METHODS OF TREATING HYPERSENSITIVE COUGH OR ITCHING USING ION CHANNEL INHIBITORY COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

|iKKR| This application claims priority to, and incorporates by reference, IIS. patent application number 16/1 15,549, filed August 28, 2.018, which is incorporated by reference in its entirety. U.S. patent application number 16/1 Ϊ 5,549 is related to Patent Cooperative Treaty application number PCT/US20i6/061918, herein incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT RIGHTS

fO002f This invention was made with Government support under Grant I R44 S086343- 01 awarded by the National institute of Neurological Disorders an Stroke, National institute of Health. The Government has certain rights in this invention.

FIELD OF THE INVENTION

jOO03} The field of the present invention relates to novel ion channel modulator compounds (inhibitors or antagonists of one ty e ion channel and/or combination of inhibition of multiple ion channels), compositions including ion channel modulators, and methods of treating conditions and disorders using the compounds and compositions, A more particular field involves compounds having selective T-typc Caw* channel inhibitory effects for mitigating hy ersensitive/chronie cough or itching, pharmaceutical formulations including such compounds, and methods lor selecti ve treatment of hypersensiti ve cough or itching.

BACKGROUND OF THE INVENTION

00041 Voltage-gated calcium (Ca ² ) channels (VGCC) play an integral role in the regulation of membrane ion conductance, cellular excitability’ and neuroiransmitter release. VGCC are composed of the pore-forming cel subunit and auxiliary o25 ppm and b subuni ts that modulate channel expression and function. Among the low voltage activated channel is the Ca»-s channel subtype, which mediates T-type calcium currents that may be targeted for treatment of epilepsy, especially’ children absence epilepsy and chronic pain (Huguenard, 1998, Cribbs et ai., 2000, Perez-Reyes et al., 2009, Perez-Reyes, 2010),

|0005J The T-typc or“low voltage-activated” calc mm channels are so named because they open for shorter duration (T ~ transient) than the L-type (L = lon lasting) calcium channels. T-type channels are activated at relatively negative membrane potentials (~ -60 mV). In man types of neurons, Ca ⁱ influx through T channels triggers low-threshold Ca ² spikes, ί which in turn elicit a burst of action potentials mediated by voltage-gated sodium (Na ^' S channels. Brief bla st firing is thought to play an important role in the synchronized activity of the thalamus and neuronal pacemaker under physiological conditions, but it also underlies a wide range of thalamocortical dy srhythmias under pathological conditions such as neuropathic pain or seizures T channels can be acti vated by mild depolarization of the cell membrane (Talley et al , 1999, Perez- Reyes, 2003, Perez-Reyes, 2010, Pexton e al., 201 1., Todorovic and Jevtovic-Todorovic, 201 1)

[0006] Molecular cloning has revealed three distinct T channel proteins, designated Cavs.r Cav and Cavs.s The C vsn and Caw 3 channels are expressed predominantly, though not exclusively, in the CNS. In contrast, the€a vs.s channel is not only present in the CNS, but also expressed in peripheral nerve cell bodies and nerve endings of afferent fibers

(Hegueuard, 1998, Cribbs et al, 2000, Perez-Reyes et al., 2009, Perez-Reyes, 2010) The Caw .2 channel is highly expressed in dorsal root ganglion (DRG) neurons, whereas little Cavs.i and virtually no Caw a are expressed in the small diameter DRG neurons (Nelson et ah 1992). The Caw .2 channels are also expresse at a lower level in several noii-ueuronal tissues, including heart, liver, kidney, and pituitary. Both diabetic neuropathy and chronic constriction inj ury models in rats lead to DRG neuron-specific upregulatitm of the Caw .2 channel and the T current density'. This pathological adaptation results in enhanced excitability of sensory neurons and causes hyperalgesia and atlodynia (Jagodic et al , 2007, Jagodic et al., 2008, Latham ei al., 2009, Messinger et al., 2009, Yue et ah, 2013).

Conversely, knockout or antisense knockdown of the Cav3.2 isoform produces analgesic effects (Messinger et al , 2009).

10007] T-type channel inhibitors have two known uses in die clinic. The anti-absence seizure effects of ethosuximide and lamotrigine are thought to be mediated b the inhibition of T channel activity in the thalamus (Gomora et al., 2001, Hugoenard, 2002 i However, both drugs are weak and not specific against the T channel (Xie et al, 1 95, Zhang et al„ 1996). T he antihypertensive effect of mibefradil is conventionally attributed to its inhibition of the T channel. However, mibefradil has poor selectivity with about 3- 10 times more potent inhibition of the T-type than of the L-type€a ⁱ current or the voltage-gated a current { Avdonin et al, 2000). Because there are no selective T channel blockers, it is unclear whether and to what extend the inhibition of T channel activity at therapeutically relevant concentrations contributes to the therapeutic usefulness of a wide range of drugs. {0008] Targeting T-chan.nel, particularly the Cavs.2 isofonn, would be highly useful, for example, in reduction of thermal hyperalgesia and mechanical altodynia under pathological conditions such as diabetic neuropathy. Several efforts to discover potent and selective T- type Ca ² channels have been described in the literature, as exemplified below.

{0009] i,4-Substimted. piperidines, for example,“compound 30” (3, 5-dicliioro-iV- f [1 -(3,3- dimethylbutyl)-3-t1uoropiperidm-4-yl]meihyl)benzamide) and“TTA-P2 ^M (3,5-dichloro-N- ((l-((2,2-dimeilTylfetraliydro-2H-pyran-4-yl)methyi)-4-fliio ropipertdin-4- yl)methyl)benzamide) were synthesized by Merck and found to potently block the T-Type Cav3.2 channel [J. Med Chero 51, 3692, (2008); 3. Med. Cliern. 51, 6471 , (2008); US 2010/0222387; US 20 ! 3/8501773] TTA-A2 suppresses active wake, promotes slow-wave sleep (Kraus et a!., 2010), and prevents weight gain in mice on a high-fat diet (liebele et al,

{0010] A scaffold hopping approach afforded ML218 (3,5~Dichloro-N~[[(l a,5a,6-exo,6a)- 3-(3,3-dime hylbotyi)-3~azabicycio[3 J .0]hex-6-yl]methyi]benzamide, C1D 451 15620) selective T-Type Ca~ ^r inhibitor. ML2 i 8 possess acceptable in vivo rat PK and was efficacious in a precSiiuca! Parkinson model. Thus, ML218 is a useful new biologic probe to study T-Type€a ²ⁱ function in vitro and in vivo (Xie et al., 2010, Xiang et al, 2011). fOOIl] Certain lactam acetamides have been described by Abbott and others as Cav s and C v3.2 calcium channel blockers, and ABT-639 has been reported as a Cavs.2 calcium channel blocker for treatment of diabetic neuropathic pain through peripheral action, because ABT- 639 is presumed to not penetrate the blood brain barrier (Jarvis et al ,, 2014)

{0012] N~PiperidinyI acetamide derivati ves as calcium channel blockers have bee described by Zalicus Pharmaceuticals, Ltd. (US8569344 (2013); US8377968 (2013)). A piperidine-based compound, Z944, inhibits Cav3 channels in a voltage-dependent manner and is able to attenuate thalamic burst firing and suppress absence seizures in rats (Tringham et al., 2012). Z944 has shown promising results in clinical Phase S studies of pain in humans (Lee, 2014).

Despite the fact that many T-type Ca ⁺ channel inhibitors have been discovered and have advanced to different stages of development, no FDA-approved selective T-type channel inhibitory compounds are available for clinical applications.

{0014 j Cough is a physiological defense mechanism for the clearance of foreign materials and of excessive bronchial secretion in the airways, but it is also a common symptom of a variety of respiratory diseases. The cough reflex is triggered by the activation of rapidly adapting receptors (or irritant receptors) within the larynx, trachea and the proximal bronchi, and of Ofiber endings found in the airway walls of bronchi. Afferent signals are transmited through the sensory' vagal fibers to the cough center which has been experimentally

identified as being in the region of the solitary nucleus in the medulla within the brain ( ase, Wakita et at. 1970). From the cough center, the impulses travel through the efferent pathways to the respiratory muscles (diaphragm, intercostal and abdominal muscles) and the airways (Irwin, Rosen et a! 1977).

10015] Experimental studies have shown that peripheral neurons ma be involved in

“hypersensitive cough.” This type of cough is a chromc/persistant cough that can result from an acute cough, or from a cough syndrome or disease such as COPD, asthma, OI reflux, post- nasal drip syndrome and exposure to pollutants including smog an sildfire smoke (see, e.g., Chung and Widdi combe, The Pharmacology and Therapeutics of Cough, in Handbook of Experimental Pharmacology ISSN 0171-2004, Library' of Congress Control Number:

200892959, 2009 Springer-Verlag Berlin Heidelberg).

|0016] Similar to cough, which is a defensive mechanism to eliminate irra ains or pathogens within the airway under physiological conditions, itch is also a defensive mechanism to protect our body against bugs, harmful chemicals and poisonous plants by causing scratching responses. However, persistant or chronic itchy skin (pruritus) under pathological conditions is a significant unmet clinical problem. Over 30 million people in U.S. suffer from eczema, including atopic dermatitis, and about 7 million people suffer from psoriasis. Furthermore, pruritus can be a symptom of an underlying internal disease, including liver disease, kidney failure, iron deficiency anemia, thyroid problems or cancers, such as leukemia and lymphoma. In hemodialysis patients, the prevalence of chronic kidney disease associated pruri tus is high as 55% in both men and women (Prevalence of chronic kidney disease- associate pruritus among adult dialysis patients: A meta-analysis of cross-sectional studies, Hu et a!.).

{0017 j Currently, there is no efficient therapy for the irresistible itch symptoms of various chronic diseases associated pruritus or itching. A recent study implicated Cav 3 2 channel activation in NaMS-induced itching in experimental animals (Wang et a!.. Scientific Reports 5:16768 (2015), suggesting the Cav 3.2 channel might be a target for anti-iehmg compounds

{0018] In fact, the present inventors have discovere that T-type Ca ^2* channel inhibitors disclosed herein ate useful for the treatment and prevention of hypersensitive cough; for example, EX-T7, EX-128, EX- 130 and EX- 132 The present inventors have also discovered that T-type€a ^: channel inhibitors disclosed herein are useful for the treatment and prevention, for example, EX-31, EX-55, EX-130, EX-132 and A FA-258 (be., Z944), A FA- 309 and AFA-358. The highly potent and selective T-type Ca ²ⁱ channel inhibitors, EX- 128 and AFA-258 did not produce anti-itching effects in both of the itch models, ehioroqume- and histamine-induced itching. Unexpectedly, however, compounds that are mixed

modulators of key ion channels, including voltage-gated Na channels, exemplified by EX-31, EX- 130 and AF A-358, are effective against both chloroquine- and histamine-induced models of itching.

SUMMARY OF THE INVENTION

[00I9J The current invention provides compounds, formulations and methods of use for the treatment and prevention of hypersensitive cough and/or itching, in which key ion channels, particularly the T-type Ca ²⁺ channels are involved. The compounds and methods can be used in both human and veterinary medicine.

} 020] In one aspect, the invention provides a method of treating chronic cough, the method comprising the step of administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

wherein R ¹ is phenyl substituted with one to t hree substituents, each of which is a member selected from the group consisting of F, Cl, and CFy thereby treating chronic cough.

10021} In one embodiment, the compound is;

wherein R and R ^5b are members each independently selected fro the group consisting of F,

Ci, and CFs.

|0022] In another embodiment, the compound is:

f0027] In another embodiment, the hypersensitive or chronic cough is caused by a disease or syndrome selected from the group consisting of COPD, asthma, GI reflux, post-nasal drip syndrome and chronic exposure to pollutants.

f0O28j In another embodiment the compound is administered orally or nasally

f0 29J In one aspect, the method comprising the step of administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereo wherein the compound is selected from the group consisting of: i0«30| EX-31

[0037] In one embodiment, the itching is caused by atopic dermatitis, psoriasis, kidney failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, toxic plant exposure, chemical exposure, smog exposure, insect bites or allergic reaction to a food aliergan.

[0038] In another embodiment, the compound is administered orally or nasally.

[0039] I another aspect, the invention provides method of treatin itching, the method comprising the step of administering a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein die compound is selected from the group consisting of:

10040] EX-31

[0041] EX-130 , or

[0042] AFA-358

|0043] In one embodimemt, the itching is caused by atopic dermatitis, psoriasis, kidney failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure anemia, thyroid disease, toxic plant exposure, chemical exposure, smog exposure, insect bites or allergic reaction to a food aliergan.

[9044] In another embodiment, the compound is administered orally or nasally. BRIEF DESCRIPTION OF THE DRAWINGS

(0045] FIG. 1A. Fig ΊA. Effects of a representative compound EX- 17 at three doses (3, 10 and 30 mg/kg) and the benchmark dextromethorphan (60 mg/kg) on the number of cough events were determined in a model of citric acid-induced cough in nai ve, conscious guinea pigs. All test compounds were formulated with 0 5% hydroxyl Propyl Cellulose and given orally by gavage (p.o.) Data are given as mean ± SEM ofn ~ 8 animals per group. P-value {<0.05 indicated by *) represent significant difference compared with the vehicle-treated control group using one-way ANOVA followed by Fisher’s LSD post-hoc test.

(0046] Fig IB. Effects of EX-17 at three doses (3, 10 and 30 mg/kg) and dextromethorphan (60 mg/kg) on the latency to first cough event were determined in citric acid-induced cough in guinea pigs. EX-17 (30 mg/kg) and dextromethorphan (60 mg/kg) caused significant increases the latency compared with the vehicle-treated control group using one-way

ANOVA followed by Fisher’s LSD post-hoc test (to be double cheeked).

(8047] Fig 2A. Effects of three compounds EX-128, EX-130 and EX-132 (each 30 mg/kg) and the benchmark dextromethorphan (60 mg/kg/kg) on the number of cough events were determined in a model of citric acid-induced cough in naive, conscious guinea pigs. All test compounds were formulated with 0.5% hydroxyl Propyl Cellulose an given via p.o. Data are given as mean ± SEM of n ~ 8 animals per group. P-value (<0.05 indicated by *) represent significant difference compared with the vehicle-treated control group using one-way ANOVA followed by Fisher’s LSD post-hoc test.

(0048] Fig 2B Effects of three compounds EX-128, EX-130 and EX-132 and

dextromethorphan on the latency to first cough event were determined in citric acid-induced cough in guinea pigs. There is a trend of increasing the latency but. not reaching significant difference compared with the vehicle-treated control group using one-way ANO VA followed by Fisher’s LSD post-hoc test.

(0049] Fig 3 A and B: Effects of AFA compounds on inhibition of itching scratching behavior in two well-established itching models in mice.

DETAILED DESCRIPTION OF THE IN VENTION

(0050] As described herein, the present invention provides new methods of treating

hypersensitive or chronic cough using inhibitors of selective T-type channel inhibitory compounds, 10051 ] Chronic cough a symptom caused by a variety of respiratory disorders affects the quality of life and further exacerbates respiratory pathological conditions. Pharmacological interventions are currently confined to treating the cause of cough, and symptomatic

treatment options controlling the cough per se with an acceptable therapeutic index axe also limited The centrally acting cough therapy. such as dextromethorphan and codeine, both of which are opiates used as a cough suppressant m the dime, depresses the cough center, and is considered the most clinically effective, although sedative and addictive effects can limit their use. Local anesthetics that interfere with the conduction of afferent nerve impulses have been shown to be peripherally active antitussive compounds, but their considerable side effects make their use unsuitable. Extracellular adenosine S’-iriphosphafe (ATP) activates P2X receptors in cell surface and in primary afferent nerves. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in the management of cough, pain inflammation and certain neurodegenerative diseases (North 2016).

10052] hi contrast, little is known about die role of T-type Ca ^{2 :} channels in cough reflex and in persistent cough under pathological conditions. Although T-type Ca ² channels, mainly the Cav ^' 3,2 subtype expressed in nodose ganglion (Pachuau and Martin-Caraballo, 2007) and play a role in modulation of its axons, vagal nerve excitability, the conventional T-type Ca ² channel locker Nr' (300 mM) apparently did not alter the responses of guinea pig

tracheobronchial cough receptor fibers or nociceptors to citric acid (Canning and Chou, 2004). Therefore, the possible efficacy of T-type Ca ^{2 i} channel modulators with regard to antitussive property in a model of citric acid-induced cough in guinea pigs was investigated using new compounds (for example, EX- 37, EX-12S, EX- 130 and EX- 132) that potently and selectively inhibit the T-type Ca ² channels (see, e.g., PCT/US20! 6/061918, herein

incorporate by reference in its entirety) and compared die results to a clinically used treatment with dextromethorphan .

16053] Many chronic itch disorders are not responsive to commonly used anti -histamine drugs suggesting that histamine-independent itch models may be more relevant for

identification of no vel target and discovery of ne w compounds for chronic itch treatment. A recent identi ficat ion of the first spinal cord itch recep tor, gastri -releasing peptide recep tor (GRPR) triggered extensive molecular studies of itch transmission pathways in the nervous system GRP -GRPR signaling mediates histamine- independent pathway both in acute and chronic itch. Which ion channels mediated the specific itching signaling pathway are currently unknown, though a variety of ion channels such as the voltage -gated sodium (Na) channel, N-type Cav2.2, the T-type C&v3.2 channels and transient receptor potential vamUoid 1 (TRPVi) channels have been suggested to be involved in itch transmission pathways (3 Neurol Set. 1999 Jan 15; 162(2): 162-8. Positive symptoms in multiple sclerosis: their treatment with sodium channel blockers, lidocaine and mexiletioe. Sakurai Ml, Kanazawa LT Therefore, the possible etlkaey of T-type Cav channel modulators with regard to anti-itching properties in two differenct model of itch in mice was investigated using new compounds (for example, EX-31, EX-55, EX-130, EX-132, AEA-25S, AFA-309 and AFA-358) that potently and selectively inhibit the T-type Ca ^2’ channels (see, e g., PCT/US2016/06191 B, herein incorporated by reference in its entirety)

(605 j Below are definitions of representative types of hypersensitive cough and itching in which the compounds, pharmaceutical formulations and methods find use in treating.

16055] The term‘‘method of treating hypersensitive or chronic cough” means partial or full relief from the symptoms of coug or the prevention of hypersensitive cough, often defined as chronic couch of more than eight weeks in duration, including the descriptions of hypersensiti ve cough provided herein. The hypersensitive or chronic cough can be caused by a disease or syndrome selected from the group consisting of COPD, asthma, Gl reflux, post- nasal drip syndrome and chronic exposure to pollutants such as smog and wildfire smoke.

|00561 The term“method of treating itching” means partial or full relief from the symptoms of itching or the prevention of itching. The itching can be caused by atopic dermatitis, psoriasis, kidney failure, cholestasis, diabetes, leukemia, lymphoma, eczema, liver failure, anemia, thyroid disease, toxic plant exposure, chemical exposure, smog exposure, insect bites or allergic reaction to a food allergan.

(0057] "Compound of the invention," as used herein, refers to the compounds discussed herein and salts (e.g. pharmaceutically acceptable salts) of these compounds

10058} “Alkyl” is intended to embrace a univalent saturated linear or branched

hydrocarbon chain ha ving the number of carbon atoms specified, or if no number is specified, having 1 to 8 carbon atoms,“Alfcylene” refers to a similar group, which is divalent

‘Optionally substituted” alkyl refers to either an unsubstituted alkyl group, or an alkyl group substituted with one or more substituents (such as one, two, three, four, or five substituents) selecte from the group consisting of -Oi l , -(C i-Ca aikyi)-OH, halo, f!uoro, chloro, bronio, iodo, -(Cs-C ^' ₄ alkyl), -(Cs-Cr) haloalkyl, -(Ci-Ca) perhaloa!ky!, -0-(CJ~C4 alkyl), -0~(Ci-C4 haloalkyf), -0~iCi-Ct perhaioalkyl), -(C ^’ S-CI) perfluoroalkyl, -(OO^ Q) alkyl, ~(0 ^::: 0)~

(CA-CA) ha!oalkyl, -(COHCi-Ci) perhaloalkyl, -N¾ -NHCCi-CU alkyl), -N(Ct-C4

a!ky!)(C -Gi alkyl) (where each Ci-C t alky! is chosen independently of the

other), -NO2, ~CN, isocyano (NC-), oxo (=0), ~C(~0)H, ~C( ^: 0 (Cs-C4

alkyl), -COOH, -C(===0)-0 (Ci-C4 alkyl), -C(=0)NH2, -C(=)ONH(Ci-C4 alkyl), -C(-0)N(Ci-

C alkyl H Cs-Ci. alkyl ) (where each C1-C4 alkyl is chosen independently of the

other), -SH, -(Ci-Ct aikyl)-$H, -S-(Ci-C4 alkyl), -S(=OMCi-C4 alkyl), -SG Ct-C» alkyl), and -SOHCi-C* perf!uoroalkyl). Examples of such substituents

are -CHJ, -CH2CH3, -CFS, -CBiCFy -CF2CF3, -OCH.% -NBiCHs), -M(CH: 2,- SC¾ and

SO;( ^' l l·.. ‘Optionally substituted alkylene ^,? groups can be unsubstituted, or substituted in the same manner as substituted alkyl groups.

(0059J “Cycloalkyl” is intended to embrace a univalent saturate cyclic hydrocarbon chain having the number of carbon atoms specified, or If no number is specified having 3 to 10 carbon atoms, or 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms.“Cycloa!ky!ene” refers to a similar group, which is divalent Cydoalkyl and cycloalkylene groups can be

unsubstituted, or substituted in the same manner as substituted alkyl groups. j 1060] “Alkenyl” is intended to embrace a univalent linear or branched hydrocarbon chain having at least one carbon-carbon double bond, and ha ving the number of carbon atoms specified, or if no number is specified, having 2 to 8 carbon atoms.“Alkenylene” refers to a similar group, which is divalent. Alkenyl and alkenylene groups can be unsubstituted, or substituted in the same manner as substituted alkyl groups where chemically possible.

|0061] “Cycloalkenyl” is intended to embrace a univalent cyclic hydrocarbon chain having at least one carbon-carbon double bond and ha ving the number of carbon atoms specified, or if no number is specified, having 4 to 10 carbon atoms, or 4 to 8 carbon atoms or 4 to 6 carbon atoms.“Cycloalkenyiene ^'5 refers to a similar group, which is divalent. Cycloalkenyl and cycloalkenyiene groups can be unsubstituted, or substituted in the same manner as substituted alkyl groups where chemically possible

(0062] “A!kynyt” is intended to embrace a univalent linear or branched hydrocarbon chain having at least one carbon-carbon triple bond, and having the number of carbon a toms specified, or if no number is specified, having 2 to 8 carbon atoms.“A!kynytene” refers to a similar group, which is divalent. Alkynyl and alkynylene groups can be unsubstituted, or substituted in the same manner as substituted alkyl groups where chemically possible. |Q063) “ApT ^' JUS defined as a univalent aromatic ring system. Ary! groups include monocyclic aromatic rings and polycyclic aromatic ring systems containing the number of carbon atoms specified, or if no number is specified, containing six to twenty carbon atoms.

In other embodiments, aryl groups may contain six to ten carbon atoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2 -naphthyl, 1 -py.rroiyf 2- pyiToly! . 3-pyrrolyI, 3-pyrazolyl, 2-irnidazolyl, 4-imkiazolyl, pyrazinyi, 2-oxaxolyL 4- oxazolyl, 5-oxazolyI, 3-isoxazolyi, 4-isoxazolyi, 5-isoxa olyi, 2-thiazolyl, 4-thiazo!yl, 5- fhiaxolyl, 2-furyl, 3-fury!, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyI, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benziraidazolyI, 5-mdolyl, I-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quino!.yl, and 6-qninolyl.

10064] In some embodiments, aryl groups can be unsubstituted. In other embodiments, aryl groups can be substituted with, for example, one, two, three or more substituents

independently selected from the group consisting of -OH, -(Ci-thj a!kyli-OH, halo, iluoro, chloro, bromo, iodo, -(CJ-C4 alkyl), -(Ci-C4) haloalkyl, -fCi-C4) perhaloalkyl, -0-(Ci-C4 alky!), -0-(Cs-C4 haloalkyl), -0-(Ci-C4 perhaloalkyl), -(Ct-Cf) perflitoroalkyl, -(O0)-{Ci- C4.) alkyl, -(OOMG-G haloalkyl, -(C=OM€i-C4) perhaloalkyl, -NH2, -NH(Ci-C* alkyl), -N(CJ-C4 alkyl){Cs-C4 alkyl) (where each C4-C4 alkyl is chosen independently of the other), -NO2, -CN, (NC-), -C(=0)H, -C(=0)-(Ci-C4 alkyl), -COOH, -C(=0)-0-(Ci-C4 alkyl), -C(-0)NH ₂ , -CH0NH(CVC4 alkyl), -C(-0) (Ci-C4 aikyi)(0-C4 alkyl) (where each Ci-Q alkyl is chosen independently of the other), ~SH, -(Ci-Ct aIkyI)~Sl:l and-S-CiO alkyl in some embodiments, any of the aryl and heteroaryl groups 1s optionally substituted, e.g. , with one or more groups referred to herein as an“aryl group substituent”.“Arylene” refers to a similar group, which is divalent

[0065] The terns“heieroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized A heteroaryl group can be attached to the remainder of the molecule through a heteroatom.

|QQ66] “HydrocarbyP is defined as a univalent hydrocarbon group, that is, a group comprised of hydrogen and carbon, whether aliphatic or aromatic, acyclic or cyclic, or any combination of, or all of, aliphatic, aromatic, acyclic and cyclic. Hydrocarby! groups have the number of carbon atoms specified, or if no number is specified, having i to 10 carbon atoms. “Hydrocarby lene” refers to a similar group, which is divalent. Hydrocarby! an bydroeafb Sene groups can be unsubstituted, or substituted in the same manner as substituted alkyl groups where chemically possible.

[0067] “Heterocycle” or a“heterocyclic group” is defined as a ring system which contains the number of carbon atoms specified, and one or more heteroatoms (such as one to six heteroatoms, or one to three heteroatoms, or one heteroatom), where heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, an phosphorus.“Heteroaryf is defined as an aromatic ring system which con tai ns the number of carbon atoms specified, and one or more heteroatoms (such as one to six heteroatoms, or one to three heteroatoms, or one heteroatom), where heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, and phosphorus; heteroaryl gro ups are a subset of heterocyc lic gro ups . In some embodiments, heteroatoms for heterocycly 1 and heieroaryl groups are selected from the group consisting of oxygen an nitrogen. I various embodiments, heterocyclic groups may contain two to twent carbon atoms and one to six heteroatoms, two to twelve carbon atoms and one to four heteroatoms, two to twelve carbon atoms and one to three heteroatoms, two to ten carbon atoms and one to three heteroatoms, two to six carbon atoms and one to three heteroatoms, or two to six carbon atoms and two to four heteroatoms. In some embodiments, heterocyclic groups can be unsubstituted. In other embodiments, heterocyclic groups can be substituted on any chemically possible valence with for example, one, two, or three substituents independently selected from the group consisting of -OH, -(C1-C4 alkyl)-OH, halo, fluoro, chloro, bromo, mdo, -(C1-C4 alkyl), -(C1-C ₄ ) haioalkyl, -(Ch-C ) perhaloalkyi, -0-(Ci~C ₄ alkyl), -0-(Ci-C4 haioalkyl), -0-(€J-€ ₄ perhaloalkyi), -(C1-C4) perfluoroalkyl, -(C=0)-{Ci-C4) alkyl, -(C=0)~ (C1-C4) haioalkyl, ~(C >MCI~C4) perhaloalkyi, - l¾ -NH(Ci~C-i alkyl), ~N ^' (CI-C4

alkyi)(C>.-C4 alkyl) (where each i-C ₄ alkyl is chosen independently of the

other), -NCh, -CN, (NC~), -C(-C))H, -C(0)-(Ci-C4 alkyl), -COOH, -C(-0)-0-(Ci-C4 alkyl), -C(=0)NH2, -C(=)ONH(Ci-C4 alkyl), -C( ^» 0)N(Ci-C* aikyi)(Ci-C ₄ alkyl) (where each Ci-Gt alkyl is chosen independently of the other), -SH, -(C1-C ₄ aiky!)-SH and -S-C ₁ -C4 alkyl Examples of heterocydes include aziridine, oxirane, oxetane, azetidiae, pyrrolidine, pyrrole, tetrahydrofuran, furan, thiolane, thiophene, imidazolidine, imidazole, pyrazohdme, pyrazole, 1 ,2,3-triazo!e, 1,2,4-triazole, piperidine, pyridine, pyran, piperazine, and

morpholine

[0068] A“heteroalkyl” group is defined as a univalent hydrocarbyi group, where one or more of the carbon atoms have been independently replaced by a leteroaiom at any

chemically possible location, where heteroatoms include, but are not limited to, oxygen, ni trogen, sulfur , and phosphorus. Oeleroalkyl groups have the number of carbon atoms specified, or if no number is specified, having 1 to 10 carbon atoms, and also at least one heteroatom, such as 1 to 5 heteroatoms, 1. to 4 heteroatoms, 3 to 3 heteroatoms, 3 to 2 heteroatoms, or one heteroatom. “Heteroalkyiene” refers to a similar group, which is di valent. Heteroalkyl and heteroalkyiene groups can be unsnbstftuted, or substituted in the same manner as substituted alkyl groups where chemically possible. Examples of heteroalkyl and heteroalkyiene groups include, but are not limited to, ethylene glycol and polyethylene glycol moieties, such as (-CHjCHa-OVH (a monovalent betero!ialkyl group) and

(-C H2CH2 0~)n (a divalent heteroalkyiene group) where n is an integer front 1 to 12 inclusive, and propylene glycol and polypropylene glycol moieties, such as

(-CH2CH(C¾)-0-)U-H (a monovalent heteroalkyl group) and (-C¾CB(CH3)-0- (a divalent heteroalkyiene group) where n is an integer from 1 to 12 inclusive. The

heteroatom(s) 0, N and S and Si may be placed at arty interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CE -CHs-O-CHa, -CH2-CH2-NH-CH3, -CH2-CH2- N(Cft)-C¾, -CH2-S-CH2-CH3, -CH2-CH2,-S(0)-C¾, -CH2-CH ₂ -$(0)2-C¾, -CHCH-0- CHs, -Si(CHj)j, -CH2-CH-N-OCH5, and -Cif :H-N(Q¾)~Cf¾. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and ~CH2-0-Si(Cft)3. Similarly, the term“heteroalkyiene” by itself or as part of another substituent means a divalent radical derive front heteroalkyl, as exemplified but not limited by, -CH2-CB2-S-CH2-CH2- and ~ Chb-S-Ofa-C 11: - l l-CIfe-. For heteroalkyiene groups, heteroatoms can also occupy either or both of the chain termini (e.g, alky ietieoxy , aikylenedioxy, alkyleneamino,

alkylenediatnino, and the like). Still further, for alkylene and heteroalkyiene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -CCfe ’- represents both €(Q)OR ⁵ and ~ 0C(0)R . jth)6 j The various groups described above can be attached to the remainder of the molecule at any chemically possible location on the fragment, including attachment via a substituent when the group is substituted. For the purposes of drawing the struc tures, groups are typically attached by replacement of a hydrogen, hydroxyl, methyl, or methoxy group on a“complete” molecule to generate the appropriate fragment, and a bond is drawn from the open valence on the fragment to the remainder of the molecule. For example, attachment of the heteroalkyl group CH2-O-CH3 proceeds by removal of a hydrogen from one of the

IS methyl groups of ClTs-O-CTk, to generate the heteroalkyl fragment -CHd-O-CBs, from which a bond is drawn from the open valence to the remainder of the molecule

10070] Reference to“about” ^' a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of“X”.

{0071 j The terms“a” or“an,” as used in herein means one or more unless the context clearly indicates otherwise.

|O072} By“subject,”“individual,” or“patient” is meant an individual organism, preferably a vertebrate, mor preferably a mammal, most preferably a human.

|0O73] The description is intended to embrace all salts of the compound describe herein, as well as methods of using such salts of the compounds. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the tree compound (neutral compound or non-salt compound). The desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with au acid. Examples of inorganic acids include, hut are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

Examples of organic adds include, but are not limited to, formic- acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, ma!onic acid, succinic acid, fomaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, ntandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those of skill in the art: by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and al uminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N’- dibenzyletbylenediamme, and triethyiamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. For lists of pharmaceutically acceptable salts, see, for example, P. H. Stahl and Cl G. Wemiuth (eds.)“Handbook of Pharmaceutical Salts, Properties, Selection and Use” Wiley- VCH, 20P (ISBN: 978-3-90639-051-2). Several pharmaceutically acceptable salts are also disclosed in Berge, 3. Phami. Set. 66:1 (1977).

56 £0074) The phrase "therapeutically effective amount" as used herein means that amount of a compound, material, or formulation comprising a compound of the present invention which is effecti ve for producing some desired therapeutic effect by inhibition of a T-Channel in at least a sub-population of cells in an animal, thereby blocking or lessening the biological consequences of that pathway in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment

£0075) in an exemplary embodiment the invention provides a method for treating a condition described herein in a mammal, the method comprises administering to the mammal a therapeutically effective amount of a compound described herein, or a compound according to a formula described herein, or a pharmaceutically acceptable salt thereof, sufficient to treat the condition, thereby treating the condition. In an exemplary embodiment, according to any method described herein, the mammal is in need of treatment with the compound. In an exemplary embodiment, according to any method described herein, the mammal is a dog, a cat, a horse, a pig, a cow, a sheep, a mouse, a guinea pig, or a. rat. In an exemplary

embodiment, according to any method described herein, the mammal is a human.

{0076] In an exemplary embodiment, the invention provides a method for treating a condition described herein in a mammal, the method comprises administering to the mammal a therapeutically effective amount of a pharmaceutical formulation described herein, sufficient to treat the condition, thereby treating the condition. In an exemplary embodiment, according to any method described herein, the mammal is in need of treatment with the pharmaceutical formulation. In an exemplary embodiment, according to any method described herein, die mammal is not otherwise in need of treatment wit the pharmaceutical formulation. In an exemplary embodiment, according to any method described herein, the mammal is a mouse or a rat. In an exemplary embodiment, according to any method described herein, the mamma! is a human.

£0077] The term“ICso” refers to the concentration causing a 50% inhibition of the specific binding of the control substance. 101178) The following abbreviations may he used herein·.

about

+ve or pos. ion positive ion

A heat

Ac Acetyl

can acetonitrile

AccG acetic anhydride

Aq aqueous

AcOH acetic acid

Bn benzyl

Boc tert-butyloxycarbonyl

BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride

BSA bovine serum albumin

Bu

Bz benzoyl

Calcd or Cale’d calculated

Cbz carboxybenzyloxy beiizylcarbamate

Cone concentrated

NMR, chemical shift in parts per million (ppm) day(s) or doublet (NMR)

l,8Ahazabicyclo[5.4.0]undec~7~ene

dichioroethane

dichloromethane

2,3~dich!oro~5,6-dicya!io- 1 ,4-benzoc uinone

diethylamine

di i sopropylethy S am in e

4-dimethylaminopyridme

i ,2-di ethoxyethane

DMF N,N~dimethyIformamide

Dess-Martin periodinane; 1 ,1, 1 -triacetoxy- 1 , 1 -dihydro-

DMP

1 ,2-benziodoxoI-3(l H)-one

DMSO dimethyl sulfoxide

DPPA D ip hen y ip hos p iioryl azide

DRG Dorsal Root Ganglion

EDO or EDO N-etfayl~NX3~diraethylaimnopropyi)carbodiimide EGTA ethylene glycol tetraaceiic acid

Bq equivalent

m orES eleetrospray ionization

Et ethyl

EfcO diethvl ether

EfcN ifiethy!amine

EtOAc ethyl acetate

EtOH ethyl alcohol

G gram(s)

H hoirr(s) EAT LI 0-(7-azabenzoiriazo 1- 1 ~yl }~ N L' N’ , - tetramethyluronmm he xafiuorophosphate

O-benzotriazole-jM^^hN’-tetramethyl-troniu -

HBTU

hexa.fi uorophosphate

HEPES 4-(2-hydroxyethyI)- 1 -piperazmeethanesulfonic acid

Ilex hexanes

HMPA hexameihylphosphotamide

ml. rnilliliterisi

M mo lets)

MS mass spectrometry

MsCt methanesulfouyl chloride

MTBE or MtBE methyl tert- butyl ether

m/z mass-to-c barge ratio

NaHMDS sodium hexamethyldisilazide

NaOtBu sodium tert-hutoxide

NBS N-bromosuccinimide

nBuLi n-bttyl lithium

NMO N-methy!morpholine-N-oxide

NMP l-methyl-2-pyrrolidinone

NMR nuclear magnetic resonance

PBS phosphate buffered saline

PMB paramethoxybenzyl

Pr propyl

Prep-HPLC Preparative high pressure l iquid chromatography

Ppm parts per million

p-iol para-toluoyl

PTZ pentylenetetrazole

Rac racemic

RP-HPLC or RPHPLC reversed phase high pressure liquid chromatography RT or it or r.t. room temperature sat or sat’d or said Saturated

SNI Spared nerve injury

SNL Spinal nerve ligation

TBAF tetrabutylammoni am fluoride

TBDMS tert-butyidimeihylsiiyi

TBDMS-Cl tert-buty kiimethy I si!yl chloride

TBDPS /en'-buty kli pheny 1 silyl

TEMPO { 2,2 6.6- tetr a me thy 1 p spend in- 1 ~yl)oxidanyl

tert or t tertiary

TFA or TFAA triflouroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS trimethylsilyl or trimethylsiiane

ts retention time

tBuOB tert-butyi alcohol

v/v volume per volume

£0079] In one aspect the invention provides a compound of the invention. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof in an exemplary embodiment, the salt of a compound described herein is a pharmaceutically acceptable salt in an exemplary embodiment, the invention provides a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment the invention provides a compound described in a formula provided herein. In an exemplary embodiment, the invention provides a compound described herein.

|0O80] One object of the present invention is to provide a compound, or a pharmaceutically acceptable salt thereof which can be used to treat chronic cough or itching of the general structure:

wherein R ¹ Is substituted or unsubstituted alk l, substituted or unsuhstituted aryl or substituted or unsubstituted heteroaryl; X is selected from ~N(R ⁱ⁴ )~C(~0> _% or -N(R ⁱ⁴ )- S(-0)fc-, or ·€H2~N(E ¹⁴ )-€(-0}-, or CH2-N(:ii ⁱ )-S(-Oh- or C(-0)-N( R ^t4 ) ₅ and -€¾- C(=0)-N(R ¹⁴ ), or Cl:i2~N(R ⁱ⁴ ); k is selected from i and 2; and R ¹⁴ is H or substituted or unsubstituied Ct-Ce alkyl or substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heteroalkyl; R ² is selected from substituted of unsubsiiiuted alkyl and substituted or unsubstituied heteroalkyl; R ³ , R. ⁴ , R ³ , R ⁶ are each independently hydrogen, substituted or unsubstituted -Cos alkyl, substituted or unsubstituied -Ct-g haloalkyi, a 3-, 4-, 5- or 6-membered substituted or unsubstituted cycloalkyi or substituted or unsubstituied

heterocydoalkyl group, wherein R ³ and R ⁴ along with the carbon to which they are attached optionally form a 3~ to 6-membered substituted or unsubstituted cycloalkyi or substituted or onsuhstituted heterocydoalkyl group, said heterocydoalkyl group optionally containing 1 or 2 heteroatoms independently selected from O, N or S, and said substituted cycloalkyi or substituted heterocydoalkyl group is optionally substituted with 1 , 2, or 3 substituents independently selected from F, -CJ -e alkyl and -CFs. R ^' and R ⁶ , together with the carbon to which they are attached, optionally form a 3-, 4-, 5~ or 6- membered substituted or

unsubstituted cycloalkyi or substituted or unsubstituted heterocydoalkyl group, said

heterocydoalkyl group optionally containing 1 or 2 heteroatoms independently selected from O, N or S, and said cycloalkyi or heterocydoalkyl group is optionally substituted with from 1, 2 or 3 substituents independently selected from F, -Ci- _< s alkyl, and -CFs. R ⁷ . R ^s , R ⁹ , and R ^K * are each independently hydrogen, fluorine, substitute or unsubstiiuted-Ci-i alkyl, substituted or unsubstituted-C - . haloalkyi, a 3-, 4-, 5- or 6- membered substituted or unsubstituted cycloalkyi or substituted or unsubstituied heterocydoalkyl group, wherein R and R\ together with the carbon to which they are attached, optionally form a 3-, 4-, 5-, or 6- membered substituted or unsubstituted cycloalkyi or substituted or unsubstituied

heterocydoalkyl group said heterocydoalkyl group optionally containing I or 2 heteroatoms independently selected .from O, N or S, and said substituted cycloalkyi or substituted

heterocydoalkyl group is optionally substituted with I , 2 or 3 substituents independentl selected from F, ~C _K; alkyl, or -CFj; R ⁹ and ^1® together with the carbo to which they are attached, optionally form a 3-, 4-, 5- or 6-membered substituted or unsubstituted cycloalkyi or substituted or unsubstituted heterocydoalkyl group, said heterocydoalkyl grou

containing from 1 or 2 heteroatoms independently selected from O, N or S, and the substitute cycloalkyi or substituted heterocydoalkyl group is optionally substituted with 1 , 2, or 3 substituents independently selected from F, -Cui. alkyl, or-CFs; R ^u , R ⁿ and R ¹³ are each independently hydrogen, fluorine, substitute or unsubstituted-Ci-e alkyl, substituted or imsubstituted-Ci-6 haloalkyi, a 3-, 4-, 5- or 6-membered substituted or unsubstituted cycloalkyi or substituted or unsubstituted heterocydoalkyl group, wherein R ⁵⁵ and either R* ² or ¹³ , together with the carbons to which they are attached, optionally form a 3-, 4-, 5-, 6~ or 7 -membered substituted or unsubstituted cycloalkyi or substituted or unsubstituted

heterocydoalkyl group. \mm\ In an exemplary embodiment, wherein R ² R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^w , R ⁿ , R ¹² R*\ and X are as described herein, ¹ is selected from substituted or un substituted benzyl or a substituted or unsubstituted polycyclic cyc!oalkyl ring, e.g , adamaoiyl. in an exemplary embodiment, wherein R ² , R’, R ⁴ , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^u , R ⁱ² , R ¹³ , and X are as described herein, R ¹ is substituted adafnantyl. in an exemplary embodiment, wherei ² , R ³ , R ⁴ , R ³ ,

R ⁶ , R ⁷ , R*, R ⁹ , R ^lw , R ⁱ , R ⁱ² , R ⁵³ , and X are as described herein, R ³ is substituted adamant-!- yl In an exemplary embodiment, wherein R ² , R\ R ⁴ , R ⁵ , R ⁶ , R ', R ⁸ , R ⁹ , R ^!0 , R ^u , R ^{1 2} , R ¹ , and X are as described herein, R* is unsubstituted adamantyl. In an exemplary embodiment, wherein R ² , Ry R ⁴ , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^{' f} , R ⁱ² , R ^{! l} . and X are as described herein. R ^! is unsnbstitnted adamant- 1-yl

I0»82j In an exemplary embodiment, wherein R ² , R ³ , R ⁴ , R ⁵ , Rif R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ^a , R ⁵² R ^{i ?} , and X are as described herein, ¹ is substituted by 1 , 2, 3 or 4 non-hydrogen substituents selected from halo, haloa!fcy!, substituted or unsubstituted alkoxy, and eyano

[6083] In an exemplary embodiment, the compounds of the invention used to treat chronic cough or itching have a structure according to Formula I, wherei R ² , R ³ , R ⁴ , R ⁵ . R ⁶ , R ^' , R ⁸ , R ⁹ , R ^> , R ^{! i} , R ¹² , R ¹³ , and X are as described herein, R ^f is of the formula:

wherein A, B, C and D are independently selected front“aryl group substituents"; and the indices a, b. c, and d are independently selected from 0 and 1.

[0684] In an exemplary embodiment, the compounds of the invention used to treat chronic cough or itching have a structure according to Formula 3, wherein R ² , R ^; R ⁴ , R ⁵ , R* ⁵ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R , and X are as described herein. A, B, C an D are independently selected from CN, Ci, Br, F, substituted or unsubstituted Ct-Cc. alkyl, substituted or

unsubstituted Cj-Ce heteroalkyl, substituted or unsubstituted Ci-Cs ha!oa!ky!, and substituted or unsubstituted Ci~Gs a!koxy.

[6085] In an exemplary embodiment, wherein R ⁵ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^' , R ⁸ , R ⁹ R ^Ki , R ^{3 1} , R ⁱ² , R ⁱ³ , and X are as described herein, R ² is selected from CI-CK· straight chain or branched substituted or nnsubstituied Ci-Cc. alkyl, and Ci-Cie substituted or unsubstituted Ci-Ck alkyl heteroalkyl. In an exemplary embodiment, wherein R ¹ , R ³ , R ⁴ , R ³ , R ⁶ , R ^: , R ⁸ , R ⁹ R ^Ki , R ^{! i} , R°, R ^L \ and X are as described herein, R ² includes substituted alky! or substituted

heteroalkyl groups, which are substituted with amide, oxo, substituted or unsubstituted aryl or substituted or unsubstituted heterocycloalkyl. Exemplary substituted aryl groups include substituted or unsubstituted phenyl, and an exemplary heterocycloalkyl moiety is an oxygen- containing heterocy e.

|Q0 ] In an exemplary embodiment, a compound of the invention used to treat chronic cough or itching has the formula:

wherein R*, R ² , R ⁵ , R R ⁵ , R ⁶ , R ⁷ , R ^® , R R ^u) , R ^{f ia} , R ^ut> , and X are as described herein, wherein q is an integer selected from 1 , 2, 3, 4 and 5, In an exemplary embodiment, wherein R\ R ² , R- R ⁴ , R ^: 1 R ⁶ , R ⁷ , R ^® , R ⁹ , R ^Ui , and X are as described herein, wherein R ^{i t;i} and R ^{1 ,b} are members each independently selected from H, methyl, and fluorine. In an exemplary embodiment, wherein R ⁵ , R ² , R- R ⁴ , R ⁵ , ”, R R ^s , R ^s , R ^}0 , and X are as described herein, q In an exemplary embodiment, wherein R ¹ , R ² , R1 R ⁴ , R ⁵ , R ^l \ R ⁷

R ^® , R ⁹ , R ¹⁰ , and X are as described herein, q is 1 , R is F and R ^{J i} is F.

|O087j In an exemplary embodiment, a compound of the invention used to treat chronic cough or itching has the formula:

[0088] in an exemplary embodiment, a compound of the invention used to treat chronic cough or itching has the formula:

wherein X, R ^{ , and R ² are as described herein, and q is 1 or 2

10089] In an exemplary embodiment, a compound of the invention used to treat chronic cough or itching has the formula:

wherein X, R ^f , and R ² are as described herein, and q is 1 or 2.

[0090] In an exemplary' embodiment, a compound of the invention used to treat chronic cough or itching has the formula:

wherein X, R ¹ , and R ² are as described herein, and q is 1 or 2.

[0091] In an exemplary embodiment, a compound of the in vention used to treat chronic cough or itchin has the formula:

wherein X, R*, and R ² are as described herein, and q is 1 or 2.

[0092] In an exemplary embodiment, a compound of the invention used to treat chronic cough or itching has the formula:

wherein X R ¹ , and R ² are as described herein, and q is 1 or 2

|0093j in a exemplary embodiment, wherein q, R ² , R\ R ⁴ , R ⁵ , R ¹ *, R , R ⁸ , , R ¹⁰ , and X are as described herein, wherein R ^¾ is substituted or unsubstituted benzyl or substituted or unsubstituted adamantyl. In. an exemplary embodiment, wherein q, R ² , R\ R ⁴ , R ⁵ , R. ⁶ , R ⁷ , R ⁸ _» R ^y „ R ^u> , and X are as described herein, wherein R ⁵ is substituted phenyl In an exemplary' embodiment wherein q, R ² , R ³ , R ⁴ , R ³ , R ^& , R ⁷ , R ⁸ , R ⁹ , R ⁱ⁰ , and X are as described herein, wherein R ^f is unsubstituted phenyl. In an exemplary embodiment, wherein q, R ² , R ⁴ . R ⁴ , R ^" ’, R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^u) , and X are as described herein, wherein R ¹ is substituted or unsubstituted adamantyl. In an exemplary' embodiment, wherein q, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^' , R ⁸ , R ⁹ , R ¹⁰ , and X are as described herein, wherein R* is

represents the covalent link between R* and X; and R ¹⁸ and R’ are members each independently selected from halo, haloalkyl, substituted or unsubstituted alkoxy, and cyano. In an exemplary embodiment, escribed herein,

wherein R ^; is wherein represents the covalent link between R ¹ and X; and R ^la and R ^Ib are members each

independently selected from F, Cl, Br. CFs, methoxy, methyl, and CM. in an exemplary embodiment, wherein q, R ² , R ³ , R ⁴ , R ⁵ , ⁶ , R', R ⁸ . R' ⁵ , R ¹⁰ , and X are as described herein,

wherein wherein represents the covalent link between R ^! and X; and R ⁱ⁸ and R ^ih are members each

independently selected from F, Cl, and CFs.

|0094] in an exemplary embodiment, wherein q, R ² , R ³ , R ⁴ , R ⁵ , R**, R R ⁸ , R R ¹⁰ , and X are as described herein, wherein R ² is substituted or unsubstituted alkyl. In an exemplary embodiment, wherein q. R ² , E\ _, R h ⁵ , R\ R\ R ⁸ , R ⁹ , R ⁱ⁰ , and X are as described herein, wherein R ² is substituted or irnsubstituted heteroalkyl. In an exemplary embodiment. wherein

represents the covalent link between

R ² and the piperidine nitrogen

{ 0 051 in an exemplary embodiment, the compound used to treat chronic cough or itching has the following formula:

wherein X, R ² , and R ¹ are as described herein. In an exemplary embodiment, the compound used to treat chronic cough or itching has the following formula: , wherein X, R ² , and R* are as described herein. In an exemplary embodiment, the compound is according to a formula described herein, and R ³ is phenyl substituted with one to three substituents, each of which is a member selected from the group consisting of F, Cl, and CFs. In an exemplary embodiment, the compound is according to a formula described herein, and R ³ Is phenyl substituted with one substituent which is a member selected from the group consisting of F, Cl, and CFs, in an exemplary embodiment, the compoun is according to a formula described herein, and R ^{ is phenyl substituted with two substituents which are members each individually selected from the group consisting of F, Cl, and CFs. in an exemplary embodiment, the compound is according to a formula described herein, and R ^f is phenyl substituted with thee substituents which are members each indi vidually selected from the group consisting of F, Cl, and CFs. In an exemplary

embodiment, the compound has the following formula: , wherein X,

R ² , and R* are as described herein. In an exemplary embodiment, the compound has the

following formula: , wherein X. R’, and R ^! are as described herein. f®097] In an exemplary·' embodiment, the compound used to treat chronic cough or itching

wherein X and R ¹ are as describe herein. In an exemplary embodiment, the compound is wherein X an R ¹ are as described herein. In an

exemplaiy embodiment, the compound , wherein X and R ¹ are as described herein. I an exemplary embodiment, the compound is

, wherein X and ^J are as described herein. In an

exemplary embodiment, the compound

X and R. ¹ are as described herein. In an exemplary embodiment the compound is

rein R ^* and R ² are as described herein. In an exemplary embodiment, the compound is , wherein R ^l and R ² are as described herein. In an exemplary

embodiment, the compound wherein R ¹ and R ² are as described

herein. In an exemplary embodiment, the compound i wherein R* and R ² are as described herein. In an exemplary embodiment, the compound is , wherein R ¹ and R ² are as described herein. In a exemplary

embodiment, the compound is wherein R ⁵ and R ² are as described herein.

j0999j In an exemplary embodiment, the compound

wherein X and R ² are as described herein, R ⁱ and R ^ib are members each independently selected from the group consisting of F, Cl, and CFs.

100100] In an exemplary embodiment, the compound

wherein X and R ² are as described herein, R ^}s and R ^Jb are members each independently selected from the group consisting of F, Cl, and CFs.

[00101] In an exemplary embodiment, the compound wherein

X and R ² are as described herein, R ^! is as described herein. In an exemplary embodiment, the

compound wherein X and R ^A are as described herein, R* is unsubsdtoted adamaoiyl In an exemplary embodiment, the compound is , , . In an exemplary embodiment, the compound is according to a formula described herein which contains R ^li * and R ^3b , wherein R ^ia and R ^tb are members each independently selected from the group consisting of F, Cl, and CFs In an exemplary embodiment, the compound is according to a formula described herein which contains R ^is and R ^u> , wherein R ^} * and R ^ih are members each independently selected from the group consisting of F, CL and CFs. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^!a and R ^lb , wherein R ^la is as described herein, and R ^J is F. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^la and R ^1¾ , wherein R ^{i 8} is as described herein, and R ^,b is Cl. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^Ia and R ^l wherein R ¹ * is as described herein, and R ^!b is CFs. In an exemplary embodiment, the compound is according to a formula described herein which contains R* ⁸ and R ^u> , wherein R ^}b is as described herein. and R ^5a is F. In an exemplary embodiment, the compound is according to a formula described herein which contains R and R ^3b wherein R ^5b is as described herein, and R ^!a is Cl. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^la and R ^{b , wherein R ^1b is as described herein, and R ^la is CFn In an

exemplary embodiment, th compound i wherein R~,

R ^ie and R ^lb are as described herein In an exemplary embodiment, the compound is , wherein R ² , R ^la and R ^U) afe as described herein In an

exemplary embodiment, the compound , wherein R ² ,

R ^i;i and R ^{f b} are as described herein. In an exemplary embodiment, the compound is

wherein R ² , R ^ia and R ^U) are as described herein. In an

exemplary embodiment, the compound i , wherein R

R ^ia and R ^l are as described herein. 00103| In an exemplary embodiment, the compound is , wherein R ² , R ^la and R ^ib are as described herein. In a exemplary embodiment, the compound is according to a formula described herein which contains R ^!a and R ^1¾ , wherein R ¹ * and R ^{i b} are members each independently selected fro the group consisting of F, Cl, and CFs. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^i:a and R ^ib , wherein R ⁱ⁸ and R ^3! are members each independently selected from the group consisting of F, Cl, and CFs. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^!a and R ^lb , wherein R is as described herein, an R ^lb is F In an exemplary embodiment, the compound is according to a formula described herein which contains R ^!a and R ^lb , wherein R ^Sa is as described herein, and R ^ib is CL In an exemplary embodiment, the compound is according to a formula described herein which contains R ^ls and R ^if> , wherein ^u is as described herein, and R ^i¾ is CF?. in an exemplary embodiment, the compound is according to a formula described herein which contains R ^{f 3} and R ^u> , wherein R ^lb is as described herein, and R ^ia is F. In an exemplary embodiment, the compound is according to a formul described herein which contains R ^f * and R ^3¾ , wherein R ^!ii is as described herein, and R ^ia is Cl. In an exemplary embodiment, the compound is according to a formula described herein which contains R ^u and R ^ib , wherein R ^lb is as described herein, and R ^la is CF 3. In an

exemplary embodiment, the compound i wherein R ² ,

R ^Ja an R ^!h aie as described herein in an exemplary embodiment, the compound Is , wherein R ² , PJ and R ^t!> are as described herein. In an

exemplary embodiment, the compound , wherein Ry

R ^is and R ^h are as described herein. In an exemplary embodiment, the compound is

, wherein R ² , R ¹ * and R ^!b are as described herein. In an

, wherein R ² ,

R ^ia and R ^ib are as described herein.

|00104j hi an exemplary embodiment, the compound wherein

R ² is as described herein, and R ¹ is unsobstitated adamantyi. In an exemplaiy embodiment, the compound wherein R ² is as described herein, and R ¹ is unsubstituted adamant- 1 -yl. in an exemplary embodiment, the compound is , wherein R ² is as described herein, and R ¹ is unsubstituted

adamantyi. 3h an exemplary embodiment, the compound i

wherein R ² is as described herein, and R‘ is unsubstituted adamant- 1 -yl. in an exemplary

embodiment, the compound i wherein is as described herein, and R ⁵ is unsubstituted adamantyi. In an exemplary embodiment, the compound is , wherein R ² is as described herein and R ^? is unsubstituted adamant- 1 -yl.

{80105} In an exemplary embodiment, the compound

wherein R ¹ is as described herein. In an exemplary embodiment, the compound is wherein R ¹ is as described herein in an

exemplary embodiment, the compound , wherein R ¹ is as described herein. In an exemplary embodiment, the compound is wherein ^f is as described herein. In m exemplary

embodiment, the compound i wherein R is as described herein. In an exemplary embodiment, the compound is

wherein R ^! is as described herein. In an

exemplary embodiment, the compound i wherein R* is as described herein. In an exemplary embodiment, the compound is , wherein R ¹ is as described herein, in an exemplary

embodiment, the compound i wherein R ¹ is as described herein. In an exemplary embodiment, the compound is wherein R ^¾ is as described herein. In an exemplary

embodiment, the compound i , wherein R ⁵ is as described herein. I» an exemplary embodiment, the compound is . wherein R ¹ is as described herein.

[00106] In an exemplar)· embodiment, the compound is

, wherein X, R ^{8 and R ^,b are as described herein. In an exemplar) _' embodiment, the compound is

, wherein X, SR ^hl and R ^1¾ are as described herein. In an exemplar)' embodiment, the compound is

, wherein X, R ^1a and R ^ib are as described herein.

hi an exemplary embodiment, the compound

wherein X, R ^u and R ^u> are as described herein. In an exemplar)' embodiment, the compound

In an exemplary embodiment, the compound i

wherein X, R and R ^lb are as described herein.

00I07| In an exemplary embodiment, the compound is

, wherein X is as described herein, and R ¹ is unsubstituted adamantyl. In an exemplary embodiment, the compound is , wherein X is as described herein, and R ¹ is umubstituted adamant~I~yl. In an exemplary embodiment, the compound is , wherein X is as described herein, and R is unsubstituted adamantyl in an exemplary' embodiment, the compound is , wherein is as described herein, and R ¹ Is unsubstituted adamant- ! -yl ln an exemplary _' embodiment, the compound is , wherein X is as described herein, and R ¹ Is unsubstituted adamantyl. In an exemplary embodiment, the compound is , wherein X is as described herein, and R ¹ is unsubstituted adamant-i-yl. in an exemplary embodiment, the compound is , wherein X is as described herein and R ^! is unsuhstituted adamantyl in an exemplary embodiment, the compound is , wherein X is as describe herein, and R ^! is unsubstituted adamant- 1 -yl In an exemplary' embodiment, the compound is wherein X is as described herein, and R: is unsubstituted adamantyl In an exemplary embodiment, the compoun is wherein X is as described herein, and R ¹ is unsubstituted adamant- ! -yl. In an exemplary embodiment, the compound is , wherein X is as described herem, and R ¹ is unsubstituted adamantyl In an exemplary' embodiment, the compound is , wherein X is as described herein, and R is nnsubstiinied adamant- i -yl

[001081 In an exemplary·' embodiment, the compound is

wherein R ^ls and R a re members each independently selected from the group consisting of F, Cl and CFn In an exemplary embodiment the compound is wherein R ^{3 a} and R ^ii} are members each independently selected from the group consisting of f. CL and CFh. in an exemplary embodiment, the compound is

wherein R ^ia and R ^5b are members each independently selected from the group consisting of F, CL and CFs. in an exemplary

embodiment, the compound i wherein R ^ia and R ^Sb are members each independently selected front the group consisting of F, Cl, and CF; _> . In an exemplary embodiment, the compound is

, wherein R ^Sa and R ^ib are members each independently selected from the group consisting of F, Cl, and CF In an exemplary

embodiment, the compoun , wherein R ^la and

R ⁱ are members each independently selected from the group consisting of F, Cl, and CC . In

an exemplary embodiment the compound i

wherein R ^la and R ^U: are members each independently selected from the group consisting of f. Cl, and CFs. In an exemplary embodiment, fire compound is

wherein R’ ³ and R ^ib are members each independently selected from the group consisting of F, Cl, and CF?. in an exemplary

embodiment, die compound i wherein R ^{i 3} and

R ^ib are members each independently selected from the group consisting of F, Cl, and CF .

In an exemplary embodiment, the compound is

wherein R ^la an R ^ib are members each independently selected from the group consisting of F, Cl, and CFs In an exemplary'

embodiment, the compound i wherein R and R ^u> are members each independentl selected from the group consisting of F, Cl, and CF3. In

an exemplary' embodiment, the compound i

wherein R and R ^ib are members each independently selected from the group consisting of F, CL and CFs. |qί1109 in an exemplary embodiment, the compound is wherein R ⁱ and R are members each independently selected from the group consisting ofF, Cl, and CFs. In an exemplar

embodiment, the compound wherein R ^ia and

R ^1b are members each independently selected from the group consisting of F, CL and CFA in an exemplary' embodiment, the compound is wherein R ^l8 and R ^if> are members each independently selected from the group consisting of F, Cl, and CFj In an exemplary

embodiment, the compound i wherein R ^la an R ^ib are members each independently selected from the group consisting of F, Cl, and CFs. in an exemplary embodiment, the compound is

w herein R and R ^u> are members each independently selected from the group consisting of F, Cl, and CF: _> . In an exemplary'

embodiment, the compound i wherein R ^la and

R ^u> are members each independently selected from the group consisting of F, Cl, and CF;?. In

an exemplary' embodiment, the compound i

wherein R ^ia and R ^5fc are members each independently selected from the group consisting of F, Cl, and CF3. In an exemplary embodiment, the compound is wherein R ^ia an R ^ib are members each independently selected from the group consisting of F. t Ί and CFa. In an exemplar

, embodiment the compound i wherein R ⁵ and R ^,b are members each independently selected from the group consisting of F, Cl, and CFs In an exemplary embodiment, the compound is

wherein R ^ta and R ^u> are members each independently selected from the group consisting of F, Cl and CFs. in an exemplary

embodiment, the compound i wherein R ^{! a} and

R ^{i b} are members each independently selected from the group consisting of F, Cl and CPs. In

wherein R ^!a and R ^,fc are members each independently selected from the group consisting of F, Cl, and CFs. eoiicij In an exemplary embodiment, the compound is

(H ₃ C) ₃ C.

IZ JCO ^* wherein R ¹ is ««substituted adamantyl. In an

exemplary embodiment, the compound wherein R ¹ is ««substituted adamant- i ~yl In an exemplary embodiment, the compound is wherein R ^f is unsubstituted adamantyl. In an

exemplary embodiment, the compound i wherein R ¹ is unsubstituted adamant- 1 -yl In an exemplary embodiment, the compound is

H

(H _3C C

wherein R ^[ is ««substituted adamantyl. In an exemplary

embodiment, the compound wherein R ¹ is

unsubstituted adamant-l-yl. In an exemplary embodiment, the compound is , wherein R' is unsubsiituted adamantyl. In an

exemplary embodiment, the compound wherein R ¹ is unsubstituted adamant-l -yl. In an exemplary embodiment, tbe compound i wherein

R ^l is unsubstituted adamantyl. In an exemplary embodiment, the compound is wherein R* is unsubstituted adamant- 1 -vl.

In an exemplary embodiment, the compound wherein

R* is unsubstituted adamantyl. In an exemplary embodiment, die compound is wherein R* is unsubstituted adamant- l-yl

In an exemplary embodiment. die compound wherein is unsubstituted adamantyl. In an exemplary' embodiment, the compound Is wherein is unsubstituted adamant- 1 -yl. In an "

exemplary' embodiment, the compound Is ^r ’ wherein R ^! is unsubstituted adamantyl. In an exemplary' embodiment, the compound is wherein ’ is unsubstituted adamant- l-yl

In an exemplary embodiment , the compound is w here in

R ¹ is unsubstituted adamantyl in an exemplary embodiment, the compound is unsubstituted adamant-1 ~vL i n an

N I

H R’

exemplary embodiment, the compound is #¼ ^c >* ^c' wherein R ¹ is unsubstituted adamantyi in an exemplary embodiment; the compound is wherein R ^! is unsubstimted adamant- 1-y 1 In an exemplary

embodiment the compound wherein R ⁵ is

unsubstituted adamantyi in an exemplary embodiment, the compound is wherein R ⁵ is unsubstituted adamant- 1-yl. In an

exemplary embodiment, the compound i wherein R ¹ is unsubstituted adamantyi . In an exemplary embodiment, the compound is wherein R* is unsubstituted adamant- i-yl.

jOOilll In an exemplary embodiment, the compound

or a pharmaceutically accep .Htalble salt thereof. In an exemplar}' embodiment, the compound is

exemplary embodiment, the compound i

pharmaceutically acceptable salt thereof.

[00112J in an exemplary embodiment, the compound is

pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the compound

pharmaceutically acceptable salt thereof in an exemplary embodiment, the compound is

pharmaceutically acceptable salt thereof. j001.131 In an exemplary embodiment, the compound is pharmaceutically acceptable sail thereof in an

exemplary embodiment, the compound

pharmaceutically acceptable salt thereof. In an exemplar embodiment, the compoun is

|Q0114] In an exemplary embodiment. _, the compound i

or a pharmaceutically acceptable sail thereof. In an exemplary embodiment, the compound is

or a pharmaceutically acceptable salt thereof. In an

exemplary embodiment, the compound is or a pharmaceutically acceptable salt thereof

{00115] in an exemplary embodiment the compound is

pharmaceutically acceptable salt thereof In an

exemplar ' embodiment, the compound i

pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is

pharmaceutically acceptable salt thereof.

{Q0116] in an exemplary embodiment, the compound i

or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is pharmaceutically acceptable salt thereof In an

exemplary embodiment, the compound i

pharmaceutically acceptable salt thereof.

00117) In an exemplar}·' embodiment, the compound i

or a pharmaceutically acceptable salt thereof. I an exemplar}' embodiment, the compound is

thereof in an

exemplary embodiment, the compound

phannaeettica!ly acceptable salt thereof. the compound is or a pharmaceutically acceptable salt thereof In an

exemplary embodiment, the compound i pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is pharmaceutically acceptable salt thereof.

[00119} In an exemplary embodiment, the compound

or a pharmaceutically acceptable salt thereof, wherein R ^! is unsubstituted adamant- I-y! In

an exemplary embodiment, the compound i

pharmaceutically acceptable salt thereof, wherein R ^] is unsubstituted ada ant-I-yl. In an

exemplary embodiment, the compound i

pharmaceutically acceptable salt thereof, wherein R ^f is unsubstituted adamant- 1 -yi

[00120] In an exemplary embodiment, the compound is pharmaceutically acceptable salt thereof. In a

. , , _{, t} , .

exemplary embodiment, the compound i

pharmaceutical ly acceptable salt thereof. In an exemplary embodiment, the compound is pharmaceutically acceptable salt thereof

foomi In one exemplary embodiment, the structure of AFA-358 is

1001221 In one exemplary embodiment, the structure of AFA-3G9 Is

100123) In one exemplary embodiment, the structure of AFA-258 is

{001241 In one exemplary embodiment, the structure of AF A-353 is

{0012SJ AFA-309, 353 and 358 are novel T-type Ca, ·.; channel modulators used in the treatment of pathological conditions, including pain, hypersensitive cough and itching.

|{M)126| The invention also pro vides a pharmaceutical formulation comprising a therapeutically effective amount of a compound according to Formula 1 or individually disclosed herein. The formulation further includes a pharmaceutically acceptable carrier

|0012?| The invention also provides a method for treating hypersensitive cough or tichlng responsive to selective inhibition of the T Channel known as the Cavan channel comprising administering to a mammal a therapeutically effective amount of a compound according to Formula I or individually disclosed herein.

1001281 The present invention provides compounds which are selective T-Chaimel inhibitory compounds useful for relief of hypersensitive co ugh or i tching.

|00129} The invention also includes, where chemically possible all stereoisomers and geometric isomers of the compounds including diastereomers. enantiomers, and cis/trans (E/Z) isomers. The invention also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated In a structure, the structure is Intended to embrace all possible stereoisomers of tire compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly Indicated

1901301 The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (¾), iodine-125 or carbon- 14 ( ¹⁴ C). All Isotopic variations of the compounds of the present invention, whether radioactive or not, are Intended to be encompassed within the scope of the present invention. Unless a specific isotope is indicated, the invention includes all isotopologues of the compounds disclosed herein, such as, for example, deuterated derivatives of the compounds (where H can be ² H, i.e., D),

|0O1311 In the context of the present in vention, compounds that are considered to possess activity as T-Channel inhibitors are those displaying 50% inhibition of the Ca ^: ' voltage (ICso) at a concentration of not higher than about 100 mM, preferably, not higher than about 10 mM, more preferably not higher than about l mM and most prefera ly not higher than about 100 nM.

Chemical Synthesis

100132} Terminology related to "protecting",“deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deproiection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readil y en vision those gro u ps that would be suitable as“protecting groups’'. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as“Greene's Protective Groups in Organic Synthesis; Fifth Edition” by Peter G. M. Wots, [John Wiley & Sons, New York, 2014], DO! : 10.1002/9781 1 18905074, which is incorporated herein by reference .

|0®1331 A comprehensi ve list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry The list, which is typically presented in a table entitled“Standard List of Abbreviations”, is incorporated herein by reference.

100134) In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions it is also possible to make use of variants that are in themselves known, but are not mentioned here. The starting materials, for example in the case of suitably substituted benzimidazole ring compounds, are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in die art.

Pharmaceutical Farmalai m

100135) The present invention further provides pharmaceutical formulations comprising as active agents, the compounds described herein.

[00136) in an exemplary embodiment, the invention is a pharmaceutical formulation comprising a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a therapeutically effective amount of a compound of a formula describe herein, or a pharmaceutically acceptable salt thereof

[0013?) In an exemplary embodiment, the in vention is a pharmaceutical formulation comprising a therapeutically effecti ve amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In an exemplary embodiment, the invention is a pharmaceutical formulation comprising a

therapeutically effective amount of a compound of a formula described herein, or a

pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

f0O138] In an exemplary embodiment, the invention is a pharmaceutical formulation described herein, wherein the formulation is in a unit dosage form

100139] As used herein a "pharmaceutical formulation" refers to a preparation of one or more of the compounds described herein, or physiologically acceptable salts or solvates

(including hydrates) thereof, with other chemical components suc as physiologically suitable carriers and excipients.

|0Q140| Pharmaceutical formulations containing compounds of Formulas L and. any compound described herein may be conveniently presente in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof. The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treate and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, a dose ranges from about 0.1 mg to about 7000 mg, preferably about 1 nig to about 100 mg, and more preferably, about 25 mg to about 50 mg, in single or divided doses. In some

embodiments, a dose may range from about 50 mg to about 500 mg, and preferably, about 100 g to about 500 mg. Such doses may be administered 1, 2, 3, 4, 5, 6 or more times in a day. It may be recommended that children, patients over 65 years old, and those with

impaired renal or hepatic function, initially receive low doses and that the dosage is titrated based on individual responses and/or blood levels. It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art. Further, it is noted that the clinician or treating physician knows how and when to interrupt, adjust or terminate therapy in conjunction with individual patient's response.

|00141] Pharmaceutical formulations for use in accordance with the present invention thus may be formulate in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which, can be used pharmaceutically. The carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen

109142] Compounds that inhibit T -Channels can be formulated as pharmaceutical

formulations and administered to a mammalian subject, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e , oral, rectal, topical (including dermal, buccal, sublingual, and intraocular), or parenteral, by intravenous, intramuscular, topical, transdermai, intradermai, intraarticuiar, or subcutaneous routes.

1091431 For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixtur of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragaeanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium

carbomethylcelluiose; and/or physiologically acceptable polymers such as

polyvinylpyrrolidone (PVP). If desired, disintegrating agents may he added, such as cross- linked polyvinyl pynolidone, agar or alginic acid or a salt thereof such as sodium alginate.

1001441 In addition, an enteric coating may be useful as it is may be desirable to prevent exposure of the compounds of the invention to the gastric environment.

b0145| Pharmaceutical formulations, which can be used orally, include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids such as faty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added.

1001461 Formulations for topical administration in the mouth for example buecally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragaeanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia. All formulations for oral administration should be in dosages suitable for the chosen route of administration.

{00147! For inj ection , the compounds of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's or Ringer's solution or physiological saline buffer. For transmucosal and transdermal administration, penetrants appropriate to die barrier to be permeated may be used in die formulation. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.

{001481 hot administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g.,

dichlorodifluoromethane, trichloroAuoromethane, diehloro-tetrafluoroethane or carbon dioxide in the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use i an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

{00! 49 | P hammceuticai formulations for parenteral administration include aqueous and «on-aqueous sterile injection solutions, which may contain anti-oxidants, buffers, bacteriostats and solutes, which render the formulation isotonic with the blood of the intended recipient. Formulations also include aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Pharmaceutical formulations for parenteral administration in an aqueous solution contain the active ingredients in water- soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include faty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethy! cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.

{00150! The formulations may be presented in unit-dose of multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophi!ized) condition requiring only the additio of a sterile liquid carrier, for example saline, phosphate- buffered saline (PBS) or the like, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

fOOISIl The compounds of the present invention may also be formulated in rectal

formulations such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides

1001521 Depending on the severity and responsiveness of the condi tion to he treated, dosing can also be a single administration of a slow release formulations, with course of treatment lasting front several days to several weeks or until cure is effected or diminution of the disease state is achieved. The amount of a formulation to be administered wi ll, of course, be dependent on many factors including the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician. The compounds of the invention may be administered orally or via injection at a dose from 0.001 to 250 mg kg per day. The dose range for adult humans is generally from 0.5 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg. usually around 10 mg to 200 rag. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age an sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.

1001531 As used herein, and as would be understoo by the person of skill in the art, the recitation of“a compound” is intended to include salts, solvates and inclusion complexes of that compound. The term "solvate'' refers to a compound described herein and/or from Formula I in the soli state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the sol vate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an anti olvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrms, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims. 10 154J The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, heazenesulthnic (besy late), benzoic, eamphorsu!fome, citric, ethenesuifonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamok, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, , '~dihenzyIethy1enediamine, chloroproeaine, choline, diethanolamine, ethylenediamine, meglumine ( -met ylglucamine) and procaine.

100155) The term“preventing” as used herein refers to administering a medicament beforehand to forestall or obtund an attack. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term“prevent” is not an absolute term in the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended herein.

1001561 It should be understood that i addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question. for example those suitable for oral administration may include flavoring agents.

|001571 The formulations may be presented in a packaging device or dispenser, which may contain one or more unit dosage forms containing the active ingredient. Examples of a packaging device include metal or plastic foil, such as a blister pack and a nebulizer for inhalation. The packaging device or dispenser may be accompanied by instructions for administration. Formulations comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be placed in an appropriate container and l beled for treatment of an indicated condition.

1001581 Some embodiments described herein are recited as“comprising” or“comprises” with respect to their various elements in alternative embodiments, those elements can be recited with the transitional phrase“consisting essentially of ⁵ or“consists essentially of ⁷ as applied to those elements hr further alternative embodiments, those elements can be recited with the transitional phrase“consisting of’ or“consists of’ as applied to those elements.

Tims, for example, if a compound, formulation or method is disc losed herein as comprising A and B, the alternative embodiment for that compound, formulation or method of“consisting essentially of A and B” an the alternative embodiment tor that compound, formulation or method of“consisting of A and B” are also considered to have been disclosed herein.

Likewise, embodiments recited as“consisting essentially of’ or“consisting of with respect to their various elements can also be recited as“comprising” as applied to those elements. Finally, embodiments recited as’'consisting essentially of with respect to their various elements can also be recited as“consisting of as applied to those elements and

embodiments recited as“consisting of ⁵ with respect to their various elements can also be recited as“consisting essentially of ⁵ as applied to those elements.

I0O159J When a compound or formulation Is described as“consisting essentially of’ the listed components, the compound or formulation contains the components expressly listed, and ntay contain other components which do not substantially affect the condition being treated. That is, the compound or formulation either does not contain any other components which do substantially affect the condition being treated other than those components expressly listed; or, if the compound or formulation does contain extr components other than those listed which substantially affect the condition being treated, the compound or

formulation does not contain a sufficient concentration or amount of those extra components to substantially affect the condition being treated. When a method is described as“consisting essentially of’ the listed steps, the method contains the steps listed, and may contain other steps that do no substantially affect the condition being treated, but the method does not contain any other steps which substantially affect the condition being treated other than those steps expressly listed.

|90 Q| The fol lowing examples are provided to illustrate, but not limit, the invention. The compounds disclosed herein are numbered an proceeded by tire prefix EX- or AFA-.

N? EXAMF1.ES

Example A

I vim effects of EX/AFA compounds in a re resentative hypersensitive cough model ia guinea pigs

1001611 Guinea pigs (male, 280 g body weight, Hanley CrlHA, Charles River) were

maintained in temperature 2.1 2 ^a C, humidity 55 ± 10%, 12 hours on 12 hours off light cycle, wish food and water ad libitum for at least 1 week before testing. Cough was induced with citric add aerosol inhalation and cough assessment by human manual score (Gallico. Borahi et al. 1994), Individual animals were placed ia a 41 pkxiglas observation chambers continuously .filled with 17,5% citric acid aerosol Animal cough counts were recorded for 5 min. Coughs can be recognized on the basis of sound associated with a rapid inspiration followed by a rapid expiration. Only the animal with cough counts >= 10 times/5 min was selected for experiment. The selected animal wa then randomized divided into 5 groups, n~ 8/group. Five days alter sereeuiug test, the representative AFA-compound, EX- 17 at 0, 3, 10 and 30 g kg were administered 30 minutes while the benchmark dextromethorphan hydrobromide (60 mg/kg, p.o.) 60 minute prior to the citric acid inhalation, based on their PK profiles, EX- 17 produced a dose- dependent inhibition of the number of cough events with reduction of 7.2, 3.3 and 36.8 % at dose of 3, 10 and 30 mg/kg, respectively (Fig, IA). At 30mg/k EX-i? produced comparable inhibition as dextromethorphan (40.0% at 60mg/kg, p.o.). The latency to the first cough has been used as an additional parameter to evaluate anti tussive property. EX- 17 also caused increases in the latencies of the first cough in a dose-dependent manner. Only at 30mg/kg EX- 17 and dextromethorphan hydrobromide (60 mg/kg, p.o.) reached significance under the experimental conditions (Fig IB).

[00162] Using the same test protocol, three more representative EX-compounds EX-128, -130 and -132 (each 30 mg/kg, p.o.) or vehicle were tested by orally administering30 minutes while dextromethorphan hydrobromide (60 mg/kg, p.o.) 60 minutes prior to the citric acid inhalation, based on their PK profiles;. Compared to the vehicle control compounds EX - 128 and

dextromethorphan significantly reduced the number of cough events with reduction of 39.1% and 42.6%, respectively (Fig. 2A) EX-1 0 and -132 showed a trend towards reducing the number of cough events with reduction of 33% and 15.7, respectively, without reaching significance. The latencies to the first cough were increased with three compounds and die benchmark, but none of them reached significance level under the experimental conditions (Fig 2B).

[06163] References

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PtenMcoipgical PrpBerMes of the _. Afferent _. N _. eryes Reg¾ ng,Ce gh ^' in“Pharmacology and Therapeutics of Cough’ ^' ed, Chung and Widdicomb, pp 23 47, Handbook of Experimental Pharmacology ISSN 0171-2004 (991651 Galileo, L„ A. Borg i, G. Dalla Rosa, R, Ceserani and S, Togneila (3994),

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(99166] Irwin, R. S., M. j Rosea and S. $. Braraan (1977). "Cough. A comprehensive review "

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Example B: in vtm effects of AFA/EX co poends in two representative itching models in mice

(09179] A representative panel of AFA/EX compounds was investigated on a variety of recombinant human ion channels expressed in mammalian cells and on native ion channels in dissociated rat dorsal root ganglion (DRG) neurons. As shown m Table 1, the selected 10 AFA- compounds produced differential modulations on different ion currents mediated by the selected ion channels. Thus, this panel of compounds was next investigated on their effects on itching scratching behavior in two well-established itching models in mice.

(90171] Neck model Of itch was employed. Mice (C57BL/6, male, 3 - 4 months old) were shaved at the nape of the neck 2 - 3 days before experiments. On the day of behavioral testing mice were individually placed in small plastic chambers (12 cm L * 9.5 W * 12 H) that inserted into at ordinary home-cage at least 30 min. for habituation and recorded baseline of behavior using a video camera and a piezoelectric floor sensor operated by a validated homeeage behavioral monitory system, SmartCage, which can monitor multiple mouse scratching behaviors simultaneously.

[90172] Treatment with t individual test article (30 representative AFA-compounds, each at 30 mg/kg) or vehicle (0.5% hydroxyl propyl cellulose aqueous solution containing 2% DMSO) were imraperitoaeally (ip.) injected 30 min. prior to itching induction. Mice were given an intradennal injection of 50 m| of a pruritogen, cMoroqtune or histamine into the nape of the neck. Immediately after the injection, mice were returned to their chambers and were continually recorded by the piezoelectric floor sensor for 30 min. Human manual scoring of itching scratch behavior in real-time and confirmed by video and/or piezoelectric recordings offline. The itch behavior was quantified by counting the number of scratches in a blinded to the treatment manner. A scratch was counted when a mouse lifted its hindpaw to scratch the shaved region and returned the paw to the floor or to the mouth for licking. The piezoelectric signals with a larger and regular waveform distinguished from normal homeeage activity were analyzed off-line to objectively quantifying scratch episodes and durations.

(09t73j These studies revealed unexpected findings that compounds produced differential modulation of itch scratch behavior in these two different itching models despite those compounds with similar potency against T-type Cav3.2 channels (Fig 3 A). AFA-221 {EX-31}, AFA-281 (EX-BO) and AFA-35S produced potent and equal efficacy against both chloroqume- and histamine-induced i teh lug. while AFA-. AFA-258 (Z944), AFA-322 (EX-132) and AFA- 206 (EX-55) preferentially inhibited histamine-induced itching {FIG 3B)

{00174] in conclusion, using an itching scratch behavior phenotypic analysis, one can discover novel compounds for potential treatment of chronic itch diseases.

TABLE 1 , Effects of representative AFA Compounds on recombinant and native ion channels

[00I75| h” human isoiorm Use Dep == use dependent inhibition; DRG” dorsal root ganglion; KERG“ human ether-a-go-go related gene (hERG) potassium (KQ channels

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