WO2025224601A1

WO2025224601A1 - Trpm3 antagonists for the treatment of migraine and pain

Info

Publication number: WO2025224601A1
Application number: PCT/IB2025/054157
Authority: WO
Inventors: Richard BERTZ; Beth L. EMERSON; Volkan GRANIT; Arnaud Marchand; Stuart Murray; Irfan QURESHI; Jean-Christophe VANHERCK; Thomas VOETS; Joris VRIENS
Original assignee: Katholieke Universiteit Leuven; Biohaven Therapeutics Ltd
Current assignee: Katholieke Universiteit Leuven; Biohaven Therapeutics Ltd
Priority date: 2024-04-21
Filing date: 2025-04-21
Publication date: 2025-10-30
Anticipated expiration: 2026-10-21

Abstract

Described herein are methods of treating migraine, headache, neuropathic pain, and/or nociceptive pain in a human patient in need thereof, comprising orally administering to the patient a pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a TRPM3 antagonist, or a physiologically acceptable salt thereof, as described herein.

Description

TRPM3 ANTAGONISTS FOR THE TREATMENT OF MIGRAINE AND PAIN

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Applications 63/636,822, filed on April 21, 2024; 63/652,319, filed on May 28, 2024, 63/655,571, filed on June 3, 2024; and 63/677,138, filed on July 30, 2024, which are incorporated herein by reference in their entirety.

SEQUENCE LISTING

The Instant Application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 17, 2025, is named “SEQ LIST-- 109603003.xml” and is 3,600 bytes in size. The Sequence Listing does not go beyond the disclosure in the application as filed.

FIELD OF THE DISCLOSURE

[0001] The present disclosure is related to TRPM3 antagonists for the treatment of migraine and pain as supported by pharmacokinetics and clinical studies in humans.

BACKGROUND

[0002] Despite substantial progress in therapy, migraine remains a leading cause of disability on a global scale and afflicts more than 1 billion people worldwide. Many people with migraine have inadequate symptom relief or face tolerability and safety issues with existing acute therapies. Approximately 96% of people with migraine report at least one unmet acute treatment need, and about 74% describe inadequate treatment response. New treatments are needed to meet the needs of individual patients and to address the public health burden of this highly prevalent disorder. Effective treatments have the potential to give patients more headache-free days, an outcome associated with improved work and household activity participation, as well as a reduction in associated indirect costs. In addition, suboptimal acute treatment is associated with an increased risk of migraine progression.

[0003] A migraine attack is commonly preceded by an aura, which usually includes impairment in vision as well as a tingling sensation on the face and limbs. An aura may occur a few minutes before pain begins. During a migraine attack, the patient typically suffers from moderate to severe pulsing or throbbing pain, on the sides of their head and behind the eyes. The pain intensifies for patients with any movement of the head, including actions like sneezing and coughing. Pain symptoms are often accompanied by nausea and vomiting as well as sensitivity to light, noise, and odors. Migraines can cause patients to lose the ability to perform daily tasks like driving or working, and in most cases prevent the patient from undergoing any physical activity without feeling intense pain.

[0004] Triptans, serotonin 5-HT receptor agonists, are the anti-migraine agents that are the most effective and commonly prescribed agents. Triptans bind to three serotonin receptors, 5HT1B, 5HT1D, and 5HT1F, causing the constriction of blood vessels in cranial arteries which become dilated during a migraine, thus inhibiting the neurotransmission of pain sensation. In practice, however, triptans do not provide relief to all patients and due the effect triptans have in the cranial arteries, they can cause problems in patients with cardiovascular disease, cerebrovascular disease, and the like.

[0005] Other anti-migraine agents include non-steroidal anti-inflammatory drugs (NSAIDs), typically used for pain relief during the main portion of a migraine attack. However, these drugs can be slow acting and inconsistent in alleviating pain symptoms.

[0006] Calcitonin gene-related peptide (CGRP) inhibitors are a more recently developed option for the treatment and prevention of migraines. These agents modulate the CGRP ligand or its receptor that is located within pain signaling pathways, intracranial arteries, and mast cells. With the discovery that serum levels of CGRP are elevated during a migraine attack, many CGRP inhibitors have been developed such as olcegepant, telcagepant, ubrogepant, rimegepant, and others. Despite this welcome addition to the therapeutics, not all migraine sufferers respond to the CGRP antagonists. (See, Raffaelli B, Fitzek M, Overeem LH, Storch E, Terhart M, Reuter U. “Clinical evaluation of super-responders vs. non-responders to CGRP (-receptor) monoclonal antibodies: a real -world experience”. The Journal of Headache and Pain. 2023 Feb 27;24(1): 16; Hong JB, Lange KS, Overeem LH, Triller P, Raffaelli B, Reuter U. “A scoping review and meta-analysis of anti-CGRP monoclonal antibodies: predicting response”. Pharmaceuticals. 2023 Jun 27;16(7):934)

[0007] Transient receptor potential (TRP) melastatin-3 (TRPM3) is a non-selective calcium permeable ion channel expressed in the meninges and trigeminal ganglion, which is sensitive to heat and ligand stimulation. TRPM3 promotes neurogenic inflammation (which plays a key role in migraine pathophysiology) through its effects on CGRP release as well as mechanisms that are CGRP -independent. TRPM3 sensitizes and activates nociceptors in the trigeminovascular system, and importantly, TRPM3 antagonism normalizes nociceptor function in preclinical models. In nociceptors innervating inflamed tissues, antagonisms of TRPM3 also dampens the responsiveness of TRPV1 and TRPA1 which are both TRP channels that are expressed in nociceptors implicated in migraine, suggesting that TRPM3 is an upstream target for reducing inflammatory nociception. Human transcriptomic data demonstrate TRPM3 co-expression with a spectrum of migraine-relevant genes in the human trigeminal ganglion. Further genetic analyses suggest a strong association between TRPM3 genetic variants and the risk of migraine. While there is a suggestion in the art as to the potential use of TRPM3 inhibitors to treat various pain-related disorders, no human clinical data or pharmacokinetics have been provided.

[0008] What is needed are methods for the treatment of migraine using TRPM3 inhibitors using methods validated in human pharmacokinetic studies.

BRIEF SUMMARY

[0009] In an aspect, a method of treating migraine, headache, neuropathic pain, and/or nociceptive pain in a human patient in need thereof comprises orally administering to the patient a pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a TRPM3 antagonist, or a physiologically acceptable salt thereof, wherein the TRPM3 antagonist is a molecule of Formula (I) wherein

R¹ is CH3 optionally substituted with F;

Q is -NR³R⁴; wherein

R³ is H; and

T is -O-, U is -CH2-; R⁶, R⁷ and R⁸ are each H;

V is a 5-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, or a 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the 5- membered heteroaryl and 6-membered heteroaryl are optionally substituted with -F, -Cl, Ci- C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows the pharmacokinetic profile for single oral doses of BHV-2100 in healthy subjects presented as mean concentration vs. time profiles. EC90 represents the estimated plasma concentration threshold based on a preclinical model. Error bars represent the standard deviation from the arithmetic mean. N= 6 for each dose group.

[0011] FIG. 2 shows the mean concentration vs. time profiles of single oral doses of BHV-2100 with and without a high fat meal. EC90 represents the estimated plasma concentration threshold based on a preclinical model. Error bars represent the standard deviation from the arithmetic mean. N= 6 for each dose group. EC90, 90% maximal effective concentration.

[0012] FIG. 3 shows the mean concentration vs. time profiles of single oral doses of BHV-2100 with and without famotidine. EC90 represents the estimated plasma concentration threshold based on a preclinical model. Error bars represent the standard deviation from the arithmetic mean. N= 6 for each dose group.

[0013] FIG. 4 shows the mean concentration vs. nominal time at steady state profiles after multiple doses of BHV-2100. The dashed line represents the theoretical concentrationtime profile of a second dose on a BID schedule (determined by superposition of steady-state data). EC50 and EC90 represent the estimated plasma concentration threshold based on a preclinical model. Error bars represent the standard deviation from the arithmetic mean. N= 6 for each dose group (n=5 for the 150 mg QD at steady state). BID, twice daily. QD, once daily. EC50, 50% maximal effective concentration.

[0014] FIG. 5 shows the time course of the changes in body core temperature (BCT), activity and heart rate in rats (N=8) during one hour prior and 3 hours post oral dosing of vehicle, BHV-2100 (100 mg/kg), or AMG517 (10 mg/kg). The parameter activity is expressed in arbitrary units (a.u.), corresponding to the number of automatically detected activity counts per second. [0015] FIG. 6 shows the average (± SEM) area under the curve and the average (± SEM) peak increase in BCT during the three hour-period post oral dosing of vehicle, BHV- 2100 (100 mg/kg) or AMG517 (10 mg/kg). Statistical comparison was performed using oneway ANOVA with Sidak-Holm post-hoc test.

[0016] FIG. 7. provides the time course for the oxaliplatin-induced peripheral neuropathy study in mice.

[0017] FIG. 8 shows results for the chemotherapy-induced neuropathic pain model. The plot shows the reversal of cold-induced pain (%) when vehicle, tramadol or BHV-2100 (1, 5, or 24 mg/kg) were administered 6 days after oxaliplatin treatment in mice.

[0018] FIG. 9 shows results for animals investigated for mechano-sensitivity using the electronic von Frey test in the chemotherapy induced neuropathic pain model. The mechanical threshold was calculated per animal at the start of the experiment (baseline), at day 6 post oxaliplatin injection (Day 6 pre-treatment) and 30 min post dosing of the different test conditions (Day 6 post-treatment). N= 8 male B16C57J mice.

[0019] FIG. 10 shows results for the diabetic neuropathy model in rats. The plot shows the mechanical threshold (g) for vehicle, pregabalin or BHV-2100 (1, 5, or 24 mg/kg) administered 7 days after streptozoticin (STZ) administration.

[0020] FIG. 11 shows results for the pregnenolone sulfate (TRPM 3 agonist)-induced pain model in rats. Drug was administered 30 minutes prior to TRPM3 agonist injection into the hind paw of rats. The plot shows time spent licking/lifting (Sec) for vehicle or BHV- 2100 (2, 6, or 20 mg/kg).

[0021] FIG. 12 shows results for spared nerve injury of tactile allodynia in rats. The plot shows threshold force (g) vs. time for vehicle, pregabalin (30 mg/kg) or BHV-2100 (1, 5, or 25 mg/kg).

[0022] FIG. 13 shows results for the partial sciatic nerve ligation model in rats. Drug was administered 14 days after unilateral sciatic nerve injury. The plot shows mechanical threshold (% of concentrated paw) vs. time for vehicle, pregabalin (30 mg/kg) or BHV-2100 (1, 5, or 25 mg/kg).

[0023] FIG. 14 also shows results for the partial sciatic nerve ligation model in rats. Drug was administered 14 days after unilateral sciatic nerve injury in rats. The plot shows 50% paw withdrawal threshold for ipsilateral paw and contralateral paw vs. time for pregabalin and BHV-2100 (1, 5, or 25 mg/kg).

[0024] FIG. 15 shows a protocol for a Phase 2 clinical study in the acute treatment of migraine. [0025] The above-described and other features will be appreciated and understood by those skilled in the art from the following detailed description, drawings, and appended claims.

DETAILED DESCRIPTION

[0026] There is a significant unmet need for the treatment of migraine, headache, neuropathic pain, and nociceptive pain. Despite newer treatment options, the burden and disability caused by migraine have remained high. While CGRP receptor antagonists such as rimegepant have proven to be effective for some migraine patients, a significant fraction of migraine patients do not respond to CGRP receptor antagonists. There is thus a persistent need for additional treatments for migraine. The Phase I trials described herein show that compounds of Formula (I) such as BHV-2100 exhibit excellent tolerability, safety, and favorable pharmacokinetic profiles, making them a treatment option for migraine and pain.

[0027] As shown herein, in a mouse model using pregnenolone sulphate, a known activator of TRPM3 channels, BHV-2100 (1, 5, or 25 mg/kg p.o.) reduced the rodents’ nociceptive response (licks/lifts) in a dose-dependent manner. BHV-2100 (1, 5, and 25 mg/kg, p.o.) induced a reduction of the oxaliplatin-induced cold allodynia and mechanical hypersensitivity. The analgesic effect of BHV-2100 was comparable to the analgesic effect of tramadol (5 mg/kg), without the concomitant sedative effects associated with tramadol. In a partial sciatic nerve ligation model in rats, BHV-2100 at 25 mg/kg p.o. showed significant alleviation of mechanical allodynia at 1 and 2h post-treatment. BHV-2100 (1, 5, 25 mg/kg p.o.) was tested in the tactile allodynia in the rat spared nerve injury model. In this model, BHV-2100 (25 mg/kg p.o.) produced a significant attenuation of tactile allodynia in spared nerve injury rats. In the streptozotocin (STZ)-induced diabetic neuropathy model in Lewis rats, BHV-2100 dosed at 5 mg/kg or 25 mg/kg demonstrated statistically significant beneficial effects on tactile allodynia as determined using the von Frey assay. In view of these results, BHV-2100 is also expected to be useful in the treatment of various forms of migraine as well as neuropathic pain, including diabetes-related neuropathic pain, chemotherapy -induced peripheral neuropathy, peripheral neuropathy as a result of injury or trauma, postherpetic neuralgia, carpal tunnel syndrome, sciatica, HIV-related neuropathy, and others.

[0028] Neuroinflammation in and around the trigeminovascular neurons plays a role in migraine. Preclinical data suggest that the expression of TRPM3 is increased in sensory neurons innervating inflamed tissue and that TRPM3 contributes to the hyperexcitability of inflamed neurons. These data are also relevant to migraine, given the key role of TRP channels in nociceptive signaling in the trigeminovascular system and the broad expression of TRPM3 receptors along with TRPA1 and TRPV1 by trigeminal nociceptors.

[0029] TRPM3 activation can trigger vasodilation via CGRP release. Preclinical data suggest TRPM3 leads to neurogenic inflammation in part through the release of CGRP. Beyond animal models, the effect of TRPM3 activation on the CGRP axis has been observed in isolated human tissues. In isolated human dermal arteries from subcutaneous fat, the addition of the TRPM3 agonist pregnenolone sulfate led to a significant release of CGRP.

[0030] Together, these data suggest that the antagonism of TRPM3 ameliorates neuroinflammation and neuronal hyperexcitability through both CGRP-independent mechanisms and those that are CGRP-related.

[0031] TRPM3 is present and functional in anatomically relevant sites that may initiate and propagate migraine, including the meninges and the TG. In mice, TRPM3 ligands evoke trigeminally-mediated pain.

[0032] Genetic evidence also supports the role of TRPM3 in migraine. TRPM3 is coexpressed with known migraine-relevant genes in both neuronal and non-neuronal cells within the human TG. Genetic substitutions in the S4-5 loop of TRPM3 have been shown to increase TRPM3 channel activity (Zhao S, Yudin Y, Rohacs T. “Disease-associated mutations in the human TRPM3 render the channel overactive via two distinct mechanisms”. Elife. 2020;9 (2020).) UK Biobank participants with variants in the S4-5 Loop and participants with CADDhi TRPM3 genetic variants have a significant risk of migraine and/or migraine with aura.

[0033] Described herein is a first-in-human Phase 1 study to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses (SAD and MAD) of oral BHV-2100.

[0034] BHV-2100 has been shown to potently inhibit human, rat, and mouse TRPM3. For example, BHV-2100 inhibits TRPM3 -mediated calcium responses in human embryonic stem cell-derived sensory neurons with a half-maximal inhibitory concentration of 3 nM. In multiple preclinical rodent pain models, it has shown dose-dependent pain reduction (Vriens J, Vanherck J-C, Marchand A, Carr B, Dubowchik G, Caldwell R, et al. “BHV-2100, a first- in-class TRPM3 antagonist for the treatment of pain (S13.002)”. Neurology. 2024;102(2024):6059). Initial Phase 1 clinical trials of BHV-2100 demonstrated rapid absorption and sustained concentrations above predicted efficacious levels, supporting an advantageous pharmacokinetic profile for acute treatment of migraine. BHV-2100 was also well tolerated, without the thermoregulatory adverse events observed with other TRP antagonists or sedation associated with standard-of-care pain medications.

[0035] Described herein are methods of treating migraine, neuropathic pain, or nociceptive pain in a patient in need thereof, comprising orally administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a TRPM3 antagonist, or a physiologically acceptable salt thereof, wherein the pharmaceutical composition is a composition for oral administration. In an aspect, the pharmaceutical composition is an immediate-release composition. As used herein, “immediate-release” means the composition includes no components meant to delay or prolong dissolution of the oral dosage form. That is, the composition is meant to be dissolved quickly to allow rapid absorption of the active agent.

[0036] In an aspect, the TRPM3 antagonist is a molecule of Formula (I) as described in U.S. Patent No. 12,209,081 : wherein

R¹ is QU optionally substituted with F;

Q is -NR³R⁴; wherein

R³ is H; and

T is -O-,

U is -CH₂-;

R⁶, R⁷ and R⁸ are each H; and

[0037] In an aspect, R¹ is -CH3.

[0038] In another aspect,

[0039] In an aspect, V is 5-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, wherein the 5-membered heteroaryl is optionally substituted with -F, -Cl, C1-C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F. In another aspect, V is 6-membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the 6-membered heteroaryl is optionally substituted with -F, -Cl, C1-C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.

[0040] Exemplary compounds of Formula (I) include the following:

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin- 3 -yl)methoxy)benzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)thiazol- 5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-methyl-4- (trifluoromethyl)thiazol-5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-methyloxazol-5- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-methylpyridin-3- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-methylthiazol-4- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((3-(trifluoromethyl)-lH- pyrazol-4-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((4-methylpyri din-3- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((4-methylthiazol-5- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((5-methylisoxazol-3- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((5-methylthiazol-4- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((6-methylpyri din-3- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyridazin-3- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyrimidin-4- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((l-(2,2-difluoroethyl)-lH-pyrazol-5- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2-(difluoromethoxy)pyridin-3- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2,4-dimethylthiazol-5-yl)methoxy)- 2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2,5-dimethylthiazol-4-yl)methoxy)- 2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((3-(difluoromethyl)pyridin-2- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((4-fluoro-l-methyl-lH-pyrazol-5- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l -amino-3-hydroxy-l -oxopropan-2-yl)-2-methyl-5-((l -methyl- lH-imidazol-2- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l -amino-3-hydroxy-l -oxopropan-2-yl)-2-methyl-5-((l -methyl- lH-pyrazol-5- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-methylthiazol-5- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyridin-2- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2-(difluoromethyl)pyridin-3- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2,4-dimethylthiazol-5-yl)methoxy)-

2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2-hydroxypyridin-3-yl)methoxy)-2- methylbenzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-((2-methylpyridin-

3 -yl)methoxy)benzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-((2-methylthiazol- 5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-((4-methylthiazol- 5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-((6-methylpyridin- 3 -yl)methoxy)benzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-5-((l-(2,2-difluoroethyl)-lH- pyrazol-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-5-((4-fluoro-l-methyl-lH- pyrazol-5-yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyridin-3- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((l,4-dimethyl-lH-pyrazol-5- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l -amino-3 -hydroxy- 1 -oxopropan-2-yl)-5-((4-chloro-l -methyl- lH-pyrazol-5- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((4-chloro-l-isopropyl-lH-pyrazol-5- yl) methoxy)-2-methylbenzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((3-methylisoxazol-5- yl)methyl)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((l-isopropyl-lH-pyrazol-5-yl) methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2, 4-dimethyloxazol-5-yl) methoxy)- 2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((4-methyloxazol-5- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2-isopropylthiazol-5-yl)methoxy)-2- methylbenzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((5-methylthiazol-2- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l -amino-3-hydroxy-l -oxopropan-2-yl)-2-methyl-5-((l -methyl- lH-pyrazol-3- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((l-(2,2,2-trifluoroethyl)-lH- pyrazol-5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((l-(cyclopropylmethyl)-lH-pyrazol- 5-yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((l-methyl-3-

(trifluoromethyl)-lH-pyrazol-4-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((4-(trifluoromethyl)thiazol- 5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(thiazol-2- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(thiazol-5- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l -amino-3-hydroxy-l -oxopropan-2-yl)-2-methyl-5-((l -methyl- lH-pyrazol-4- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((5-methylpyridin-2- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-methylpyrimidin-5- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyrimidin-2- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyrazin-2- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((2-methoxypyridin-3-yl)methoxy)-2- methylbenzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyridin-4- ylmethoxy)benzofuran-3-carboxamide; (S)-N-( 1 -amino-3 -hydroxy-2-m ethyl- 1 -oxopropan-2-yl)-5 -((2-methoxypyri din-3 - yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-((2-methyloxazol- 5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-(pyri din-2- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-5-((5-fluoropyridin-2- yl)methoxy)-2-methylbenzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-5-((5-fluoropyridin-2-yl)methoxy)-2- methylbenzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-(difluoromethyl)-5-((4-methylthiazol- 5-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-(difluoromethyl)-5-((6-methylpyridin- 3 -yl)methoxy)benzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-(difluoromethyl)-5-(pyridin-2- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-(difluoromethyl)-5-((2-methylthiazol- 5-yl)methoxy)benzofuran-3-carboxamide; and

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-(difluoromethyl)-5-((2-methyloxazol- 5-yl) methoxy) benzofuran-3 -carboxamide, or a physiologically acceptable salt thereof.

[0041] The term “heteroatom(s)” as used herein means an atom selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxide and sulfone.

[0042] The term “alkyl, saturated or unsaturated” as used herein encompasses saturated alkyl as well as unsaturated alkyl such as alkenyl, alkynyl, and the like. The term “alkyl” as used herein means normal, secondary, or tertiary, linear or branched hydrocarbon with no site of unsaturation. Examples are methyl, ethyl, 1 -propyl (n-propyl), 2-propyl (iPr), 1 -butyl, 2-methyl-l-propyl(i-Bu), 2-butyl (s-Bu), 2-dimethyl-2-propyl (t-Bu), 1 -pentyl (n- pentyl), 2-pentyl, 3 -pentyl, 2-methyl-2 -butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl- 1 -butyl, 1 -hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3 -methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3 -dimethyl-2 -butyl, and 3,3-dimethyl-2-butyl. The term “alkenyl” as used herein means normal, secondary or tertiary, linear or branched hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp2 double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH₂), allyl (-CH₂CH=CH₂), and 5-hexenyl (-CH₂CH₂CH₂CH₂CH=CH₂). The double bond may be in the cis or trans configuration. The term “alkynyl” as used herein means normal, secondary, tertiary, linear or branched hydrocarbon with at least one site (usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-C=CH), and 1-propynyl (propargyl, -CH₂C=CH).

[0043] The term “aryl” as used herein means an aromatic hydrocarbon. Typical aryl groups include, but are not limited to 1 ring, or 2 or 3 rings fused together, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. Fused systems of an aryl ring with a cycloalkyl ring are considered as aryl irrespective of the ring that is bound to the core structure. Fused systems of an aryl ring with a heterocycloalkyl ring are considered as heterocycloalkyl irrespective of the ring that is bound to the core structure. Thus, indoline, dihydrobenzofuran, dihydrobenzo-thiophene and the like are considered as heterocycloalkyl. Fused systems of an aryl ring with a heteroaryl ring are considered as heteroaryl irrespective of the ring that is bound to the core structure.

[0044] The term “heteroaryl” as used herein means an aromatic ring system including at least one heteroatom, i.e., N, O, or S as ring member of the aromatic ring system. Examples of heteroaryl include but are not limited to benzimidazole, benzisoxazole, benzoazole, benzodioxole, benzofuran, benzothiadiazole, benzothiazole, benzothiophene, carbazole, cinnoline, dibenzofuran, furane, furazane, imidazole, imidazopyridine, indazole, indole, indolizine, isobenzofuran, isoindole, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, oxindole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and [l,2,4]triazolo[4,3-a]pyrimidine.

[0045] By further way of example, carbon bonded heterocyclic rings are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

[0046] Preferred carbon bonded heterocycles include 2-pyridyl, 3 -pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5- pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example, nitrogen bonded heterocyclic rings are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3 -pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H- indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or B-carboline. Preferred nitrogen bonded heterocycles include 1-aziridyl, 1- azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl. Further heteroaryls in the meaning of the invention are described in Paquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; Katritzky, Alan R., Rees, C.W. and Scriven, E. “Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc. (1960) 82:5566.

[0047] As used herein with respect to a substituting group, and unless otherwise stated, the terms “monosubstituted”, “disubstituted”, “tri substituted”, “polysubstituted” and the like means chemical structures defined herein, wherein the respective moiety is substituted with one or more substituents, meaning that one or more hydrogen atoms of said moiety are each independently replaced with a substituent. For example, -Ci-6-alkyl that may be polysubstituted with -F covers -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. Likewise, -Ci-6-alkyl that may be polysubstituted with substituents independently of one another selected from -F and -Cl covers -CH2F, -CHF2, -CF3, -CH2CF3, CF2CF3, -CH2CI, - CHCh, -CCh, -CH2CCI3, CCI2CCI3, -CHC1F, -CCIF2, -CCI2CF3, -CF2CCI3, -CCIFCCLF, and the like. Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.

[0048] As used herein and unless otherwise stated, the term “solvate” includes any combination which may be formed by a derivative of this invention with a suitable inorganic solvent (e.g., hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters, ethers, nitriles and the like.

[0049] The term “physiologically acceptable salts” as used herein means the therapeutically active non-toxic salt forms which the compounds of formulae herein are able to form. Therefore, the compounds described herein optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na⁺, Li⁺, K⁺, Ca²⁺ and Mg²⁺. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. The compounds may bear multiple positive or negative charges. The net charge of the compounds may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Exemplary counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature, and that the compounds may be associated with any type of counter ion. Moreover, as the compounds can exist in a variety of different forms, encompassed herein are not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions). Metal salts typically are prepared by reacting the metal hydroxide with a compound. Examples of metal salts which are prepared in this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such acids include, for instance, inorganic acids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this term also includes the solvates which the compounds of formulae herein as well as their salts are able to form, such as for example hydrates, alcoholates and the like. Finally, it is to be understood that the compositions herein comprise the compounds in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

[0050] The compounds described herein also include physiologically acceptable salts thereof. Examples of physiologically acceptable salts include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4⁺ (wherein X is -Ci-6-alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound containing a hydroxy group include the anion of said compound in combination with a suitable cation such as Na⁺ and NX4⁺ (wherein X typically is independently selected from -H or a -Ci-4-alkyl group). However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the disclosure.

[0051] As used herein and unless otherwise stated, the term “enantiomer” means each individual optically active form of the compounds described herein, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

[0052] The term “isomers” as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formulae herein may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formulae herein may have at least one chiral center) of the basic molecular structure, as well as the stereochemically pure or enriched compounds. More particularly, stereogenic centers may have either the R- or S-configuration, and multiple bonds may have either cis- or transconfiguration.

[0053] Pure isomeric forms of the compounds are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure. In particular, the term “stereoisomerically pure” or “chirally pure” relates to compounds having a stereoisomeric excess of at least about 80% (i.e., at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms “enantiomerically pure” and “diastereomerically pure” should be understood in a similar way, having regard to the enantiomeric excess, respectively the diastereomeric excess, of the mixture in question.

[0054] Separation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of a compound can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113 :(3) 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched compound. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a- methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reversephase chromatography following methods for separation of atropisomeric naphthylisoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCel® CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak® AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like. (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) “Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase”, J. of Chromatogr. 513:375-378).

[0055] Pharmaceutical compositions can be prepared in a dosage form such as, for example, tablets, capsules, nasal sprays, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. A preferred dosage form is an oral dosage form such as a tablet or a capsule or an oral liquid dosage form.

[0056] The pharmaceutical compositions comprising a TRPM3 antagonist of Formula (I) typically also include pharmaceutically acceptable carriers (also referred to as excipients) such as, for example, binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents, flavorants, preservatives and mixtures thereof. The choice of excipients depends on the desired characteristics of the compositions and on the nature of other pharmacologically active compounds in the formulation. Excipients are known to those skilled in the art (see Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., McGraw Hill).

[0057] Examples of pharmaceutically acceptable carriers that may be used in preparing the pharmaceutical compositions include, but are not limited to, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl-cellulose, sodium carboxymethylcellulose, polyvinyl-pyrrolidone (PVP), talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen-free water and combinations thereof. If desired, disintegrating agents may be employed such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In an aspect, the flavoring agent is selected from mint, peppermint, berries, cherries, menthol, sodium chloride flavoring agents, and combinations thereof. In an aspect, the sweetener is selected from sugar, sucralose, aspartame, acesulfame, neotame, and combinations thereof.

[0058] In general, the pharmaceutical compositions may be manufactured by conventional methods known in the art, for example, by means of mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilization processes, and the like. [0059] In an aspect, the oral pharmaceutical composition is a fast-dispersing dosage form. The phrase “fast-dispersing dosage form” refers to compositions which disintegrate or disperse within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, after being placed in contact with a fluid. The fluid is preferably that found in the oral cavity, i.e., saliva, as with oral administration.

[0060] In one aspect, the oral pharmaceutical compositions are prepared in oral solid molded fast-dispersing dosage form, such as described in U.S. Pat. No. 9,192,580.

[0061] In a preferred embodiment, the pharmaceutical compositions are oral solid molded fast-dispersing dosage forms comprising a solid network of the active ingredient, a TRPM3 antagonist, and a water-soluble or water-dispersible carrier, for example a carrier containing a gelatin such as fish gelatin. Accordingly, the carrier is inert towards the active ingredient. The network is obtained by subliming solvent from a composition in the solid state, the composition comprising the active ingredient and a solution of the carrier in the solvent. The dosage forms can be prepared according to the process disclosed in Gregory et al., U.K. Patent No. 1,548,022, using fish gelatin as the carrier. Accordingly, an initial composition (or admixture) comprising the active ingredient and a solution of the fish gelatin carrier in a solvent is prepared, followed by sublimation. The sublimation is preferably carried out by freeze-drying the composition. The composition can be contained in a mold during the freeze-drying process to produce a solid form in any desired shape. The mold can be cooled using liquid nitrogen or solid carbon dioxide in a preliminary step prior to the deposition of the composition therein. After freezing the mold and composition, they are next subjected to reduced pressure and, if desired, controlled application of heat to aid in sublimation of solvent. The reduced pressure applied in the process can be below about 4 mm Hg, preferably below about 0.3 mm Hg. The freeze-dried compositions can then be removed from the mold if desired or stored therein until later use.

[0062] When the process is used with active ingredients and fish gelatin as the carrier, a solid fast-dispersing dosage form is produced having the advantages associated with the use of fish gelatin described herein. Generally, fish gelatin is categorized as being from cold water and warm water fish sources and as being of the gelling or non-gelling variety. The non-gelling variety of fish gelatin, in comparison to gelling fish gelatin and bovine gelatin, contains lower proline and hydroxyproline amino acid content, which are known to be associated with cross-linking properties and gelling ability. Non-gelling fish gelatin can remain at solution concentrations of up to about 40% as well as in temperatures as low as 20°C. In an aspect, the fish gelatin is preferably obtained from cold water fish sources and is the non-gelling type of fish gelatin. More preferably, the non-hydrolyzed form of non-gelling fish gelatin is used. In an alternative embodiment, spray-dried non-hydrolyzed non-gelling fish gelatin can be used. Fish gelatins are commercially available, for example, from Croda Healthcare.

[0063] The solid fast-dispersing dosage forms can also contain, in addition to the active ingredient and fish gelatin carrier, other matrix forming agents and secondary components. Exemplary matrix forming agents include materials derived from animal or vegetable proteins, such as other gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatinacacia complexes.

[0064] Other materials which may also be incorporated into the solid fast-dispersing dosage forms include sugars such as mannitol, dextrose, lactose, galactose, and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine. One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification (freezing). The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution of suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved. Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the fast-dissolving compositions. Exemplary coloring agents include red, black and yellow iron oxides and FD & C dyes such as FD&C Blue No. 2 and FD&C Red No. 40 available from Ellis & Everard. Exemplary flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these. Exemplary pH modifiers include edible acids and bases, such as citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide. Exemplary sweeteners include, for example, sucralose, aspartame, acesulfame K, and thaumatin. Exemplary taste-masking agents include, for example, sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbates, and microencapsulated actives.

[0065] In an aspect, the pharmaceutical composition is provided in the form of an oral solid molded fast-dispersing dosage form. In an aspect, the pharmaceutical composition comprises from about 70-80 percent by weight (“wt %”) of a TRPM3 antagonist of Formula (I), about 10-20 wt % of a fish gelatin, about 10-20 wt % of a filler, and 0.1-5.0 wt % of a flavorant. In one aspect, the filler is mannitol.

[0066] Solid compositions are normally formulated in dosage units providing from about 1 to about 1000 mg of the TRPM3 antagonist of Formula (I) per dose. Some examples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 25 mg, 37.5 mg, 50 mg, 75 mg, 100 mg, 150 mg, 250 mg, 300 mg, 500 mg, 600 mg and 1000 mg. Typical dose ranges in include from about 10-600 mg, 25-300 mg, 25-150 mg, 50-100 mg, 60-90 mg, and 70-80 mg. Liquid compositions are generally in a unit dosage range of 1-100 mg/mL. Some examples of liquid dosage units are 0.1 mg/mL, 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

[0067] The term “administering” refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods and can be a therapeutically effective dose or a subtherapeutic dose.

[0068] Described herein are methods of treating patients in need of treatment for migraine, headache, neuropathic pain, and/or nociceptive pain.

[0069] Migraine is a neurological condition characterized by moderate to severe headaches. Migraine is often accompanied by symptoms such as nausea, vomiting and/or sensitivity to light and sound.

[0070] Peripheral neuropathic pain, also called peripheral nerve pain, occurs when peripheral nerves (outside of the brain and spinal cord) are damaged. Peripheral neuropathy causes weakness, numbness and pain, especially in the hands and feet. Neuropathic pain includes diabetes-related neuropathic pain and other metabolic neuropathies, chemotherapy- induced peripheral neuropathy and other toxic neuropathies, peripheral neuropathy as a result of injury, trauma, or surgery, or other diseases, including but not limited to, postherpetic neuralgia (pain following a shingles infection) and other infections, entrapment neuropathies such as carpal tunnel syndrome (nerve compression in the wrist), mononeuropathy multiplex, small fiber neuropathy, neuropathic pain associated with Charcot-Marie-Tooth Disease and other genetic neuropathies, sciatica (pain radiating down the leg due to nerve irritation) and other painful nerve root disorders, HIV-related neuropathy, neuropathies due to cancer, and others.

[0071] Nociceptive pain is pain arising from signals from nociceptors, generally as a result of tissue damage such as from physical or chemical agents. Nociceptive pain is most often localized to the area of tissue damage.

[0072] The terms “subject” and “patient” refer any human or nonhuman animal. In the methods described herein, the patient is preferably a human patient. The term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some embodiments, the subject is a human. The terms, “subject” and “patient” are used interchangeably herein.

[0073] The terms “effective amount”, “therapeutically effective amount”, “therapeutically effective dosage” and “therapeutically effective dose” of an agent (also sometimes referred to herein as a “drug”) refers to any amount of the agent that, when used alone or in combination with another agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or relief from impairment or disability due to the disease affliction. The therapeutically effective amount of an agent can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0074] The term “treatment” refers to treatment of a condition or disease in a subject and may include: (i) preventing the disease or condition from occurring in the subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; relieving the disease or condition, i.e., causing regression of the condition; or (iii) ameliorating or relieving the conditions caused by the disease, i.e., symptoms of the disease. Treatment could be used in combination with other standard therapies or alone. Treatment or “therapy” of a subject also includes any type of intervention or process performed on, or the administration of an agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication or condition, or biochemical indicia associated with a disease.

[0075] With respect to migraine and pain, “treatment” is an approach for obtaining beneficial or desired results with a subject. Beneficial or desired clinical results include, but are not limited to, one or more of the following: improvement in any aspect of a headache including lessening severity, alleviation of pain intensity, and other associated symptoms, reducing frequency of recurrence, increasing the quality of life of those suffering from the headache, decreasing dose of other medications required to treat the headache and reducing the number of headache days per month. For migraine, other associated symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and/or movement. For cluster headache, other associated symptoms include, but are not limited to swelling under or around the eyes, excessive tears, red eye, rhinorrhea or nasal congestion, and red flushed face.

[0076] With respect to migraine and pain, “preventing” can include reversing, alleviating, ameliorating, inhibiting, slowing down the progression, development, severity, or recurrence of a symptom, complication or condition.

[0077] The term “T_max” refers to a time or period after administration of a drug when the maximum concentration (Cmax) is reached in blood, serum, a specified compartment or test area of a subject.

[0078] The term “T1/2” or half-life is the time for the plasma concentration of a drug to decrease to half of its initial value.

[0079] The term “AUC” (area under the curve) refers to a total amount of drug absorbed or exposed to a subject. Generally, AUC may be obtained from mathematical method in a plot of drug concentration in the subject over time until the concentration is negligible. The term “AUC” could also refer to partial AUC at specified time intervals.

[0080] The term “Cmax” refers to a maximum concentration of a drug in blood, serum, a specified compartment or test area of a subject between administration of a first dose and administration of a second dose. The term Cmax could also refer to dose normalized ratios, if specified.

[0081] The term “dosing interval,” refers to the amount of time that elapses between multiple doses of a formulation disclosed herein being administered to a subject. Dosing interval can thus be indicated as ranges.

[0082] The term “dosing frequency” refers to the frequency of administering doses of a formulation disclosed herein in a given time. Dosing frequency can be indicated as the number of doses per a given time, e.g., twice a day, once a day, once every other day, once a week or once in two weeks, and the like.

[0083] In an aspect, the orally administered TRPM3 antagonist of Formula (I) is administered at a dose of 25 to 250 mg, such as 25, 50, 75, 150 mg, 250 mg, or higher, either once or twice daily. [0084] In an aspect, the human patient is not responsive to CGRP inhibition, not responsive to triptan therapy, or a combination thereof.

[0085] As used herein, a human patient not responsive to CGRP inhibition can be a patient who has previously been prescribed a CGRP inhibitor and found it to lack efficacy, and additionally encompasses individuals that have not previously been prescribed a CGRP inhibitor, but whose migraines or pain would nonetheless not respond to such treatment options. It has been suggested that this population is more than 10% of migraine patients. Identifying a patient who has previously been prescribed a CGRP inhibitor and found it to lack efficacy may include providing the patient with a questionnaire and asking if they have previously taken a CGRP medication and if it was effective in treating migraine pain. Exemplary CGRP medications include erenumab (Aimovig®), galcanezumab (Emgality®), fremanezumab (Ajovy®), rimegepant (Nurtec®), eptinezumab (Vyepti®), ubrogepant (Ubrelvy®), and atogepant (Qulipta®).

[0086] As used herein, a human patient not responsive to triptan therapy can be a patient who has previously been prescribed triptan therapy, and found it to lack efficacy, and additionally encompasses individuals that have not previously been prescribed triptan therapy, but whose migraines or pain would nonetheless not respond to such treatment options. In one embodiment, the triptan is a triptan selected from the group consisting of almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan. In a more particular embodiment, the triptan is sumatriptan.

[0087] In an aspect, the human patient has a mutated TRPM3 with one or more of the following amino acid substitutions: R1670Q, A1645V, V990M and P1090Q (numbering based on SEQ ID NO: 1).

[0088] Described herein are the first clinical trials performed in humans which show that BHV-2100, and by analogy the TRPM3 antagonists of Formula (I), are particularly useful for the treatment of migraines and pain. The PK data suggests a number of features of such treatment that could not have been predicted based upon the prior art.

[0089] In an aspect, as demonstrated in the SAD study for BHV-2100, orally administering an oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) (e.g., BHV-2100) provides a T_max of 1-2 hours and a Ti/2 from 8-12 hours after a single dose. The fast T_max can be important for the acute treatment of migraine as rapid relief of migraine pain and other symptoms is a critical treatment goal. The long T1/2 can be important to maintain symptom relief as well as to control symptom recurrence. [0090] For the treatment of acute migraine attacks as they occur, the TRPM3 antagonist of Formula (I) may be taken as needed for symptom relief, such as once or twice per day, or more frequently. Treatment for acute migraine attacks can be intermittent treatment, short term treatment such as treatment over 1 day, 2 days, or up to 3 days, or ongoing treatment, e.g., preventative treatment. Acute migraine may or may not be accompanied by aura.

[0091] Treatment of acute migraine attacks is critical due to the severe and disabling nature of migraine attacks which can be accompanied by sensory disturbances. Goals of treatment of acute migraine attacks include rapid and consistent pain and symptom relief without recurrence; restored ability to function; minimal need for repeat dosing or rescue medication; optimizing self-care to reduce use of medical resources; minimizing or eliminating adverse events; reduced cost of treatment; and effective acute treatment to reduce pain, symptoms and disability associated with migraine attacks.

[0092] Efficacy in the treatment of acute migraine attacks can be defined as pain freedom and most bothersome symptom (MBS) freedom at two hours after dosing, compared to placebo. Pain freedom can be defined as a reduction of moderate or severe headache pain to no headache pain, and MBS freedom was defined as the absence of MBS as identified by the patient. Typical MBS include photophobia, phonophobia, and/or nausea.

[0093] In another aspect, as demonstrated in the MAD study for BHV-2100, orally administering pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) (e.g., BHV-2100) for a plurality of doses provides a T1/2 from 8-10 hours at steady-state. A favorable T1/2 at steady state is important for the treatment and prevention of episodic migraine (less than 15 headache days per month), and could also be useful to treat patients with chronic migraine (15 or more headache days per month).

[0094] A clinical endpoint for the preventative treatment of episodic migraine includes the change from baseline in the mean number of monthly migraine days.

[0095] For the treatment and prevention of episodic migraine, for example, the TRPM3 antagonist of Formula (I) should be taken chronically, such as daily, twice a day, once every other day, once every 3 days, or once per week. Administration chronically means administration over a long period of time, such as a week, several weeks, months or even years.

[0096] While some patients with chronic migraines can have a less robust response to triptans, for example, it is believed that the TRPM3 antagonists of Formula (I) described herein will be more favorable in the treatment and prevention of chronic migraine than the current standard of care.

[0097] Without being held to theory, it is also believed that the TRPM3 antagonists of Formula (I) described herein, due to their favorable mechanism of action and PK, will be able to prevent the progression from episodic to chronic migraine which occurs in a significant fraction of the population.

[0098] In an aspect, as demonstrated in the SAD study for BHV-2100, the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) is dose proportional across a dose of 25 to 150 mg. As used herein, “dose proportional” means increases in the administered dose are accompanied by proportional increases in the PK profile, such as the AUC or Cmax. In an aspect, the composition is dose proportional by a factor of about 1 to about 1.3 with respect to plasma concentration. Dose proportionality is important to provide a consistent and predictable outcome with increasing and decreasing doses.

[0099] The SAD and MAD studies for BHV-2100 also provide information on the EC50 and EC90 for single and multiple dosing of the TRPM3 antagonists of Formula (I) in a rat PS pain model. As used herein, the EC50 is the half maximal effective concentration of a drug, that is, the concentration where 50% of the maximal effect is observed. The EC90 is 90% of the effective concentration of a drug, that is, the concentration where 90% of the maximal effect is observed.

[00100] In an aspect, orally administering the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) provides rapid and sustained analgesic effects in the treatment of migraine and pain, wherein administering a single dose of the pharmaceutical composition provides a plasma concentration above the EC90 within 30 minutes and maintains a plasma concentration above the EC50 for at least 6 hours. In an aspect, the EC90 and the EC50 are achieved across a dose of 25 to 150 mg.

[00101] In another aspect, orally administering the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) provides sustained analgesic effects in the treatment of migraine and pain, wherein chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for at least 7 hours, preferably at least 16 hours, more preferably at least 21 hours. In an aspect, when the TRPM3 antagonist of Formula (I) is administered twice daily, and the chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for 24 hours. [00102] In another aspect, orally administering the oral, immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) provides sustained analgesic effects in the treatment of migraine, wherein chronically administering a plurality of doses of the pharmaceutical composition maintains the EC50 for at least 17 hours, preferably for 24 hours. In an aspect, when the TRPM3 antagonist of Formula (I) is administered twice daily, the chronically administering a plurality of doses of the pharmaceutical composition maintains the EC50 for 24 hours.

[00103] In an aspect, the immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) can be administered immediately after a high fat meal, wherein the T_max is delayed by approximately 1.5 hr and the Cmax is increased by less than 15%. As used herein, a high-fat meal is defined as a meal which includes 500- 600 kcal derived from fat. Without being held to theory it is believed that the immediate- release TRPM3 antagonist composition can be administered without regard to consumption of food, e.g., a high fat meal. In general, for some active agents, food-active agent interactions can influence the safety and efficacy of an orally administered drug. Depending on the active agent, an increase or decrease in potency/efficacy can be observed. Food effect studies are important to determine proper labeling for an active agent and to determine whether clinical studies should take into account the diet of the subject.

[00104] In an aspect, the immediate-release pharmaceutical composition comprising the TRPM3 antagonist of Formula (I) can be administered with a gastric acidreducing agent such as famotidine, wherein the T_max and C_max are not substantially affected by the acid reducing agent. Acid reducing agents can affect pharmacokinetics by changing gastric pH. Without being held to theory, based on the data provided herein, it is believed that the immediate-release TRPM3 antagonist composition can be administered without regard to administration of acid-reducing agents.

[00105] Exemplary gastric acid-reducing agents include proton pump inhibitors (PPI), histamine 2 receptor antagonists (H2RA), and/or an antacid. Exemplary PPIs include omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole, and dexlansoprazole. Exemplary H2RAs include cimetidine, famotidine, nizatidine, and ranitidine. Exemplary antacids include aluminum hydroxide/carbonate, calcium hydroxide/carbonate, and bismuth subsalicylate.

[00106] In an aspect, the TRPM3 antagonist of Formula (I) may be coadministered with second agent for the treatment of migraine or pain. Exemplary second agents for the treatment of migraine and pain include a CGRP inhibitor, a triptan agent, an ergot alkaloid, a non-steroidal anti-inflammatory drug, acetaminophen, butalbital, caffeine, aspirin, dexamethasone, lasmiditan, and combinations thereof.

[00107] CGRP inhibitors and triptan agents are listed above. Exemplary ergot alkaloids include dihydroergotamine and ergotamine. Exemplary non-steroidal antiinflammatory drugs include ibuprofen, naproxen, diclofenac, celecoxib, mefenamic acid, etoricoxib, and indomethacin.

[00108] The invention is further illustrated by the following non-limiting examples.

EXAMPLES

EXAMPLE 1 : Phase 1 SAD/MAD pharmacokinetic (PK) study Method

[00109] This was a randomized, double-blind, placebo-controlled sequential single-ascending dose (SAD)/ multiple ascending dose (MAD) study. Healthy adult males and females aged 18-55 years were enrolled. In the SAD cohorts, subjects were randomized 3: 1 to a single oral dose of BVH-2100 (25, 75, 150, 250 or 500 mg) or placebo under fasting conditions. In the MAD cohorts, subjects were randomized 3: 1 to oral BHV-2100 or placebo and treated for 14 days. Samples were collected up to 120 hours and analyzed for BHV-2100 using a validated liquid chromatography/mass spectrometry assay. PK parameters were calculated by noncompartmental methods. Safety evaluations throughout the study included adverse events (AE) monitoring, clinical laboratory tests, vital signs, ECGs, physical examinations, and Columbia-Suicide Severity Rating Scale (C-SSRS). A Safety Review Committee assessed the safety, tolerability, and PK data after completion of each dose level prior to dose escalation.

Results

[00110] In the SAD portion of the study, 39 subjects were treated with BHV- 2100 or placebo. The mean age of the SAD population was 35 years; the majority of the subjects were male (97%) and white (80%). The concentration-time profiles of single dose BHV-2100 are shown in FIG. 1.

[00111] As shown in FIG. 1 and Table 1, maximal drug concentrations (T_max) were achieved after approximately 1.5 to 2 hours for all doses; and the T1/2 ranged between approximately 8-12 hours. BHV-2100 thus shows rapid absorption and sustained concentrations after administration of a single dose. Also as shown in FIG. 1 and Table 1, the PK of BHV-2100 was approximately dose-proportional at doses up to 150 mg.

[00112] At the lowest dose evaluated of 25 mg, plasma concentrations achieved the 90% maximal effective concentration (EC90) by 30 minutes (min) and 2x EC90 by T_max. The EC90 was determined in the preclinical rat pain model. At a dose of 150 mg, the plasma concentration achieved 4x EC90 by 30 minutes and 7x EC90 by T_max. Levels were sustained above the EC90 for several hours at all dose levels. The pharmacokinetic parameters in the SAD study are provided in Table 1 :

Table 1 : BHV-2100 Pharmacokinetic parameters following single oral doses in healthy participants.

[00113] Data at 150 mg shows that dosing BHV-2100 with food or an acidreducing agent (famotidine) does not have a significant impact on BHV-2100 PK (FIG. 2 and FIG. 3; Table 2). While a high-fat meal delayed T_max, concentrations exceeded EC90 by 20 minutes. These data suggest BHV-2100 can be dosed without regard to the fed/fasted state of the patient or co-administration of an acid-reducing agent.

[00114] In the following tables of pharmacokinetic parameters, the data represent the geometric mean (geometric CV [%]) reported for C_max, AUCo-inf, AUCo-t, and Vz/F. Median (Min-Max) reported for T_max. Mean (SD) reported for T1/2 ei. Table 2: BHV-2100 Pharmacokinetic parameters following single oral doses in healthy participants: fed vs. fasted and w/ famotidine.

[00115] In the MAD portion of the study, 32 patients were treated. As shown in FIG. 4, at steady-state, T1/2 ranged from 8 to 10 hours. With once-daily (QD dosing), minimal accumulation was observed. The 75 mg QD dose provides plasma concentrations > EC50 over a 24-hour period. The 150 mg QD dose provides plasma concentrations > EC90 over a 24-hour period. Table 3 shows the time above EC50 and EC90 for the various dosages, and Table 4 provides selected pharmacokinetic parameters for the MAD study.

Table 3: Time above EC50 and EC90 with multiple doses of BHV-2100.

Table 4: BHV-2100 Pharmacokinetic parameters following multiple oral doses.

Conclusions:

[00116] From these studies it is concluded that BHV-2100 is a first in class, orally administered, selective antagonist of TRPM3, a target for the treatment of migraine and pain. Single doses demonstrated rapid absorption and sustained concentrations above the predicted efficacious levels at all doses tested after 20 minutes, an ideal PK profile for the treatment of migraine and pain. Daily dosing achieved plasma concentrations predicted to have sustained analgesic effects. BHV-2100 is a non-opioid candidate for the treatment of migraine and pain.

EXAMPLE 2: BHV-2100 Pharmacokinetic parameters following single serial oral doses [00117] Pharmacokinetic data after serial single oral doses of 150 mg BHV- 2100 administered as either an oral liquid suspension, an immediate-release tablet, an immediate-release tablet after a high fat meal, or an immediate-release tablet after the use of proton pump inhibitors (omeprazole) are provided in Tables 5-7. Table 5: BHV-2100 Pharmacokinetic parameters following single oral doses in healthy participants.

Table 6: BHV-2100 Pharmacokinetic parameters following single oral doses with and without food in in healthy participants.

Table 7: BHV-2100 Pharmacokinetic parameters following single oral doses with and without omeprazole in in healthy participants.

EXAMPLE 3 : Safety and tolerability

[00118] For the SAD part of the study, 39 participants received a single oral dose of BHV-2100 at doses of 25 mg (N = 6), 75 mg (N= 6), 150 mg (N = 6), 250 mg (N=6), 500 mg (N = 6), or placebo (N = 9). Based on preliminary unblinded data, BHV-2100 was well-tolerated with single doses up to 500 mg. It was found that BHV-2100 has no dose limiting toxicities, no severe adverse events and no severe treatment-emergent adverse events (TEAEs). One moderate TEAE not related to the study was reported, and all other TEAEs were mild. TEAEs are reported in Table 8. In addition, no significant trends in vital signs (including body temperature), laboratory values, or ECGs. Excellent safety and tolerability were observed, without the thermoregulatory adverse events observed with other TRP antagonists, or sedation observed with standard-of-care pain medications.

Table 8: TEAEs in SAD study.

[00119] All but one of the TEAEs were mild in severity. The only TEAE of moderate severity, reported in one participant, was gastroenteritis sapovirus, which was considered by the investigator to be unrelated to the study drug. All TEAEs in participants who received BHV-2100 had an outcome of recovered/resolved. One TEAE (dental fracture) in the placebo group did not resolve.

[00120] For the MAD part of the study, a total of 24 participants received BHV-2100: 18 participants received 14 days of single oral doses of BHV-2100 at 25 mg (N = 6), 75 mg (N= 6), 150 mg (N = 6) or placebo (N=6). Six (6) participants received 150 mg BHV-2100 BID for 14 days or placebo (N=2). There were no deaths, SAEs, severe AEs, or AEs leading to discontinuation of the study drug in the SAD or MAD cohorts of study BHV2100-101. Similarly, there were no identified trends in laboratory tests or treatment- related findings in vital signs, ECGs, or C-SSRS.

[00121] TEAEs occurred in 3/24 participants exposed to BHV-2100 in the MAD portion of the study. All but one of the TEAEs were mild in severity. The only TEAE of moderate severity, reported in one participant, was anxiety that was considered by the investigator to be unrelated to the study drug. All TEAEs recovered/resolved. Within individual treatment groups (including placebo) or in the pooled MAD population who received BHV-2100 (N=24), there were no TEAEs that occurred in > 2 participants.

[00122] The BHV2100-102 study enrolled 18 participants, including 15 males and 3 non-childbearing potential females. Eligible participants were randomized to 1 of 6 treatment sequences based on a Williams design for the first 3 periods and a fixed fourth period and received each of the following treatments according to the randomization scheme:

• Treatment A: A single dose of 150 mg BHV-2100 administered as a suspension in the fasted state (reference)

• Treatment B: A single dose of 150 mg BHV-2100 administered as an IR tablet in the fasted state

• Treatment C: A single dose of 150 mg BHV-2100 administered as an IR tablet after consumption of a high-fat breakfast

[00123] After participants completed the first 3 periods, all participants received the following treatment in Period 4:

• Treatment D: A single dose of 150 mg BHV-2100 administered as an IR tablet in the fasted state with 40 mg of omeprazole

[00124] There were no deaths, SAEs, severe AEs, or AEs leading to discontinuation of the study drug. There were no identified trends in laboratory tests or treatment-related findings in vital signs, ECGs, or C-SSRS. Based on preliminary unblinded data, BHV-2100 was well-tolerated.

[00125] During Periods 1 through 3, 7/18 (38.9%) participants reported TEAEs. The only AE that occurred in > 2 participants was headache (3/18 [16.7%]). In 6/18 (33.3%) participants, the TEAEs were considered by the investigator to be related to study drug. Headache, the only TEAE that occurred in > 2 participants during Periods 1 through 3, was considered possibly related to treatment in 2/18 (11.1%) participants. [00126] During Period 4, 3/18 (16.7%) participants reported TEAEs (flatulence, neck pain, headache, constipation) after omeprazole 40 mg alone. The TEAEs of flatulence, headache, and constipation were considered by the investigator to be related to omeprazole 40 mg.

[00127] During Period 4, 1/18 (5.6%) participants reported a TEAE (dermatitis contact) after a single oral dose of 150 mg BHV-2100 administered as an IR tablet in the fasted state with 40 mg of omeprazole. The TEAE was considered unrelated to study drug.

[00128] All AEs reported in this study (Periods 1 through 4) were mild in severity.

EXAMPLE 4: Effect of BHV-2100 on body core temperature in rats

[00129] This study was designed to evaluate whether BHV-2100 has an effect on body core temperature (BCT), heart rate, and activity in rats. AMG517, a potent and selective TRPV1 antagonist was used as a comparator, since this and other TRPV1 antagonists were shown to cause hyperthermia in preclinical and clinical studies.

[00130] Eight animals underwent a surgical operation for implantation of a telemetric device (Physiotel™ HD; Data Science International) at 10 days before the study, allowing telemetric monitoring of BCT, heart rate and activity. Measurement of BCT, heart rate and activity was performed in standard rat housing cages, which were placed on top of receiver systems that record the biological parameters, and analyzed using Ponemah software (Data Science International).

[00131] These animals were tested 3 times, where each test included a baseline measurement of 1 hour, followed by p.o. dosing of (1) vehicle, (2) BHV-2100 (100 mg/kg) and (3) the TRPV1 antagonist AMG517 (10 mg/kg), and then further measurement during 3 hours. All animals were dosed in this order; there was a 4-day recovery period between dosings. After the third dosing and measurement, animals were sacrificed.

[00132] Six animals were subdivided into two groups of 3 animals, and used in a satellite experiment to determine the PK of the dosed compounds in plasma. These animals were dosed with either BHV-2100 (p.o. lOOmg/kg; N=3) or AMG517 (p.o. 10 mg/kg; N=3), and blood samples (200 pl) were collected from the tail vein at 30 min, 1.5 hours and 3 hours post dosing. After the last blood collection, animals were sacrificed.

[00133] FIG. 5 shows the time course of BCT, activity and heart rate in rats following p.o. treatment with vehicle, AMG517, or BHV-2100. Compared to vehicle, animals treated with the TRPV1 antagonist AMG517 exhibited a prolonged period of increased BCT following dosing, while BHV-2100-treated animals did not show such an effect on BCT. Animals treated with BHV-2100 or AMG517 did not differ from vehicle- treated animals with regards to activity or heart rate (data not shown).

[00134] FIG. 6 provides the statistical analysis for the effects of the treatments on BCT. Compared to vehicle, both the AUC and the maximal change in BCT (max AT) were significantly higher in animals treated with AMG517. No significant differences were observed between animals treated with BHV-2100 or vehicle.

[00135] Table 9 provides the plasma concentrations of BHV-2100 and AMG517 at 45, 90, and 180 minutes post oral dosing of BHV-2100 (100 mg/kg) or AMG517 (10 mg/kg). These data were obtained from the rats in the satellite group.

Table 9: Plasma Concentrations of BHV-2100 and AMG517.

[00136] In summary, a single dose of BHV-2100 (100 mg/kg, p.o.) was without effect on the body core temperature compared to vehicle over a time period of 3 hours post dosing. In contrast, AMG517 (10 mg/kg, p.o.) caused sustained hyperthermia, in line with the literature on this and other TRPV1 antagonists (Gavva NR, “Body -temperature maintenance as the predominant function of the vanilloid receptor TRPV1”. Trends Pharmacol Sci., 2008, 29: 550-557).

EXAMPLE 5: BHV-2100 reverses established pain states in oxaliplatin-induced peripheral neuropathy in mice

[00137] The potential role of the TRPM3 antagonist, BHV-2100 in Chemotherapy-induced peripheral neuropathic pain (CIPNP) to alleviate chemotherapy- induced peripheral neuropathic pain, like cold allodynia and mechanical hypersensitivity was investigated.

[00138] Forty male B16C57J mice were included in the study. Five different groups of eight male animals each (total of 40 mice) received a single dose (i.p.) of oxaliplatin (6 mg/kg) at the start of the study. All animals were tested for cold sensitivity and mechanosensitivity before (baseline), at day 6 post oxaliplatin injection (pre-treatment) and 30 min post dosing of vehicle/ BHV-2100 (1, 5, 25 mg/kg) (post-treatment) via the acetone spray test and the electronic von Frey filament, respectively. Tramadol (5 mg/kg) treatment was included as positive reference control. Blood sampling was done at the end of the experiment to quantify plasma exposure levels used to assess the drug's PK/PD parameters.

Cold sensitivity

[00139] Cold sensitivity was tested by the acetone spray test. Briefly, thirty minutes prior to the start of the experiments, all the animals were placed in a testing apparatus consisting of eight chambers with a mesh floor in order to acclimatize the mice with the environment. After the acclimation, a volume of 50 pl of acetone was applied to one hind paw and the responses were monitored for 60 seconds post application. Responses to a cold stimulation were graded according to the following 5-point scale: 0-no response; 1 -brief lift, sniff, flick, or startle; 2-jumping, paw shaking; 3-multiple lifts, paw lick; 4- prolonged paw lifting, licking, shaking, or jumping; 5-paw guarding. Pain scores were determined by two independent researchers based on post-hoc analysis of video-recorded behavioral experiments, without knowledge of genotype or treatment.

[00140] The time course of the experiment is provided in FIG. 7. On day 0, all forty male C57B16J mice (10-12 weeks old) received a single oxaliplatin (6 mg/kg) injection. The test product was administered on day 6. The 5 different test conditions were: 1) vehicle (vhc), 2) BHV-2100 (1 mg/kg), 3) BHV-2100 (5 mg/kg), 4) BHV-2100 (25 mg/kg) and 5) Tramadol (5 mg/kg). Dosing occurred via oral gavage, with a volume of 2 ml. The vehicle consisted of water supplemented with HPMC (1% by weight) and Tween® 80 (0.5% by volume).

[00141] All animals treated with oxaliplatin (6 mg/kg) showed an increased acetone-induced pain score at day 6 (day 6 pre-treatment), indicating the development of cold allodynia. The acetone-induced pain score was significantly reduced 30 minutes post dosing of BHV-2100 at concentrations 5 mg/kg and 25 mg/kg, while vehicle treated animals maintained their cold hypersensitivity (day 6 post treatment). The positive control, tramadol (5mg/kg) also induced a strong reduction of the cold allodynia in oxaliplatin-treated animals. FIG. 8 shows the reversal of cold-induced pain (%) for the different treatments.

Mechanical sensitivity

[00142] Mechanical allodynia was assessed by von Frey test using an electronic device (Bioseb, France). Mice were placed individually in an eight-place chamber with a mesh floor and acclimatized for at least 30 minutes prior testing. Each paw was poked 4 times with a non-hygroscopic polypropylene von Frey tip of uniform diameter (0.8 mm) and the paw withdrawal threshold was calculated as the average of these four consecutive measurements. The numeric value of the force required to induce the paw withdrawal was recorded automatically by the apparatus.

[00143] FIG. 9 illustrates that oxaliplatin injection induced a strong reduction in the von Frey threshold in mice 6 days after dosing (day 6 pretreatment). Treatment with BHV-2100 induced a dose dependent increase in the mechanical hypersensitivity, which was comparable to Tramadol (5 mg/kg) treatment (day 6 post treatment). In contrast, vehicle treated animals showed a similar von Frey threshold compared to pre-test conditions.

[00144] Oral dosing of BHV-2100 induced a dose-dependent reduction of the oxaliplatin-induced cold allodynia and mechanical hypersensitivity. The effects of BHV- 2100 were significant (compared to vehicle) at doses of 5 mg/kg and 25 mg/kg for cold allodynia and at a dose of 25 mg/kg for mechanical allodynia. At the highest tested dose (25 mg/kg), the effect of BHV-2100 was comparable to the analgesic effect obtained with Tramadol (5 mg/kg).

EXAMPLE 6: Efficacy of BHV-2100 I STZ-induced diabetic neuropathy in rats

[00145] The STZ-induced diabetic neuropathy (i.e., peripheral nerve pain) model is a screen used to identify potential analgesics to treat diabetes-related neuropathic pain and possibly other types of peripheral nerve pain. Treatment with BHV-2100 (5 mg/kg or 25 mg/kg p.o.) or GRTR322 (pregabalin; 30 mg/kg p.o.) demonstrated statistically significant beneficial effects on pain in the STZ-induced diabetic neuropathy model in Lewis rats as determined by von Frey analysis.

[00146] Mean von Frey absolute thresholds were statistically significantly increased toward normal at 1 hour post-dose in rats treated with 30 mg/kg GRTR322 (pregabalin) and at 2 hours post-dose in rats treated with 5 mg/kg or 25 mg/kg BHV-2100 as compared to vehicle-treated control rats (FIG. 10). Mean AUC calculations for von Frey absolute thresholds from 0 to 2 hours post-dose on Day 7/8 were statistically significantly increased in rats treated with 30 mg/kg GRTR322 (pregabalin) (27% increase), 5 mg/kg BHV-2100 (25%), or 25 mg/kg BHV-2100 (26%) as compared to vehicle control rats.

EXAMPLE 7: Evidence of efficacy of BHV-2100 in the pregnenolone sulfate (PS; TRPM 3 agonist)-induced pain model

[00147] In vivo efficacy of BHV-2100 was evaluated in male Wistar rats with acute pain induced by a single injection of PS in the right hindpaw. To evaluate the doseresponse relationship, 30 min prior to PS injection, animals (n = 8/group) were dosed PO with vehicle (water containing 1% HPMC by weight and 0.5% Tween 80 by volume); BHV- 2100 at 2, 6, or 20 mg/kg; or, as a positive control, the selective TRPM3 antagonist CIM124750 at 30 mg/kg, a dose shown in previous studies to fully inhibit PS-induced pain behavior.

[00148] After PS injection, animals were video recorded for a period of 10 minutes, with the video subsequently analyzed for PS-induced pain behaviors. During the entire experiment, animals were observed for sedation and lethargy. At 30 minutes after PS injection, blood samples were collected from the tail vein for analysis of concentration of BHV-2100 in plasma.

[00149] The dose-dependent effect of BHV-2100 on PS-induced nociceptive behavior was analyzed for the total time of licking/lifting of the injected paw and the number of licks and lifts as shown in FIG. 11. ED50 values were 1.3 mg/kg and 1.4 mg/kg for total time of licking/lifting and the number of licks and lifts, respectively. Analysis of BHV-2100 or CIM124750 concentration in plasma showed that all groups were exposed to drug and that concentration in plasma increased with BHV-2100 dose. BHV-2100 did not evoke any sign of lethargy during the period of 45 minutes post-dose.

EXAMPLE 8: Evidence of efficacy of BHV-2100 in spared nerve injury model of tactile allodynia in rats

[00150] The spared nerve injury (SNI) model in the rat involves a selective transection to two (tibial and peroneal) of the three terminal branches of the sciatic nerve, the sural nerve remaining intact. Over a period of days, the lateral portion of the affected paw, which is innervated by the sural branch, develops a hypersensitivity to a tactile or thermal stimulus. Quantification of the behavioral, i.e. flinch or withdrawal, response to an evoked sensory stimulus applied to the affected region represents the primary measure of this model. [00151] The primary purpose of these studies in male SD rats was to examine the effect of BHV-2100 (1, 5, 25 mg/kg p.o.) in the tactile allodynia in the rat SNI model. GRTR322 (pregabalin) was used a blinded control in this study. Pregabalin (30 mg/kg i.p.) was included as a reference control.

[00152] SNI surgery produced a robust ipsilateral tactile allodynia as evidenced by a significant (P0.001; t-test) decrease in the threshold force necessary to induce a withdrawal response in SNI relative to Sham operated animals (Sham ~14g; SNI/Vehicle ~ 0.6g).

[00153] BHV-2100 (5 and 25 mg/kg oral) produced a significant attenuation of the tactile allodynia in SNI rats (FIG. 12).

EXAMPLE 9: Evidence of efficacy of BHV-2100 in partial sciatic nerve ligation-induced neuropathic pain in rats

[00154] BHV-2100 and GRTR322 (pregabalin) were screened for efficacy in partial sciatic nerve ligation (PSNL) model of neuropathic pain. BHV-2100 at 25 mg/kg p.o. showed significant reversal of mechanical allodynia at 1 and 2 hr post treatment. GRTR322 (pregabalin) at 30mg/kg p.o. also exhibited antinociceptive effect over a period of 2hr. Significant elevation of contralateral PWT with GRTR322 (pregabalin; 30 mg/kg) showed good correlation with signs of mild sedation noticed during cage-side observation.

Pregabalin (20mg/kg; p.o.), included as a reference control, demonstrated significant increase in both contralateral PWT (FIGs. 13, 14) as well as ipsilateral PWT (FIG. 14) with reduced mobility.

[00155] Significant maximum possible effect (MPE) of BHV-2100 at 5 mg/kg and 25 mg/kg was observed at 1 hr and 2 hr post administration. BHV-2100 at 25 mg/kg produced maximum possible nociceptive effect of about 60% whereas GRTR322 (pregabalin) at 30mg/kg achieved a peak effect of 107% and pregabalin at 20 mg/kg showed 92% MPE at 2 hr post dose.

EXAMPLE 10: Fixed sequence open-label drug-drug interaction (DDI) study

[00156] The goal is to determine the effect of multiple-dose administration of BHV-2100 on the single dose PK of drospirenone/ethinyl estradiol (DSRP/EE). The study population is 24 healthy females of non-childbearing potential, 18-65 years of age. Day 1 : A single oral dose of DSRPZEE 3 mg/0.3 mg administered in the morning after an overnight fast of at least 10 hours. Days 5-17: 150 mg BHV-2100 BID, approximately every 12 hours. Day 15: a single oral dose of DSRPZEE 3 mg/0.3 mg administered at 1 hour ±5 minutes after administering BHV-2100 in the morning. All morning doses administered after an overnight fast of at least 10 hours. Evening doses administered at least 2 hours after completion of the evening meal. It is expected that there will be no effect on BHV-2100 PK with the coadministration of DSRPZEE.

EXAMPLE 11 : Randomized double-blind, placebo and active reference controlled, 6-way intra-individual crossover trial

[00157] The goal of this study is to evaluate the anti -nociceptive and anti- hyperalgesic properties of BHV-2100 vs. placebo and BHV-7000 (selective Kv7.2/7.3 activator) vs. placebo in 2 laser-evoked potential (LEP) skin models. The study population is 24 healthy adult males. Treatments are as follows:

• A: BHV-2100 25 mg single-dose (tablet in oral suspension)

• B: BHV-2100 75 mg single-dose (tablet in oral suspension)

• C: BHV-2100 150 mg single-dose (tablet in oral suspension)

• D: BHV-7000 75 mg single-dose (one 50 mg ER and one 25 mg ER oral tablet)

• E: 400 mg ibuprofen

• F: placebo

[00158] It is predicted that BHV-2100 will demonstrate proof of antihyperalgesic efficacy in this experimental model of UV-induced human pain.

EXAMPLE 12: Phase 2 study of BHV-2100 in the acute treatment of migraine

[00159] The Phase 2 clinical study will be a randomized, double-blind, placebo-controlled trial. The population will be 450 participants with at least a one year history of migraine with and without aura. Patients will be randomized 1 : 1 : 1 : 1 across 3 doses and placebo. The BHV-2100 doses are projected to be 25 mg/75 mg/150 mg. The treatment phase will be a single dose once daily for up to 45 days to treat eligible migraine. Clinical endpoints can include pain relief/freedom (2 hours post dose), and freedom from the most bothersome symptoms of migraine (2 hours post dose). FIG. 5 is a schematic of the Phase 2 clinical trial.

[00160] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers. The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein.

[00161] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A method of treating migraine, headache, neuropathic pain, and/or nociceptive pain in a human patient in need thereof, comprising orally administering to the patient a pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a TRPM3 antagonist, or a physiologically acceptable salt thereof, wherein the TRPM3 antagonist is a molecule of Formula (I) wherein

R¹ is CH3 optionally substituted with F;

Q is -NR³R⁴; wherein

R³ is H; and

T is -O-,

U is -CH2-;

R⁶, R⁷ and R⁸ are each H;

The method of claim 1, wherein R⁴ is

3. The method of claim 1, wherein V is a 5-membered heteroaryl selected from the group consisting of oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, and imidazolyl, wherein the 5-membered heteroaryl is optionally substituted with -F, -Cl, C1-C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.

4. The method of claim 1, wherein V is a -membered heteroaryl selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein the 6- membered heteroaryl is optionally substituted with -F, -Cl, C1-C3 alkyl optionally substituted with -F, or C1-C3 alkoxy optionally substituted with -F.

5. The method of claim 1, wherein the compound of Formula (I) is selected from (S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((2-(trifluoromethyl)pyridin-

3 -yl)methoxy)benzofuran-3 -carboxamide;

(S)-N-(l-amino-3-hydroxy-2-methyl-l-oxopropan-2-yl)-2-methyl-5-((2-methylpyridin- 3 -yl)methoxy)benzofuran-3 -carboxamide;

(S)-N-(l -amino-3 -hydroxy- 1 -oxopropan-2-yl)-2-methyl-5-((l -methyl- lH-pyrazol-3- yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-((l-methyl-3-

(trifluoromethyl)-lH-pyrazol-4-yl)methoxy)benzofuran-3-carboxamide;

(S)-N-(l-amino-3-hydroxy-l-oxopropan-2-yl)-2-methyl-5-(pyridin-4- ylmethoxy)benzofuran-3-carboxamide;

(S)-N-( 1 -amino-3 -hydroxy-2-m ethyl- 1 -oxopropan-2-yl)-5 -((2-methoxypyri din-3 - yl)methoxy)-2-methylbenzofuran-3-carboxamide;

6. The method of any of the foregoing claims, wherein the pharmaceutical composition for oral administration is an immediate-release composition.

7. The method of claim of claim 6, wherein the immediate-release composition is an oral fast-dispersing dosage form.

8. The method of claim 7, wherein the oral fast-dispersing dosage form is an oral solid molded fast-dispersing dosage form comprising a fish gelatin carrier.

9. The method of claim of any of the foregoing claims, wherein the TRPM3 antagonist of Formula (I) is orally administered at a dose of 25 to 250 mg, such as 25, 50, 75, 150 mg, or 250 mg, either once or twice daily.

10. The method of claim of any of the foregoing claims, wherein the human patient is not responsive to CGRP inhibition, not responsive to triptan therapy, or a combination thereof.

11. The method of any of the foregoing claims, wherein the human patient has a mutated TRPM3 with one or more of the following amino acid substitutions: R1670Q, A1645V, V990M, and P1090Q (numbering based on SEQ ID NO: 1).

12. The method of any of the foregoing claims, wherein the pharmaceutical composition provides a T_max of 1-2 hours and/or a ti/2 from 8-12 hours after administering a single dose.

13. The method of claim 12, wherein the patient is in need of treatment or prevention of acute migraine attacks.

14. The method of any of the foregoing claims, wherein the pharmaceutical composition provides a ti/2 from 8-10 hours at steady-state after chronically administering a plurality of doses.

15. The method of claim 14, wherein the patient is in need of treatment or prevention of episodic migraine.

16. The method of claim 15, wherein the pharmaceutical composition is administered chronically.

17. The method of any of the foregoing claims, wherein the pharmaceutical composition is dose proportional across doses of 25 to 150 mg.

18. The method of claim 17, wherein the composition is dose proportional by a factor of about 1 to about 1.3 with respect to AUC, Cmax, or both.

19. The method of any of the foregoing claims, wherein the pharmaceutical composition provides rapid and sustained analgesic effects in the treatment of migraine, wherein administering a single dose of the pharmaceutical composition provides a plasma concentration above 90% of the effective concentration (EC90) within 30 minutes and maintains a plasma concentration above 50% of the effective concentration (EC50) for at least 6 hours.

20. The method of claim 19, wherein the TRPM3 antagonist of Formula (I) is administered at a dose of 25 to 150 mg.

21. The method of claim 19 or 20, wherein the patient is in need of treatment or prevention of acute migraine attacks.

22. The method of any of the foregoing claims, wherein the pharmaceutical composition provides sustained analgesic effects in the treatment of migraine, wherein chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for at least 7 hours, preferably at least 16 hours, more preferably at least 21 hours.

23. The method of claim 22, wherein the TRPM3 antagonist of Formula (I) is administered at a dose of 25 to 150 mg.

24. The method of claim 23, wherein the pharmaceutical composition is administered twice daily, and the chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for 24 hours.

25. The method of any of the foregoing claims, wherein the pharmaceutical composition provides sustained analgesic effects in the treatment of migraine, wherein chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC50 for at least 17 hours, preferably for 24 hours.

26. The method of claim 25, wherein the TRPM3 antagonist of Formula (I) is administered at a dose of 25 to 150 mg.

27. The method of claim 26, wherein the pharmaceutical composition is administered twice daily, and the chronically administering a plurality of doses of the pharmaceutical composition maintains a plasma concentration above the EC90 for 24 hours.

28. The method of any of the foregoing claims, wherein the pharmaceutical composition is administered immediately after a high fat meal, and wherein the T_max is delayed by approximately 1.5 hr and the Cmax is increased by less than 15%.

29. The method of any of the foregoing claims, wherein the pharmaceutical composition is administered with an acid-reducing agent, and wherein the T_max and the Cmax are substantially unaffected by the acid reducing agent.

30. The method of any of the foregoing claims, wherein the TRPM3 antagonist of Formula (I) is co-administered with second agent for the treatment of migraine.

31. The method of claim 30, wherein the second agent for the treatment of migraine comprises a CGRP inhibitor, a triptan agent, an ergot alkaloid, a non-steroidal antiinflammatory drug, acetaminophen, butalbital, caffeine, aspirin, dexamethasone, Lasmiditan, or a combination thereof.

32. The method of any of the foregoing claims, wherein the neuropathic pain comprises a metabolic neuropathy, a chemotherapy-induced peripheral neuropathy, peripheral neuropathy resulting from trauma, peripheral neuropathy resulting from injury, peripheral neuropathy resulting from surgery, postherpetic neuralgia, an entrapment neuropathy, mononeuropathy multiplex, small fiber neuropathy, neuropathy associated with Charcot-Marie-Tooth Disease, a genetic neuropathy, neuropathy associated with a nerve root disorder, an HIV-related neuropathy, or a neuropathy associated with cancer.