wherein the excipient is present at a weight percent (w / v) of less than about, e.g., 10%, 5%, 2.5%, 1%, or 0.5%. In embodiments, the excipient is present at a weight percent between about, e.g., 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1%, or 0.5% to 1%. InDocket: 2262-122 PCTembodiments, the excipient is present at a weight percent between about, e.g., 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15%, or 1% to 15%.[000388] In embodiments, parenteral compositions may be administered as needed, e.g., once, twice, thrice or four or more times daily, or continuously depending on the subject’s needs.[000389] In embodiments, parenteral compositions of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, are provided, wherein the pH of the composition is between about 4.0 to about 8.0. In embodiments, the pH of the compositions is between, e.g., about 5.0 to about 8.0, about 6.0 to about 8.0, about 6.5 to about 8.0. In embodiments, the pH of the compositions is between, e.g., about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In embodiments, the pH of the aqueous solution is, e.g., about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.[000390] In embodiments, provided herein are methods of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in a respective amount described herein, wherein the composition provides an in vivo plasma profile having a Cmax less than about 800 ng / ml. In embodiments, the composition provides improvement for more than 6 hours after administration to the subject.[000391] In embodiments, pharmaceutical compositions including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, provide an in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, having a Cmax less than about, e.g., 2000 ng / ml, 1000 ng / ml, 850 ng / ml, 800 ng / ml, 750 ng / ml, 700 ng / ml, 650 ng / ml, 600 ng / ml, 550 ng / ml, 450 ng / ml, 400 ng / ml 350 ng / ml, or 300 ng / ml and wherein the composition provides improvement of next day functioning of the subject. In embodiments, the pharmaceutical composition provides an in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, having a Cmax less than about, e.g., 250 ng / ml, 200 ng / ml 150 ng / ml, or 100 ng / ml and wherein the composition provides improvement of next day functioning of the subject. In embodiments, the pharmaceutical composition provides improvement in one or more symptoms of tinnitus, acute sensorineuralDocket: 2262-122 PCThearing loss, age-related hearing loss or Meniere’s disease for more than 6 hours after administration.[0003921 In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition containing a compound according to a compound according to a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the composition provides a consistent in vivo plasma profile having a AUC0-∞of less than about 900 ng*hr / ml. In embodiments, the pharmaceutical composition provides improvement in next day functioning of the subject. In embodiments, the compositions provide an in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, having a AUC0-∞of less than about, e.g., 850 ng*hr / ml, 800 ng*hr / ml, 750 ng*hr / ml, or 700 ng*hr / ml and wherein the pharmaceutical composition provides improvement of next day functioning of the subject. In embodiments, the composition provides improvement in tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 6 hours after administration.[000393J In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition provides an in vivo plasma profde of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, having a AUC0-∞of less than about, e.g., 650 ng*hr / ml, 600 ng*hr / ml, 550 ng*hr / ml, 500 ng*hr / ml, or 450 ng*hr / ml. In embodiments, the composition provides an in vivo plasma profde of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, having a AUCo-«> of less than about, e.g., 400 ng*hr / ml, 350 ng’hr / ml, 300 ng*hr / ml, 250 ng*hr / ml, or 200 ng*hr / ml. In embodiments, the pharmaceutical composition provides an in vivo plasma profile of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, having a AUC0-∞of less than about, e.g., 150 ng*hr / ml, 100 ng*hr / ml, 75 ng*hr / ml, or 50 ng*hr / ml. In embodiments, the pharmaceutical composition provides improvement of next day functioning of the subject afterDocket: 2262-122 PCTadministration for more than, e.g., 4 hours, 6 hours, 8 hours, 10 hours, or 12 hours, after administration of the composition to the subject.[0003941 In embodiments, the Tmaxprovided by a pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 3 hours. In embodiments, the Tmaxprovided by the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 2.5 hours. In embodiments, the Tmaxprovided by the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 2 hours. In embodiments, the Tmaxprovided by the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 1.5 hours. In embodiments, the Tmaxprovided by the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 1 hour. In embodiments, the Tmaxprovided by the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 0.5 hour. In embodiments, the Tmaxprovided by the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is less than 0.25 hour.[000395] In embodiments, the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, provides a dissolution of at least about 80% within the first 20 minutes of administration to a subject in need thereof. In embodiments, the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, provides a dissolution of at least about, e.g., 85%, 90% or 95% within the first 20 minutes of administration to a subject in need thereof. In embodiments, the pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, provides a dissolution of at least 80% within the first 10 minutes of administration to a subject in need thereof.[000396] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a first pharmaceutical dosage including a sub-therapeutic amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof. InDocket: 2262-122 PCTembodiments, treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease includes administering to a subject in need thereof a pharmaceutical composition containing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, in a sub-therapeutic amount, wherein the composition provides improvement in one or more symptoms of the tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease for more than 6 hours after administration.[000397] A sub -therapeutic dosage is an amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, that is less than the amount typically required for a therapeutic effect. In embodiments, a sub-therapeutic dosage is an amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, that alone may not provide improvement in at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease but is sufficient to maintain such improvement. In embodiments, the methods provide administering a first pharmaceutical composition containing an effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, that provides improvement in at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease and a second composition containing a subtherapeutic amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, that maintains the improvement. In embodiments, after administration of the first pharmaceutical composition, the second pharmaceutical composition may provide a synergistic effect to improve at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease.[000398] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease including administering to a subject in need thereof or diagnosed with tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease a first pharmaceutical composition including a first pharmaceutical dosage of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, wherein the first pharmaceutical dosage provides improvement for more than 6 hours after administration, and a second pharmaceutical composition including a sub-therapeutic dosage of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof.[000399] In embodiments, the first or the second pharmaceutical composition are provided to the subject once in the evening and once in the morning. In embodiments, the total amount of aDocket: 2262-122 PCTcompound according to Formula (I), or a pharmaceutically acceptable salt thereof, administered to a subject in a 24-hour period is any of the respective amounts described herein.[0004001 In embodiments, the first and / or the second pharmaceutical compositions may be provided with conventional release or modified release profiles. The first and second pharmaceutical compositions may be provided at the same time or separated by an interval of time, e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, etc. In embodiments, the first and the second pharmaceutical compositions may be provided with different drug release profiles to create a two-phase release profile. For example, the first pharmaceutical composition may be provided with an immediate release profile, e.g., ODDF, parenteral, etc., and the second pharmaceutical composition may provide an extended release profile. In embodiments, one or both of the first and second pharmaceutical compositions may be provided with an extended release or delayed release profile. Such compositions may be provided as pulsatile formulations, multilayer tablets or capsules containing tablets, beads, granules, etc. In embodiments, the first pharmaceutical composition is an immediate release composition. In embodiments, the second pharmaceutical composition is an immediate release composition. In embodiments, the first and second pharmaceutical compositions are provided as separate immediate release compositions, e.g., film, tablets or capsules. In embodiments the first and second pharmaceutical compositions are provided 12 hours apart.[000401] It should be understood that respective dosage amounts of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, that are provided herein are applicable to all the dosage forms described herein including conventional dosage forms, modified dosage forms, the first and second pharmaceutical compositions, as well as the parenteral formulations described herein. Those skilled in the art will determine appropriate amounts depending on criteria such as dosage form, route of administration, subject tolerance, efficacy, therapeutic goal and therapeutic benefit, among other pharmaceutically acceptable criteria.[000402] Combination therapies utilizing a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, can include at least a second pharmacologically active agent and can include administration of the active agents together in the same admixture, or in separate admixtures. In embodiments, the pharmaceutical composition can include two, three, or more active agents. In embodiments, combination therapies involve administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, inDocket: 2262-122 PCTcombination with other active agents. A compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and other active agents may be administered together at the same time or separately in spaced apart intervals. A compound according to Formula (I), or a pharmaceutically acceptable salt thereof, and the other active agents may be administered in a single dosage form or in separate dosage forms.[000403] In embodiments, the combinations result in a more than an additive effect on the treatment of the disease or disorder. Thus, treatment is provided for tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease with a combination of agents that combined, may provide a synergistic effect that enhances efficacy and reduces side effects.[000404] In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, is administered in combination with anti-inflammatory medications. Suitable anti-inflammatory medications include corticosteroids and nonsteroidal anti-inflammatory medications. In embodiments, a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, is administered in combination with one or more benzodiazepines.[000405] In embodiments, a co-therapy of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, is effective to reduce frequency or severity of symptoms in the subject greater than any of the compounds administered alone. In embodiments, the co-therapy produces a more than additive result compared to compounds administered individually.[000406] The second pharmaceutically active agent may include analgesics, anti-inflammatory agents, antidepressants, calcium channel antagonists, glutamate receptor antagonists, CGRP agonists, CGRP antagonists, anticonvulsants (e.g., baclofen type), osmoregulators, sodium channel blockers, anticonvulsants, antiarrhythmics, and neuroprotectives. In embodiments analgesics may include opioids, non-steroidal analgesics, gabapentin, and alpha-adrenergic agonists. In embodiments, the second active agent may include a sulfonamide, for example, acetazolamide, azosemide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide (HCT, HCTZ, HZT), indapamide, mefruside, metolazone, piretanide,Docket: 2262-122 PCTtripamide xipamide, dichlorphenamide (DCP), dorzolamide, ethoxzolamide, sultiame, or zonisamide. In embodiments, the second active agent may include a thiazide, for example, bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyl cl othi azide, polythiazide, tri chi or-m ethiazide, chlorthalidone, indapamide, metolazone or quinethazone.[000407] In embodiments, the second active agent may include a NK1 receptor antagonist, for example, 2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-l-carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or pharmaceutically acceptable salts or solvates thereof, 4-(S)-(4-acetyl-piperazin-l-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-l-carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof, and 2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[l,2- -a]-pyrazin-2-yl)-piperi dine- 1 -carboxylic acid [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide or pharmaceutically acceptable salts or solvates thereof.[000408] In embodiments, the second active agent may include risperidone, ziprasidone, haloperidol, pimozide, fluphenazine, clonidine or guanfacine. In embodiments, the second active agent may include methylphenidate, methamphetamine, dextroamphetamine, atomoxetine, bupropion, guanfacine, or clonidine. In embodiments, the second active agent may include naltrexone, disulfiram, acamprosate, topiramate, buprenorphine, methadone, or pregabalin.[000409] In embodiments, the second active agent may include a benzodiazepine. The benzodiazepine may include diazepam, alprazolam, estazolam, clobazam, clonazepam, clorazepate, chi ordi azepoxide, flurazepam, triazolam, temazepam, midazolam, halazepam, quazepam, lorazepam, oxazepam, derivatives thereof, or pharmaceutically acceptable salts thereof.[000410] In embodiments, the second active agent may include clonazepam and / or clobazam. In embodiments, provided herein are methods of treating tinnitus including administering to a subject in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in any of the amounts described above in combination with clonazepam. In embodiments, provided herein are methods of treating tinnitusDocket: 2262-122 PCTincluding administering to a patient in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g.Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in any of the amounts described above in combination with clobazam. In embodiments, provided herein are methods of treating ASNHL including administering to a patient in need thereof a pharmaceutical composition including a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in any of the amounts described above in combination with clonazepam. In embodiments, provided herein are methods of treating ARHL including administering to a patient in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in any of the amounts described above in combination with clobazam. In embodiments, provided herein are methods of treating Meniere’s disease including administering to a patient in need thereof a pharmaceutical composition including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in any of the amounts described above in combination with clonazepam.[000411] The disclosed combinations may provide improved treatment compared to either active agent alone. For example, the combinations may provide synergy, e g., low dose treatments may be particularly effective in reducing or eliminating symptoms of subjective tinnitus. Likewise, the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of ASNHL. Likewise, the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of ARHL. Likewise, the combinations may provide synergy, e.g., low dose treatments may be particularly effective in reducing or eliminating symptoms of Meniere’s disease.Docket: 2262-122 PCT[000412] In embodiments, the pharmaceutical compositions include 0.1 mg to 30 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.5 mg to 25 mg, 0.5 mg to 20 mg, 0.5 to 15 mg, 1 mg to 25 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1.5 mg to 25 mg, 1.5 mg to 20 mg, 1.5 mg to 15 mg, 2 mg to 25 mg, 2 mg to 20 mg, 2 mg to 15 mg, 2.5 mg to 25 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 3 mg to 25 mg, 3 mg to 20 mg, 3 mg to 15 mg clobazam or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical compositions include 5 mg to 20 mg, 5 mg to 10 mg, 4 mg to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14 mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg clobazam or a pharmaceutically acceptable salt thereof. In embodiments, the pharmaceutical compositions include 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 12 mg, 12.5 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 17.5 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, or 30 mg clobazam or a pharmaceutically acceptable salt thereof or amounts that are multiples of such doses. In embodiments, the pharmaceutical compositions include 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, or 20 mg clobazam or a pharmaceutically acceptable salt thereof.[000413] In embodiments, the adult dose of clobazam may be 5-60 mg daily in divided doses or as a single dose given at night. For example, the adult dose of clobazam may be 5-10 mg, 5-20 mg, 5-25 mg, 5-30 mg, 5-35 mg, 5-40 mg, 5-50 mg, 5-55 mg, 10-15 mg, 10-20 mg, 10-25 mg, 10-30 mg, 10-35 mg, 10-40 mg, 10-45 mg, 10-50 mg, 10-55 mg, 10-60 mg, 15-20 mg, 15-25 mg, 15-30 mg, 15-35 mg, 15-40 mg, 15-50 mg, 15-55 mg, 15-60 mg, 20-25 mg, 20-30 mg, 20-35 mg, 20-40 mg, 20-45 mg, 20-50 mg, 20-55 mg, 20-60 mg, 25-30 mg, 25-35 mg, 25-40 mg, 25-50 mg, 25-55 mg, 25-60 mg, 30-35 mg, 30-40 mg, 30-45 mg, 30-50 mg, 30-55 mg, 30-60 mg, 35-40 mg, 35-50 mg, 35-55 mg, 35-60 mg, 40-45 mg, 40-50 mg, 40-55 mg, 40-60 mg, 45-50 mg, 45-55 mg, 45-60 mg, 50-55 mg, or 55-60 mg, daily in divided doses such as twice a day, three times a day, or as a single dose given at night.[000414] It should be understood that, as described herein, the pharmaceutical compositions including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, and a second pharmacologically active agent, may include at least one, two, three or more dosage forms that contain a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g.,Docket: 2262-122 PCTCompound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, and the second pharmacological active ingredient separately. For example, a first dosage for including a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g.Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, and a second dosage form including a benzodiazepine. Alternatively, e.g., the pharmaceutical compositions may include both a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, and a benzodiazepine within a single dosage form.[000415] In embodiments, provided herein are methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, including administering to a patient in need a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g. Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof, together or separately, wherein the patient experiences improvement of at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, for more than 4 hours after administration of the pharmaceutical composition(s) to the patient. In embodiments, the improvement of at least one tinnitus symptom for more than 6 hours after administration of the a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof, to the patient is provided in accordance with the present disclosure. In embodiments, improvement of at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, for more than, e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in combination with clobazam or a pharmaceuticallyDocket: 2262-122 PCTacceptable salt thereof to the patient is provided in accordance with the present disclosure. In embodiments, improvement in at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, for at least e.g., 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, or 24 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof to the patient is provided in accordance with the present disclosure. In embodiments, improvement in at least one symptom of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, for 12 hours after administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof to the patient is provided in accordance with the present disclosure.[000416] In embodiments, provided herein methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, including administering to a patient in need thereof a pharmaceutical composition a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, wherein the composition provides improvement in tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, the next day.[000417] In embodiments, provided herein methods of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, including administering to a patient in need thereof a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, e.g., Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H, or a pharmaceutical salt of any of the preceding, in combination with clobazam or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, the next day.Docket: 2262-122 PCT[000418] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosure herein belongs.[000419] The term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, and / or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.[000420] “Improvement” refers to the treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, measured relative to at least one symptom.[000421] “Improvement in one or more symptoms of tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, a day after administration” refers to improvement wherein the beneficial effect of at least one symptom lasts over a period of time, e.g., 6 hours, 12 hours, 24 hours etc.[000422] “Improvement in next day functioning” or “wherein there is improvement in next day functioning” refers to improvement after waking from an overnight sleep period wherein the beneficial effect of administration of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, applies to at least one symptom of a syndrome or disorder herein and is discernable, either subjectively by a subject or objectively by an observer, for a period of time, e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc. after waking.[000423] " PK" refers to the pharmacokinetic profile. Cmaxis defined as the highest plasma drug concentration estimated during an experiment (ng / ml). Tmax is defined as the time when Cmaxis estimated (min). AUCo-«> is the total area under the plasma drug concentration-time curve, from drug administration until the drug is eliminated (ng hr / ml). The area under the curve is governed by clearance. Clearance is defined as the volume of blood or plasma that is totally cleared of its content of drug per unit time (ml / min).Docket: 2262-122 PCT[000424] "Treating" or "treatment" refers to alleviating or delaying the appearance of clinical symptoms of a disease or condition in a subject that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition. In certain embodiments, “treating” or “treatment” may refer to preventing the appearance of clinical symptoms of a disease or condition in a subject that may be afflicted with or predisposed to the disease or condition, but does not yet experience or display clinical or subclinical symptoms of the disease or condition. "Treating" or "treatment" also refers to inhibiting the disease or condition, e.g., arresting or reducing its development or at least one clinical or subclinical symptom thereof. "Treating" or "treatment" further refers to relieving the disease or condition, e.g., causing regression of the disease or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject to be treated may be statistically significant, mathematically significant, or at least perceptible to the subject and / or the physician. Nonetheless, prophylactic (preventive) and therapeutic (curative) treatment are two separate aspects of the disclosure herein.[000425] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe"-e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset and the like, when administered to a human. In embodiments, this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a state government, as the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U. S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.[000426] “Effective amount” or “therapeutically effective amount” means a dosage sufficient to alleviate one or more symptoms of a disorder, disease, or condition being treated e.g., tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease, or to otherwise provide a desired pharmacological and / or physiologic effect.[000427] “ Co-administered with”, “co-therapy”, “in combination with”, “a combination of’, “combined with” or “administered along with” may be used interchangeably and mean that two or more agents are administered in the course of therapy. The agents may be administered together at the same time or separately in spaced apart intervals. The agents may be administered in a single dosage form or in separate dosage forms.Docket: 2262-122 PCT[000428] ‘ ‘Patient in need thereof’ or “subject in need thereof’ includes individuals that have been diagnosed tinnitus, acute sensorineural hearing loss, age-related hearing loss or Meniere’s disease. The methods may be provided to any individual including, e.g., wherein the patient is a neonate, infant, a pediatric patient (6 months to 12 years), an adolescent patient (age 12-18 years) or an adult (over 18 years). “Patient” and “subject” are used interchangeably herein. It should be understood that infants can receive a pediatric dose.EXAMPLES[000429] The Examples provided herein are included solely for augmenting the disclosure herein and should not be considered to be limiting in any respect.[000430] The following Examples establish: Compound A is capable of directly binding to KCC2, as measured using cellular thermal shift assay (CETSA). Compound A potently increases KCC2 activity without modifying its plasma membrane stability or the phosphorylation of key regulatory sites, as measured by patch-clamp recording and TI flux. This contrasts to other indirect potentiators of KCC2, which have been shown to increase expression levels on the plasma membrane, enhance its expression, increase transcription of the SLC12A5 gene, or modify its phosphorylation (Gagnon el al., Nat. Med. 19, 1524-1528 (2013); Lee et al., Brain: a journal of neurology 145, 950-963 (2022); Prael lii et al.,. Front Cell Dev Biol 10, 912812 (2022); Tang et al., Sci. Transl. Med. 11. 10.1126) (2019)). Consistent with its role in limiting neuronal excitability, Compound A reduced neuronal Cl’ accumulation and the development of late recurrent discharges (LRDs) in acute brain slices exposed to 0-Mg. Compound A rapidly accumulated in the brain when dosed IV, IP, or SC to concentrations ranging from 40-0.6 pM, dependent upon the route of administration. Importantly, as measured in the open field, Compound A appeared to have no gross effects on mouse behavior.[000431] The Examples establish that in mice treated with Compound A and diazepam, neuronal cell death in the hippocampus was significantly reduced compared to controls treated with diazepam alone. This effect may be due to the ability of Compound A to limit hyperexcitability, but previous in vitro and in vivo studies have shown that reducing KCC2 expression levels, or transiently inhibiting it, are sufficient to induce neuronal apoptosis.Likewise, modifying KCC2 expression levels during development also impacts neuronal viability.Docket: 2262-122 PCTExample 1Identification of small molecules that activate and directly bind to KCC2[000432J A multi-tiered high-throughput screening assay was used, leveraging a proprietary library of 1.3 million small molecule compounds from AstraZeneca (Cambridge, UK) to identify chemical entities capable of activating KCC2. A single point concentration of 30 pM was used to identify potassium flux using an established thallium (TI+) influx FLIPR assay as the primary read out in HEK-293 cells overexpressing KCC2 (Cardarelli et al., Nat. Med. 23, 1394-1396 (2017); Conway et al., J Biol Chem 292, 21253-21263 (2017); Lee etal., 2022, supra).Compounds that exhibited >20% potentiation of KCC2 activity with EC50 of <30pM were selected for further optimization. This approach resulted in the identified subseries of fused pyrimidine compounds as KCC2 activators, which are denoted as subseries A (SSA; Fig 1A).[000433] Neuronal Cultures. Hippocampal neurons were prepared from Sprague Dawley El 8 embryos and plated at 450,000 per dish and maintained at 37°C in a humidified 5% CO2 incubator for 10-25 days before experimentation (Lee etal., Nat. Neurosci. 14, 736-743 (2011)).[000434] Cell Culture and biotinylation. HEK-293 cells were purchased from ATCC (CRL-1573) and transfected with human KCC2 and GFP expression plasmids using Lipofectamine 2000. Cells were utilized for experimentation 48-72h following transfection. Cells were biotinylated at 4°C using NHS-Biotin. Following lysis and purification on immobilized avidin beads, cell surface and total fractions were subject to immunoblotting as outlined previously (Conway et al., 2017, supra).[000435] FLIPR TI Flux assay. HEK-293 cells were washed with HBSS, and then incubated with loading buffer containing Tl sensitive fluorescent dye (https: / / www.moleculardevices.com), 20 pM bumetanide 20 pM ouabain and 2.5 mM probenecid for 1 h at room temperature (RT) under control conditions or with drugs in the dark using a FlexStation 3 microplate reader (Molecular Devices) and imaged 525nM for 30min. Stimulus buffer was added containing 5 mM K+ / 0.5 mM Tl+and cells were imaged every 1.5 over a 190 second time course The initial rate Tl+uptake (Relative Fluorescence Units (RFU) per second) was determined following additionDocket: 2262-122 PCTof the stimulus buffer as outlined previously (Conway etal., 2017, supra) (Lee et al., 2022, supra).Example 2Identification of Compound A[000436] Determining if compounds in SSA directly interact with KCC2. This was tested using a cellular thermal shift assay (CETSA), which measures the ability of a drug to modify the thermal stability of its target in whole cells (Kawatkar et al., ACS Chem. Biol. 14, 1913-1920 (2019); Martinez et al., Sci Rep 8, 9472 (2018)).[000437] 2×106transfected HEK-293 cells were incubated with 30pM drug or vehicle for 90 min at 37°C and then heated from 37-58°C for 5min. Cells were rapidly chilled to 25°C and NP40 was added to a final concentration of prior to snap freezing in liquid nitrogen. Following 5 freeze / thaw cycles lysates were centrifuged at 12,000xg to remove denatured proteins and associated cell debris. The supernatant cell and tissue lysate samples, or immunoprecipitated KCC2 samples were separated by SDS-PAGE and subsequently immunoblotted with KCC2 antibodies (1:2000, Millipore #07-432), KCC2-S940, KCC2-pT1007 (1:2000, PhosphosSolutions, #1568) actin and GAPDH (1:3000, SantaCruz #sc-32233) as detailed in previous studies (Lee et al., 2011, supra (Conway et al., 2017, supra), and the level of soluble KCC2 at each temperature was normalized to that seen at 37°C. This data was then used to determine the temperature at which 50% of KCC2 was denatured.[000438] Aliquots of HEK-293 cells expressing KCC2 were exposed to 30pM SSA, heated from 37-55°C. The remaining level of soluble native KCC2 at each temperature was measured by immunoblotting and normalized to the level seen at 37°C which was given a value of 1. SSA-1 reduced the thermal stability of KCC2 compared to vehicle, which demonstrated target engagement. To gain insights into affinity, isothermal dose response analysis was performed at 50°C revealing a KD of 395.6 ± 23.5 nM of SSA for KCC2 (Fig. 1B-D). SSA derivatives were further optimized for affinity, optimal drug like properties and predicted brain penetration by in vitro cellular uptake assays, which resulted in the identification of Compound A (Fig. IE), Dose response measurements with Compound A were then made at 50°C and this data was used to estimate its relative affinity for KCC2 (Kawatkar et al., 2019, supra) (Martinez et al., 2018, supra). To control for compounds that may indirectly modulate KCC2 activity, via modifying its phosphorylation (Kahle et al., Trends Neurosci. 36, 726-737 (2013); Moore et al., Proc. Natl.Docket: 2262-122 PCTAcad. Sci. U. S. A. 775, 10166-10171 (2018); Silayeva et al, Proc. Natl. Acad. Sci. U. S. A. 772, 3523-3528 (2015); Smalley et al., Front. Mol. Neurosci. 13, 563091 (2020)), the effect of Compound A to modify the activity of a panel of 144 protein kinases (SelectScreen;Thermofisher)' was studied. This panel included protein kinase C isoforms, OSR1, SPAK (STK39) and with-no-lysine kinases (WNK), all of which phosphorylate KCC2 on multiple residues to indirectly modify its activity (Kahle et al., 2013, supra, Smalley et al., 2020, supra). Compound A did not modify the activity of this kinase panel.[000439] As measured by TI+ flux, Compound A exhibited an ECso for KCC2 of 261.4 ± 22.2nM and a maximum potentiation of 90% at a saturating concentration of 3pM using a 1% 0-cyclodextrin (BCD) vehicle (Fig. IF). Several studies have shown that the activity and plasma membrane accumulation of KCC2 is potentiated via phosphorylation of S940, a process mediated by the activity of protein kinase C and protein phosphatase 1 (Lee et al, 2011, supra, Lee et al., J Biol Chem 282, 29777-29784 (2007); Moore et al., Proc. Natl. Acad. Sci. U. S. A.775, 10166-10171 (2018); Moore et al., Trends Neurosci. 40, 555-571 (2017); Silayeva et al., Proc. Natl. Acad. Sci. U. S. A. 772, 3523-3528 (2015)). The ability of Compound A to modulate the activity of a KCC2 construct was tested in which this key residue for phospho-dependent modulation of KCC2 was mutated to an alanine (S940A). Significantly, Compound A increased the activity of KCC2-S940A construct (Fig. 1G). Finally, the specificity of Compound A for other solute transporters was examined using the TI+ assay using HEK-293 cells expressing KCC3, KCC4, or NKCC1. Compared to KCC2, effects on KCC3, KCC4, and NKCC1 were only-seen at concentrations more than 35-fold that of KCC2 (>100p. M) (Fig. 1G).[000440] These results suggest that Compound A binds directly to KCC2 and acts to increase its activity with minimal effects on other solute transporters that regulate neuronal Cl‘ accumulation.Example 3Compound A potentiates KCC2 activity without modifying its plasma membrane accumulation or phosphorylation[000441] To confirm the validity of our measurements using TI+ flux, KCC2 was expressed in HEK-293 cells with the al subunit of the glycine receptor (GlyRal) which forms homomeric glycine-activated ion channels when expressed in this system. The gramicidin perforated patch clamp technique was used to measure the reversal potential for GlyRal -mediated currents (EGLY)Docket: 2262-122 PCTin cells exposed to Compound A. The use of this technique, while limited in throughput, facilitates high resolution single-cell recordings without disturbing endogenous intracellular Cl" levels (Cardarelli etal., 2017, supra, Conway etal., 2017, supra). To calculate EGLY, cells were exposed to 50 pM Gly and the polarity of Gly-induced currents was determined at different holding potentials. Brief (15 min) incubation with either 0.3 pM (approx. ECso) or 3 pM Compound A induced shifts of -15.6 ± 4.5 (p=0.022), and -32.2 ± 9.5 (p=0.001) mV in EGLY respectively, while vehicle was without effect (-0.8 ± 0.5mv; p=0.512) (Fig 2A-B). As determined using the Nernst equation, these negative shifts in EGLY by Compound A corresponded to reduced intracellular CT levels of Fig. 2B; Compound A; 5.2 ± 1.2; vehicle = 7.9 ±1.2 mM; p = 0.0104).[000442] The effects of Compound A on the plasma membrane stability of KCC2 expression was assessed using biotinylation, as described previously (Cardarelli etal., 2017, supra, Conway et al., 2017, supra). Compared to vehicle, 0.3 pM or 3 pM Compound A did not modify the level of KCC2 on the plasma membrane (Fig.2C; 94.5 ± 8.4%, p=0.745 and 104.7 ± 8.4% of control; p=0.736 respectively). The reliability of the biotinylation procedure was assessed via immunoblotting with antibodies against the cytosolic protein actin. Actin was present in the total lysates but was absent from the surface fractions (Fig. 2C).[000443] The activity of KCC2 is subject to dynamic modulation via phosphorylation of critical intracellular residues within its C-terminal cytoplasmic domain. Central to this process are serine 940 (S940) and threonine 1007 (T1007), which activate and inhibit KCC2 activity respectively (Moore etal., 2017, supra). Therefore, the effects of Compound A on the phosphorylation of these residues was examined using immunoblotting with characterized phospho-specific antibodies pS940 and pT1007, respectively. Compound A (3pM) did not significantly modify phosphorylation of S940 (95.3 ± 10.2% of control; p=0.764), or T1007 (108 ± 10.2% of control; p=0.649) (Fig. 2D).[000444] The foregoing suggests that Compound A potentiates KCC2 activity without modifying either its plasma membrane accumulation or the phosphorylation of key regulatory sites.Docket: 2262-122 PCTExample 4Compound A reduces neuronal Cl~ accumulation in vitro[0004451 To test if Compound A modifies neuronal Cl’ levels gramicidin-perforated patchclamp recording was used to measure the reversal potentials of GABAA receptor mediated currents (EGABA) in 18-20 Div hippocampal neurons (Lee et al., 2011, supra, Moore et al., 2018, supra). At this developmental stage, GABAAR receptor activation leads to hyperpolarization, a phenomenon critically dependent upon KCC2 (Kontou et aL, J Biol Chem, 100364 (2021)).[000446] Neuronal Patch clamp assays. Neuronal cell culture recordings were performed in bath saline at 34°C. For gramicidin perforated-patch experiments, pipettes contained (in mM): 140 KC1 and 10 HEPES, pH 7.4 KOH. For whole-cell experiments, pipettes contained (in mM): 115 K-meth-SO4, 30 KC1, 2 Mg-ATP, 4 Na- ATP, 0.4 Na-GTP, and 10 HEPES, pH 7.4 KOH. Bath saline contained the following (in mM): 140 NaCl, 2.5 KC1, 2.5 CaCh, 2.5 MgCL, 10 HEPES, and 11 glucose, pH 7.4 NaOH (Kontou et al., 2021, supra). All compound solutions were applied to cells using a three-barreled 700 pm pipe positioned just above the cell (Warner Instruments). Compound A was applied in Img / mL 2-Hydroxypropyl-P-cyclodextrin, and its effects were compared to this vehicle alone. 10 mV voltage-ramp protocols over 1-s periods were used to determine the reversal potentials of the leak- subtracted muscimol-activated GABAAR currents. All voltages from whole-cell experiments were corrected offline using a calculated liquid junction potential value (13.6 mV) in Clampex (Molecular Devices). For gramicidin perforated-patch experiments, intracellular CL values were back-calculated using measured EGABA values and the Nernst equation:_ RT [ion]oEjon — zF r [ion i];where E is the ion’s reversal potential, R is the universal gas constant, T is temperature in kelvins, F is Faraday’s constant, z is the charge of the ion, [chloride]; is the intracellular chloride concentration and [chloride]ois the extracellular ion concentration.[000447] Measurements were performed in the presence of bumetanide (10pM) and tetrodotoxin (TTX; 300nM) to limit the contributions of NKCC1 and activity dependent shifts in chloride levels, respectively (Lee et al., 2011, supra). Cultures were exposed to Compound A or vehicle for 15 min and voltage ramps were used to determine changes in the reversal potential of GABAAR receptor currents over time (Fig 3A). These data were then used to determine shiftsDocket: 2262-122 PCTsubsequently, using [Cl’] levels. At 15 min 300nM Compound A (an approximately EC50 concentration) significantly reduced EGABA from -75 ± 3.1 to -85.1 ± 4.2mV (Fig 3B; p=0.0104), a net -9.1 ± 2.2 mV negative shift, reflecting a 2.2 ± 0.6 mM reduction in Cl’ (Fig 3C; p=0.0153). In contrast, vehicle did not significantly modify EGABA (Fig 3B; 0 = -77.2 ± 3.3, 15 = -78.0 ± 4.3 mV respectively, p=0.580) or chloride levels.[000448] To measure the effects of Compound A on KCC2 activity under more dynamic conditions cultures in Compound A were incubated for Ih and subjected to whole cell patchclamp recording to artificially impose a 32 mM Cl’ load on neurons via the patch pipette (Lee et al., 2022, supra, Moore et al., 2018, supra ). 5 min after break-in, an initial EGABA value was determined and the effects of a subsequent 5 min incubation with VU0463271 was assessed. Compound A-treated cells exhibited lower basal EGABA values compared to controls (Fig.3C; Fig.3D -59.3 ± 2.1 and -47.4 ± 2.3 mv, respectively, p=0.025). Likewise, VU0463271 induced shifts in EGABA were larger for cultures treated with Compound A (Fig.3C; Fig.3D 17.5 ± 4.6 and 5.4 ± 4.2mV, respectively, p=0.009).[000449] Thus, Compound A reduces neuronal Cl’ levels and slows the development of hyperexcitability in an ex vivo system.Example 5Compound A rapidly accumulates in the brain in vivo[000450] PK studies. Mice were injected intraperitoneally (IP), intravenously (IV), or subcutaneously (SC), with Compound A and 5% BCD in a maximum volume of 300pl. Plasma and brain samples were rapidly frozen on dry ice. Tissue extracts were treated with Acetonitrile and Compound A levels were quantified using LC-MS / MS (Integrated Analytical Solutions, Inc, Berkeley, CA 94710; www.ianalytical.net).[000451] To examine the ability of Compound A to cross the blood brain barrier, mice were injected with a single 25 mg / kg IV bolus; accumulation in the brain was evident within 30 minutes min in the brain and plasma to 7.6 ± 4.4 and 41.5 ± 11.5 and 11.2 pM respectively (Fig.4A). Likewise, a 50 mg / kg IP injection resulted in the accumulation of Compound A in the brain to 2.67 ± 0.21 and 4.1± 0.13 pM 2 and 4 hr later (Fig. 4B). Drug accumulation in the brain was examined following SC injection (Fig. 4C; 50 mg / kg). Accumulation was detected at 30min and reached a maximal concentration of 675.75 ± 80.5nM at 4 hr, a level that was maintained 8h laterDocket: 2262-122 PCT(Fig. 4C)[000452] Given the ability of Compound A to accumulate in the brain, it was examined to see if it also causes any gross effects on animal behavior. Mice were injected with Compound A (SC; 50mg / kg), or vehicle and their behavior was compared in the open field test (Tretter et al., Proc. Natl. Acad. Sci. U. S. A. 106, 20039-20044 (2009); Vien et al., Frontiers in molecular neuroscience 15, 817996 (2022)). Compound A did not modify the total distance traveled during the test trial (Fig. 4D; Compound A = 6134.2 ± 235.3 cm, and vehicle = 6453.7 ± 215.4 cm; p=0.253, n= 11 mice). Likewise, time spent in the center zone was comparable (Fig. 4D;Compound A = 18.4 ± 2.1, and vehicle 16.6 ± 2.5 % of total time; p=0.658, n=l 1 mice).[000453] Collectively, these results suggest that Compound A accumulates in the brain when dosed IV, IP or SC, and does not lead to any stereotyped effects on behavior.Example 6Prospective Assessment of the Efficacy of Compound A, Compound B, Compound C, Compound D, Compound E. Compound F, Compound G. and Compound H, in Patients with Tinnitus[000454] This study is designed to determine whether Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H leads to an improvement in tinnitus. The primary objective of this study may be to evaluate include the identification of a set of parameters that may best characterize the efficacy of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, and Compound H from Baseline to Week 6 and Week 12 of in adult subjects with tinnitus across different dose levels and in two dosing schedules. The following dosing schedules may be tested against placebo: (1) Once daily (o.d.): An evening dose; and (2) Twice daily (b.i.d.): Evening and morning doses titrated to target doses. The tests are separately repeated for each of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, and Compound H.[000455] These tests will be administered at four full day site visits (Screening, Baseline, Interim and End of Treatment) by an appropriately trained professional to provide the test to an adult tinnitus patient. Assessments may be based on patient’s perception of symptoms. TinnitusDocket: 2262-122 PCTloudness- visual analogue scale (VAS) [ Time Frame: each week: the time between the questionnaire results at the beginning and compared to the results after each week following initial administration. Tinnitus loudness scale: A range of 1-10 scale. The patients choose which number reflects the loudness of the subjective tinnitus which the patients suffer from. The higher the number: the louder the tinnitus. Tinnitus suffer scale: A range of 1-10 scale. The patient chooses which number reflects the best the degree in which the tinnitus causes the patient to suffer: the higher the score- the worse is the tinnitus.[000456] Evaluation of sleep includes analysis by actigraphy to measure: (1) Sleep Onset Latency (SOL); (2) Total Sleep Time (TST); (3) Wake After Sleep Onset (WASO) = total # of wake epochs after sleep onset; (4) Nocturnal Awakenings (NA); and / or (5) Sleep Efficiency = total sleep time (TST) of time in bed (TIB). Additional evaluation of sleep may include analysis of parent / caregiver logs of sleep patterns that include: (1) bed time; (2) time of sleep onset; (3) number and duration of awakenings; (4) number of disruptive behavior; (5) time of last awakening; and (6) daytime sleepiness.[000457] Each study will include three treatment groups. For example, a total of approximately 75 subjects may be enrolled and at the completion of a study with approximately 25 subjects in each of the three treatment groups: 1) single evening dose 2) morning and evening dose and 3) placebo.[000458] All subjects may receive a morning dose (either active or placebo) and an evening dose (either active or placebo) during the entire duration of treatment. For example, two dosing schedules of Compound A, Compound B, Compound C, Compound D, Compound E, Compound F, Compound G, or Compound H may be tested: a single evening dose (o.d.) and a morning plus evening dose (b.i.d) designed to provide a more sustained exposure. Schedule C is morning and evening placebo. All subjects may be up-titrated to the target dose unless this target dose is not tolerated (titration conventions described below). All subjects may receive treatment for a maximum of 12 weeks at their optimal tolerated dose. Doses may range from 0.08 mg / kg to 4 mg / kg. For example, a 70 kg subject could initially receive from about 5.5mg to about 280 mg / kg.[000459] Doses may be progressively increased in increments (active or placebo) to a target dose (in the evening), and morning dose. Each dose escalation may be performed after adequate tolerability has been assessed by caregiver and investigator. For example, treatment initiation atDocket: 2262-122 PCTDay 1 with 1 dose (active (Act) or placebo (Pic)) in the evening. Then target up-titration may begin at Day 3 (window + 2 days): If no adverse event (AE) related to the study drug is observed by caregiver and / or the investigator, another dose (active or placebo) is added in the evening. Again at Day 7 (window + 2 days), Day 10 (window + 2 days and Day 14 (window + 2 days) if no AE related to the study drug is observed by caregiver and / or the investigator, another dose (active or placebo) may be added in the morning.[000460] Slowed up-titration or delayed up titration will be acceptable if tolerability does not allow immediate further dose-escalation at any of the above detailed days (3, 7, 10, 14). Downtitration in the case tolerability is not acceptable after a previous up-titration step or during the course of the 12 week treatment, dose can be reduced to the previous level or even further. However, once a tolerable dose has been reached, it shall remain constant for the duration of the treatment period. Once a target dose is achieved the treatment may continue. For example, at Day 14: Earliest day the target dose can be reached the subject may be kept stable until End of Treatment visit (week 12) unless intolerability requires down-titration.[000461] All subjects will be screened for participation in the study up to 28 days prior to the first dose administration. Inclusion criteria may include one or more of the following: (1) Age > 18 years, < 40 years; (2) Must possess a clinical diagnosis of tinnitus. Descriptive statistics may be used to summarize all primary and secondary endpoints as well as baseline variables, by treatment group. For continuous variables, n, number of missing values, mean, standard deviation, median, minimum, and maximum will be provided. For categorical variables, frequency and percentage will be presented for each category. Confidence intervals (CI) will be provided where meaningful. All Cis will be two-sided 95% confidence intervals.[000462] It should be understood that the examples and embodiments provided herein are exemplary examples and embodiments. Those skilled in the art will envision various modifications of the examples and embodiments that are consistent with the scope of the disclosure herein. Such modifications are intended to be encompassed by the claims.

Claims

Docket: 2262-122 PCTWhat is claimed is:

1. A method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, comprising administering a compound according to Formula (I),(I),or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; C3-7cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy wherein -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-C1-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;R2is selected from -H; -halo; and -C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;A is selected fromDocket: 2262-122 PCTR3is selected from -H; -Ci-ealkyl; -C2-6alkenyl; -C2-6alkynyl; C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -C1-3alkyl optionally substituted by 1 or 2 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9;R4aand R4bare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R4cand R4dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3, or R4cand R4dtogether with the carbon to which they are attached represent carbonyl;R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R6is selected from -H; -halo; -NH2; -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-C1-3alkyl;R7is selected from NR10R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -C1-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -C(O)OH; -C1-3alkylene-NHC(O)C1-6alkyl; -C1-3alkylene-NHC(O)OC1-6alkyl; C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they areDocket: 2262-122 PCTattached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H;R8and R9are each independently selected from -H and -C1-6 alkyl;R10is -C1-6 alkyl;R11is selected from -C1-6alkyl optionally substituted with 1 or 2 substituents selected from -F and -C1-6alkoxy; and -(CH2)nR12;R12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;m is 0 or 1; andn is 1, 2 or 3,to a subject in need thereof in an amount of from about 0.01 mg to about 1500 mg.

2. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the total amount of the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, administered to the subject in a twenty -four hour period is between about 1 mg and about 1000 mg.

3. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the method provides improvement in at least one symptom of tinnitus selected from the group consisting of ringing, roaring, static, buzzing, hissing, whooshing, cricket noises, jackhammer noises and whistling, in one or both ears.

4. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the method provides improvement in at least one symptom of acute sensorineural hearing loss selected from the group consisting of aural fullness, hearing loss and tinnitus.Docket: 2262-122 PCT5. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the method provides improvement in at least one symptom of age-related hearing loss selected from the group consisting of mild hearing loss, reduced ability to perceive certain high-pitched sounds, reduced ability to perceive certain low-pitched sounds and total loss of hearing.

6. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the method provides improvement in at least one symptom of Meniere’s disease selected from the group consisting of vertigo, fluctuating hearing loss, progressive, permanent loss of hearing, tinnitus, aural fullness and hypersensitivity to sounds.

7. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound A:

8. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound B:Docket: 2262-122 PCT9. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound C:

10. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound accordingto Formula (I), or a pharmaceutically acceptable salt thereof, is Compound D:Docket: 2262-122 PCT11. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound E:

12. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound F:

13. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound G:Docket: 2262-122 PCT14. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is Compound H:

15. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered enterally.

16. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 15, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered orally, sublingually, buccally, transdermally, intranasally, vaginally or rectally.

17. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered parenterally.

18. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered in the form of a liquid for parenteral use, a tablet, a capsule, a caplet, a pill, an oral liquid, a lozenge, a film, a powder, an aerosol, or a patch.

19. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered as an extended release dosage form.Docket: 2262-122 PCT20. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered as an instant release dosage form.

21. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered as a delayed release dosage form.

22. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the subject is a human subject.

23. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered from one to four times daily.

24. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 1, wherein the compound according to Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with a medication selected from the group consisting of a corticosteroid, a benzodiazepine, a nonsteroidal anti-inflammatory, an opioid, gabapentin, pregabalin, a sulfonamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlor-methiazide indapamide, mefruside, metolazone, piretanide, tripamide xipamide, dichlorphenamide, dorzolamide, ethoxzolamide, sultiame, zonisamide, quinethazone, aNKl receptor antagonist, risperidone, ziprasidone, haloperidol, pimozide, fluphenazine, clonidine, guanfacine, methylphenidate, methamphetamine, dextroamphetamine, atomoxetine, bupropion, guanfacine, or clonidine, naltrexone, disulfiram, acamprosate, topiramate, buprenorphine and methadone.Docket: 2262-122 PCT25. The method of treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease, according to claim 24, wherein the benzodiazepine is selected from the group consisting of diazepam, alprazolam, estazolam, clobazam, clonazepam, clorazepate, chlordiazepoxide, flurazepam, triazolam, temazepam, midazolam, halazepam, quazepam, lorazepam and oxazepam.

26. Use of a compound according to Formula (I),(I),or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; Ca-vcycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -C2-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-C1-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;R2is selected from -H; -halo; and -C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;A is selected fromDocket: 2262-122 PCTR3is selected from -H; -Ci-ealkyl; -C2-6alkenyl; -C2-6alkynyl; C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -C1-3alkyl optionally substituted by 1 or 2 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9;R4aand R4bare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R4cand R4dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3, or R4cand R4dtogether with the carbon to which they are attached represent carbonyl;R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R6is selected from -H; -halo; -NH2; -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-C1-3alkyl;R7is selected from NR10R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -C1-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -C1-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -C(O)OH; -C1-3alkylene-NHC(O)C1-6alkyl; -C1-3alkylene-NHC(O)OC1-6alkyl; C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they areDocket: 2262-122 PCTattached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H;R8and R9are each independently selected from -H and -C1-6 alkyl;R10is -C1-6 alkyl;R11is selected from -C1-6alkyl optionally substituted with 1 or 2 substituents selected from -F and -C1-6alkoxy; and -(CH2)nR12;R12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;m is 0 or 1; andn is 1, 2 or 3,for the manufacture of a medicament for treatment of tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease.

27. A compound according to Formula (I),or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-6alkenyloxy; C2-6alkynyloxy; Cs-ycycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy andDocket: 2262-122 PCTcycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -Ci-3alkyl, -Ci-salkoxy and -C2-8alkynyloxy wherein -Ci-3alkyl, -Ci-salkoxy and -C2-salkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;R2is selected from -H; -halo; and -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;A is selected fromR3is selected from -H; -Ci-6alkyl; -C2-6alkenyl; -C2-6alkynyl; C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -Ci-3alkyl optionally substituted by 1 or 2 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9;R4aand R4bare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R4cand R4dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3, or R4cand R4dtogether with the carbon to which they are attached represent carbonyl;R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R6is selected from -H; -halo; -NH2; -CN; -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3Docket: 2262-122 PCTsubstituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(O)-C1-3alkyl;R7is selected from NR10R11; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -Ci-6alkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Ci-salkylene-NHC(O)OCi-6alkyl; C3-5cycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H;R8and R9are each independently selected from -H and -C1-6 alkyl;R10is -C1-6 alkyl;R11is selected from -Ci-ealkyl optionally substituted with 1 or 2 substituents selected from -F and -Ci-3alkoxy; and -(CH2)nR12;R12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;m is 0 or 1; andn is 1, 2 or 3,for use in treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease.

28. A pharmaceutical composition comprising a compound according to Formula (I),Docket: 2262-122 PCT(I),or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C2-6alkyl; C2-6alkenyl; C2-6alkynyl; C2-6alkoxy; C2-ealkenyloxy; C2-6alkynyloxy; C3-?cycloalkyl; -O-C3-7cycloalkyl; C6-10aryl; -O-(CH2)m-C6-10aryl; 6 membered heteroaryl; and thiophenyl; wherein alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cycloalkyl are optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3 and wherein aryl and heteroaryl are optionally substituted with 1 or 2 substituents selected from -halo, -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy wherein -C1-3alkyl, -C1-3alkoxy and -C2-3alkynyloxy are optionally substituted with 1, 2, or 3 substituents selected from -F, -CF3, -NHC(O)O-Ci-6alkyl or two substituents together with the carbon to which they are attached form diazirinyl;R2is selected from -H; -halo; and -Ci-3alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3;A is selected from-oxide thereof;R3is selected from -H; -C1-6alkyl; -C2-6alkenyl; -C2-6alkynyl; C3-7cycloalkyl; and a 5 or 6 membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkylDocket: 2262-122 PCTare optionally substituted by 1, 2 or 3 groups selected from -F, -CF3, -Cnsalkyl optionally substituted by 1 or 2 substituents selected from -F, -CF3, -C(O)NR8R9and -NR8R9;R4aand R4bare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R4cand R4dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3, or R4cand R4dtogether with the carbon to which they are attached represent carbonyl;R5a, R5b, R5cand R5dare each independently selected from -H and -C1-3 alkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3;R6is selected from -H; -halo; -NH2; -CN; -Ci-salkyl optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and -CF3; -C(O)O-Ci-3alkyl; -C(O)NR8R9; -C(O)OH; and -NHC(0)-CI.3 alkyl;R7is selected from NR1ORU; a 5 to 7 membered monocyclic heterocycloalkyl; and a 5 or 6 membered monocyclic heteroaryl; wherein the heterocycloalkyl and heteroaryl are optionally substituted with 1, 2 or 3 groups selected from -CN; -Ci-ealkyl optionally substituted with 1, 2 or 3 substituents selected from -F, -CF3 and -OH; -Ci-3alkoxy optionally substituted with 1, 2 or 3 substituents selected from -F and CF3; -C(O)OH; -Ci-3alkylene-NHC(O)Ci-6alkyl; -Cnsalkylene-NHC(O)OCi-ealkyl; Cs-scycloalkyl; or the heterocycloalkyl is optionally substituted with two substituents on the same ring carbon which together with the carbon atom to which they are attached form a 5 to 7 membered monocyclic heterocycloalkyl; and wherein when R7is morpholinyl and R1is unsubstituted phenyl, R2is not -H;R8and R9are each independently selected from -H and -C1-6 alkyl;R10is -C1-6 alkyl;R11is selected from -Ci-ealkyl optionally substituted with 1 or 2 substituents selected from -F and -Ci-3alkoxy; and -(CH2)nR12;Docket: 2262-122 PCTR12is a 5 or 6 membered heteroaryl, a 3 to 5 membered cycloalkyl or a 3 to 6 membered heterocycloalkyl;m is 0 or 1; andn is 1, 2 or 3,and a pharmaceutically acceptable carrier for use in treating tinnitus, acute sensorineural hearing loss, age-related hearing loss, or Meniere’s disease.

29. A pharmaceutical composition according to claim 28, wherein the carrier includes one or more of the following: a diluent, a binder, a lubricant, a disintegrant, a fdler, a coating composition, an adjuvant, a stabilizer, a flavoring, a colorant, a glidant, a thickening agent, a solvent, a solubility enhancer, a suspending agent, a buffering agent, a isotonicity agent, a antimicrobial preservative, an antioxidant, a chelating agent.

30. A pharmaceutical composition according to claim 28, further comprising a medication selected from the group consisting of a corticosteroid, a benzodiazepine, a nonsteroidal antiinflammatory, an opioid, gabapentin, pregabalin, a sulfonamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, polythiazide, trichlor-methiazide indapamide, mefruside, metolazone, piretanide, tripamide xipamide, dichlorphenamide, dorzolamide, ethoxzolamide, sultiame, zonisamide, quinethazone, aNKl receptor antagonist, risperidone, ziprasidone, haloperidol, pimozide, fluphenazine, clonidine, guanfacine, methylphenidate, methamphetamine, dextroamphetamine, atomoxetine, bupropion, guanfacine, or clonidine, naltrexone, disulfiram, acamprosate, topiramate, buprenorphine and methadone.

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